BioPAX pathway converted from "Developmental Biology" in the Reactome database. Developmental Biology As early steps towards capturing the array of processes by which a fertilized egg gives rise to the diverse tissues of the body, examples of eleven processes have been annotated. Aspects of two processes involved in most developmental processes, <b>transcriptional regulation of pluripotent stem cells</b>, and <b>activation of HOX genes during differentiation</b> are annotated. More specialized processes include <b>nervous system development</b> , aspects of the roles of cell adhesion molecules in <b>axonal guidance</b> and <b>myogenesis</b>, of <b>transcriptional regulation in pancreatic beta cell</b>, <b>transcriptional regulation of granulopoeisis</b>, and <b>transcriptional regulation of white adipocyte differentiation</b>, molecular events of <b>"nodal" signaling</b>, <b>LGI-ADAM interactions</b>, <b>keratinization</b>, and <b>transcriptional regulation of testis differentiation. Reviewed: Maness, PF, Krauss, RS, Walmod, PS, Jensen, J, 2011-08-22 Edited: Matthews, L, 2011-05-06 Nervous system development Neurogenesis is the process by which neural stem cells give rise to neurons, and occurs both during embryonic and perinatal development as well as in specific brain lineages during adult life (reviewed in Gotz and Huttner, 2005; Yao et al, 2016; Kriegstein and Alvarez-Buylla, 2009). Authored: Rothfels, Karen, 2020-01-31 Reviewed: Orlic-Milacic, Marija, 2020-01-23 Edited: Rothfels, Karen, 2020-01-31 Axon guidance Axon guidance / axon pathfinding is the process by which neurons send out axons to reach the correct targets. Growing axons have a highly motile structure at the growing tip called the growth cone, which senses the guidance cues in the environment through guidance cue receptors and responds by undergoing cytoskeletal changes that determine the direction of axon growth. <br>Guidance cues present in the surrounding environment provide the necessary directional information for the trip. These extrinsic cues have been divided into attractive or repulsive signals that tell the growth cone where and where not to grow. <br>Genetic and biochemical studies have led to the identification of highly conserved families of guidance molecules and their receptors that guide axons. These include netrins, Slits, semaphorins, and ephrins, and their cognate receptors, DCC and or uncoordinated-5 (UNC5), roundabouts (Robo), neuropilin and Eph. In addition, many other classes of adhesion molecules are also used by growth cones to navigate properly which include NCAM and L1CAM.<br>For review of axon guidance, please refer to Russel and Bashaw 2018, Chedotal 2019, Suter and Jaworski 2019).<br>Axon guidance cues and their receptors are implicated in cancer progression (Biankin et al. 2012), where they likely contribute to cell migration and angiogenesis (reviewed by Mehlen et al. 2011). Authored: Garapati, P V, 2009-05-28 19:40:55 Reviewed: Maness, PF, Walmod, PS, 2009-05-25 Edited: Garapati, P V, 2009-05-28 19:40:55 Semaphorin interactions Semaphorins are a large family of cell surface and secreted guidance molecules divided into eight classes on the basis of their structures. They all have an N-terminal conserved sema domain. Semaphorins signal through multimeric receptor complexes that include other proteins such as plexins and neuropilins. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:38 Sema4D in semaphorin signaling Semaphorin 4D (Sema 4D/CD100) is an axon guidance molecule with two disulfide-linked 150-kDa subunits. SEMA4D is structurally defined by a conserved 500-amino acid extracellular domain with 16 cysteines (sema domain) and also an Ig-like domain C-terminal to the sema domain. Sema4D is expressed on the cell surface as a homodimer; cysteine 679 within the sema domain is required for this dimerization.<br>The main receptors for Sema4D are plexin-B1 and CD72. The activation of plexins by semaphorins initiates a variety of signaling processes that involve several small GTPases of the Ras and Rho families. Sema4D-Plexin-B1 interaction appears to mediate different and sometimes opposite effects depending on the cellular context. Plexin-B1 activation inhibits integrin-mediated cell attachment and cell migration through the activation of the R-RasGAP activity inherent to plexin-B1 or through the inhibition of RhoA. However, activation of plexin-B1 by Sema4D stimulates the migration of endothelial cells by mediating the activation of RhoA. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:38 Sema4D mediated inhibition of cell attachment and migration Repulsive Sema4D-Plexin-B1 signaling involves four GTPases, Rnd1, R-Ras, Rho and Rac1. Sema4D-Plexin-B1 binding promotes Rnd1-dependent activation of the plexin-B1 GAP domain and transient suppression of R-Ras activity. R-Ras inactivation promotes PI3K and Akt inactivation followed by GSK-3beta activation and CRMP2 inactivation. Plexin-B1 also transiently associates with and activates p190Rho-GAP, triggering a transient decrease in activated Rho. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:38 LEFT-TO-RIGHT 2.7.10.2 SEMA4D interacts with Plexin-B1:Met Sema4D binds Plexin-B1 to induce repulsive or attractive effects in neuronal and nonneuronal cells. Plexins constitute a large family of transmembrane proteins that function as receptors for semaphorins and their interaction governs cell adhesion and migration in a variety of tissues. All B-class plexins can interact with the receptor tyrosine kinases Met and ErbB2. The binding of Sema4D to plexin-B1 stimulates the intrinsic tyrosine kinase activity of Met, leading to the phosphorylation of both Plexin-B1 and Met. The phosphorylation of the plexin-B1/Met complex induced by Sema4D is crucial for epithelial cell migration and invasive growth. Sequence alignment reveals the presence of 13 conserved tyrosine residues (highly conserved sites 1918, 1953, 2038), but the specific tyrosine residues phosphorylated in the cytoplasmic domain of plexins in response to semaphorin stimulation have not yet been identified. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 cytosol GENE ONTOLOGY GO:0005829 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 79 113592 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592 Reactome R-ALL-113592 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113592.5 Reactome http://www.reactome.org COMPOUND C00002 additional information MI MI:0361 Plexin-B1:Met Reactome DB_ID: 419634 plasma membrane GENE ONTOLOGY GO:0005886 PLXNB1 Plexin-B1 PLXB1_HUMAN Reactome DB_ID: 3008951 UniProt:O43157 PLXNB1 PLXNB1 KIAA0407 PLXN5 SEP FUNCTION Receptor for SEMA4D (PubMed:19843518, PubMed:20877282, PubMed:21912513). Plays a role in GABAergic synapse development (By similarity). Mediates SEMA4A- and SEMA4D-dependent inhibitory synapse development (By similarity). Plays a role in RHOA activation and subsequent changes of the actin cytoskeleton (PubMed:12196628, PubMed:15210733). Plays a role in axon guidance, invasive growth and cell migration (PubMed:12198496).SUBUNIT Monomer, and heterodimer with PLXNB2 after proteolytic processing (PubMed:12533544, PubMed:17916560, PubMed:18411422, PubMed:18275816, PubMed:19843518, PubMed:20877282, PubMed:21912513). Binds RAC1 that has been activated by GTP binding (PubMed:11035813, PubMed:17916560, PubMed:18275816, PubMed:19843518). Interaction with SEMA4D promotes binding of cytoplasmic ligands (PubMed:10520995, PubMed:12198496, PubMed:19843518). Interacts with PLXNA1 (By similarity). Interacts with ARHGEF11 and ARHGEF12 (PubMed:12196628). Interacts with ERBB2 (PubMed:15210733). Interacts with MET (PubMed:12198496, PubMed:15184888). Interacts with MST1R (PubMed:15184888). Interacts with RRAS (PubMed:19843518). Interacts with RHOD (PubMed:17916560). Interacts with RND1 (PubMed:12730235, PubMed:17916560, PubMed:18275816, PubMed:19843518). Interacts with NRP1 and NRP2 (PubMed:10520995).TISSUE SPECIFICITY Highly expressed in fetal kidney, and at slightly lower levels in fetal brain, lung and liver.PTM Phosphorylated on tyrosine residues by ERBB2 and MET upon SEMA4D binding.PTM Proteolytic processing favors heterodimerization with PLXNB2 and SEMA4D binding.SIMILARITY Belongs to the plexin family. Homo sapiens NCBI Taxonomy 9606 UniProt O43157 20 EQUAL 2135 EQUAL Reactome Database ID Release 79 3008951 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3008951 Reactome R-HSA-3008951 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3008951.1 1 MET Hepatocyte growth factor receptor MET_HUMAN Reactome DB_ID: 419603 UniProt:P08581 MET MET FUNCTION Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of muscles and neuronal precursors, angiogenesis and kidney formation. In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells. May regulate cortical bone osteogenesis (By similarity).FUNCTION (Microbial infection) Acts as a receptor for Listeria monocytogenes internalin InlB, mediating entry of the pathogen into cells.ACTIVITY REGULATION In its inactive state, the C-terminal tail interacts with the catalytic domain and inhibits the kinase activity. Upon ligand binding, the C-terminal tail is displaced and becomes phosphorylated, thus increasing the kinase activity.SUBUNIT Heterodimer made of an alpha chain (50 kDa) and a beta chain (145 kDa) which are disulfide linked. Binds PLXNB1. Interacts when phosphorylated with downstream effectors including STAT3, PIK3R1, SRC, PCLG1, GRB2 and GAB1. Interacts with SPSB1, SPSB2 and SPSB4 (By similarity). Interacts with INPP5D/SHIP1. When phosphorylated at Tyr-1356, interacts with INPPL1/SHIP2. Interacts with RANBP9 and RANBP10, as well as SPSB1, SPSB2, SPSB3 and SPSB4. SPSB1 binding occurs in the presence and in the absence of HGF, however HGF treatment has a positive effect on this interaction. Interacts with MUC20; prevents interaction with GRB2 and suppresses hepatocyte growth factor-induced cell proliferation. Interacts with GRB10. Interacts with PTPN1 and PTPN2. Interacts with LECT2; this interaction may have an antagonistic effect on receptor activation (PubMed:27334921). Interacts with HSP90AA1 and HSP90AB1; the interaction suppresses MET kinase activity (PubMed:26517842).SUBUNIT (Microbial infection) Interacts via extracytoplasmic residues 25-656 with L.monocytogenes InlB; MET can bind HGF, its endogenous ligand, and InlB simultaneously (PubMed:11081636, PubMed:17662939). InlB probably dimerizes upon binding to MET, which encourages subsequent dimerization of MET (Probable).TISSUE SPECIFICITY Expressed in normal hepatocytes as well as in epithelial cells lining the stomach, the small and the large intestine. Found also in basal keratinocytes of esophagus and skin. High levels are found in liver, gastrointestinal tract, thyroid and kidney. Also present in the brain. Expressed in metaphyseal bone (at protein level) (PubMed:26637977).DOMAIN The kinase domain is involved in SPSB1 binding.DOMAIN The beta-propeller Sema domain mediates binding to HGF.PTM Autophosphorylated in response to ligand binding on Tyr-1234 and Tyr-1235 in the kinase domain leading to further phosphorylation of Tyr-1349 and Tyr-1356 in the C-terminal multifunctional docking site. Dephosphorylated by PTPRJ at Tyr-1349 and Tyr-1365. Dephosphorylated by PTPN1 and PTPN2.PTM Ubiquitinated. Ubiquitination by CBL regulates MET endocytosis, resulting in decreasing plasma membrane receptor abundance, and in endosomal degradation and/or recycling of internalized receptors.PTM (Microbial infection) Tyrosine phosphorylation is stimulated by L.monocytogenes InlB. Tyrosine phosphorylation is maximal 10-20 minutes after treatment with InlB and disappears by 60 minutes. The phosphorylated residues were not identified.DISEASE Activation of MET after rearrangement with the TPR gene produces an oncogenic protein.DISEASE Defects in MET may be associated with gastric cancer.DISEASE A common allele in the promoter region of the MET shows genetic association with susceptibility to autism in some families. Functional assays indicate a decrease in MET promoter activity and altered binding of specific transcription factor complexes.DISEASE MET activating mutations may be involved in the development of a highly malignant, metastatic syndrome known as cancer of unknown primary origin (CUP) or primary occult malignancy. Systemic neoplastic spread is generally a late event in cancer progression. However, in some instances, distant dissemination arises at a very early stage, so that metastases reach clinical relevance before primary lesions. Sometimes, the primary lesions cannot be identified in spite of the progresses in the diagnosis of malignancies.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. UniProt P08581 25 EQUAL 1390 EQUAL Reactome Database ID Release 79 419603 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419603 Reactome R-HSA-419603 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419603.1 1 Reactome Database ID Release 79 419634 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419634 Reactome R-HSA-419634 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419634.1 SEMA4D dimer Reactome DB_ID: 373690 SEMA4D Semaphorin 4D Reactome DB_ID: 197744 UniProt:Q92854 SEMA4D SEMA4D C9orf164 CD100 SEMAJ FUNCTION Cell surface receptor for PLXNB1 and PLXNB2 that plays an important role in cell-cell signaling (PubMed:20877282). Regulates GABAergic synapse development (By similarity). Promotes the development of inhibitory synapses in a PLXNB1-dependent manner (By similarity). Modulates the complexity and arborization of developing neurites in hippocampal neurons by activating PLXNB1 and interaction with PLXNB1 mediates activation of RHOA (PubMed:19788569). Promotes the migration of cerebellar granule cells (PubMed:16055703). Plays a role in the immune system; induces B-cells to aggregate and improves their viability (in vitro) (PubMed:8876214). Induces endothelial cell migration through the activation of PTK2B/PYK2, SRC, and the phosphatidylinositol 3-kinase-AKT pathway (PubMed:16055703).SUBUNIT Homodimer (PubMed:20877282). Interacts with PLXNB2 (By similarity). Interacts with PLXNB1 (PubMed:10520995).TISSUE SPECIFICITY Strongly expressed in skeletal muscle, peripheral blood lymphocytes, spleen, and thymus and also expressed at lower levels in testes, brain, kidney, small intestine, prostate, heart, placenta, lung and pancreas, but not in colon and liver.SIMILARITY Belongs to the semaphorin family. UniProt Q92854 22 EQUAL 862 EQUAL Reactome Database ID Release 79 197744 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197744 Reactome R-HSA-197744 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197744.1 2 Reactome Database ID Release 79 373690 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=373690 Reactome R-HSA-373690 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-373690.1 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 79 29370 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370 Reactome R-ALL-29370 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29370.5 COMPOUND C00008 SEMA4D:MET:p-Y-PLXNB1 Sema4D:pPlexin-B1:Met Reactome DB_ID: 419621 MET:p-Y-PLXNB1 Reactome DB_ID: 419623 1 p-Y-PLXNB1 phosphorylated Plexin B1 Reactome DB_ID: 419609 O4'-phospho-L-tyrosine MOD MOD:00048 20 EQUAL 2135 EQUAL Reactome Database ID Release 79 419609 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419609 Reactome R-HSA-419609 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419609.1 1 Reactome Database ID Release 79 419623 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419623 Reactome R-HSA-419623 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419623.2 1 1 Reactome Database ID Release 79 419621 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419621 Reactome R-HSA-419621 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419621.2 ACTIVATION activeUnit: #Protein2 GENE ONTOLOGY GO:0004713 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 79 419649 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419649 Reactome Database ID Release 79 419646 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419646 Reactome R-HSA-419646 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419646.1 18025083 Pubmed 2008 ErbB-2 and met reciprocally regulate cellular signaling via plexin-B1 Swiercz, JM Worzfeld, T Offermanns, S J Biol Chem 283:1893-901 12198496 Pubmed 2002 The semaphorin 4D receptor controls invasive growth by coupling with Met Giordano, S Corso, S Conrotto, P Artigiani, S Gilestro, G Barberis, D Tamagnone, L Comoglio, PM Nat Cell Biol 4:720-4 LEFT-TO-RIGHT Active Rac1 interacts with Plexin-B1:Sema4D Active Rac1 interacts with Plexin-B1:Sema4A The cytoplasmic tails of plexins have two domains, C1 and C2, which are highly conserved and act as GAP for small GTPases like Rac1. Active Rac1 binds directly to a binding domain of Plexin-B1 in the linker region between C1 and C2. The functional consequence of the plexin-B1/Rac interaction is not understood but this binding might sequester Rac1 away from p21-activated kinase (PAK). Plexin-B1 can compete with PAK for binding to active Rac and this competition results in the ability of plexin-B1 to inhibit Rac-induced PAK activation. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 RAC1:GTP Reactome DB_ID: 442641 GTP Guanosine 5'-triphosphate GTP)(4-) Reactome DB_ID: 29438 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI CHEBI:37565 Reactome Database ID Release 79 29438 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29438 Reactome R-ALL-29438 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29438.4 COMPOUND C00044 1 RAC1 Reactome DB_ID: 351141 UniProt:P63000 RAC1 RAC1 TC25 MIG5 FUNCTION Plasma membrane-associated small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins to regulate cellular responses such as secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization, neurons adhesion, migration and differentiation, and growth-factor induced formation of membrane ruffles (PubMed:1643658, PubMed:28886345). Rac1 p21/rho GDI heterodimer is the active component of the cytosolic factor sigma 1, which is involved in stimulation of the NADPH oxidase activity in macrophages. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. Stimulates PKN2 kinase activity (PubMed:9121475). In concert with RAB7A, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts (PubMed:1643658). In podocytes, promotes nuclear shuttling of NR3C2; this modulation is required for a proper kidney functioning. Required for atypical chemokine receptor ACKR2-induced LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In neurons, is involved in dendritic spine formation and synaptic plasticity (By similarity). In hippocampal neurons, involved in spine morphogenesis and synapse formation, through local activation at synapses by guanine nucleotide exchange factors (GEFs), such as ARHGEF6/ARHGEF7/PIX (PubMed:12695502). In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3. In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in PAK1 activation and eventually F-actin stabilization (By similarity).FUNCTION Isoform B has an accelerated GEF-independent GDP/GTP exchange and an impaired GTP hydrolysis, which is restored partially by GTPase-activating proteins. It is able to bind to the GTPase-binding domain of PAK but not full-length PAK in a GTP-dependent manner, suggesting that the insertion does not completely abolish effector interaction.ACTIVITY REGULATION Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. GTP hydrolysis is stimulated by ARHGAP30.SUBUNIT Interacts with NISCH. Interacts with PIP5K1A. Interacts with the GTP-bound form of RAB7A. Interacts with SRGAP2. Interacts with CYFIP1/SRA-1. Interacts with PLXNB3. Interacts with ARHGDIA; the interaction is induced by SEMA5A, mediated through PLXNB3 and inactivates and stabilizes RAC1. Interacts (GTP-bound form preferentially) with PKN2 (via the REM repeats); the interaction stimulates autophosphorylation and phosphorylation of PKN2. Interacts with the GEF proteins PREX1, RASGRF2, FARP1, FARP2, DOCK1, DOCK2 and DOCK7, which promote the exchange between GDP and GTP, and therefore activate it. Interacts with PARD6A, PARD6B and PARD6G in a GTP-dependent manner. Part of a quaternary complex containing PARD3, some PARD6 protein (PARD6A, PARD6B or PARD6G) and some atypical PKC protein (PRKCI or PRKCZ), which plays a central role in epithelial cell polarization. Found in a trimeric complex composed of DOCK1 and ELMO1, which plays a central role in phagocytosis of apoptotic cells. Interacts with RALBP1 via its effector domain. Interacts with PLXNB1. Probably found in a ternary complex composed of DSCAM, PAK1 and RAC1. Interacts with DSCAM; the interaction requires PAK1. Part of a complex with MAP2K3, MAP3K3, CCM2 and DEF6. Interacts with BAIAP2, BAIAP2L1 and DEF6. Interacts with Y.pseudotuberculosis YPKA and PLCB2. Interacts with NOXA1. Interacts with ARHGEF2. Interacts with TBC1D2. Interacts with UNKL. Interacts with USP6. Interacts with SPATA13. Interacts with ARHGEF16; mediates activation of RAC1 by EPHA2. Interacts with ITGB4. Interacts with S100A8 and calprotectin (S100A8/9). Interacts with PACSIN2. Interacts with ITGB1BP1. Interacts (when active) with PPP5C (via TPR repeats); activates PPP5C phosphatase activity and translocates PPP5C to the cell membrane. Interacts with RAPH1 (via Ras associating and PH domains) (PubMed:18499456). Interacts with MTSS2 (via IMD domain); this interaction may be important to potentiate PDGF-induced RAC1 activation (PubMed:20875796). Interacts with PAK2 (PubMed:20696164). Interacts (GTP-bound form) with SH3RF1 and SH3RF3 (PubMed:20696164). Found in a complex with SH3RF1, MAPK8IP1/JIP1, MAP3K11/MLK3, MAP2K7/MKK7 and MAPK8/JNK1. Interacts (both active GTP- or inactive GDP-bound forms) with SH3RF2 (By similarity). Interacts (GTP-bound form preferentially) with CYRIB (PubMed:31285585, PubMed:30250061). Interacts with DOCK4 (via DOCKER domain); functions as a guanine nucleotide exchange factor (GEF) for RAC1 (PubMed:16464467). Interacts with GARRE1 (PubMed:31871319).TISSUE SPECIFICITY Isoform B is predominantly identified in skin and epithelial tissues from the intestinal tract. Its expression is elevated in colorectal tumors at various stages of neoplastic progression, as compared to their respective adjacent tissues.DOMAIN The effector region mediates interaction with DEF6.PTM (Microbial infection) AMPylation at Tyr-32 and Thr-35 are mediated by bacterial enzymes in case of infection by H.somnus and V.parahaemolyticus, respectively. AMPylation occurs in the effector region and leads to inactivation of the GTPase activity by preventing the interaction with downstream effectors, thereby inhibiting actin assembly in infected cells. It is unclear whether some human enzyme mediates AMPylation; FICD has such ability in vitro but additional experiments remain to be done to confirm results in vivo.PTM GTP-bound active form is ubiquitinated by HACE1, leading to its degradation by the proteasome.PTM (Microbial infection) Glycosylated at Tyr-32 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rac and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-35 by C.difficile toxins TcdA and TcdB in the colonic epithelium, and by P.sordellii toxin TcsL in the vascular endothelium (PubMed:7777059, PubMed:7775453, PubMed:8626575, PubMed:19744486, PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7777059, PubMed:7775453).PTM (Microbial infection) Glycosylated (O-GlcNAcylated) at Thr-35 by C.novyi toxin TcdA (PubMed:8810274). O-GlcNAcylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:8810274).SIMILARITY Belongs to the small GTPase superfamily. Rho family. UniProt P63000 1 EQUAL 189 EQUAL Reactome Database ID Release 79 351141 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=351141 Reactome R-HSA-351141 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-351141.1 1 Reactome Database ID Release 79 442641 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442641 Reactome R-HSA-442641 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-442641.1 Sema4D:pPlexin-B1:Met:RAC1-GTP Reactome DB_ID: 400679 1 1 Reactome Database ID Release 79 400679 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400679 Reactome R-HSA-400679 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400679.1 Reactome Database ID Release 79 400682 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400682 Reactome R-HSA-400682 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400682.1 11937491 Pubmed 2002 The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding Vikis, HG Li, W Guan, KL Genes Dev 16:836-45 11035813 Pubmed 2000 The semaphorin receptor plexin-B1 specifically interacts with active Rac in a ligand-dependent manner Vikis, HG Li, W He, Z Guan, KL Proc Natl Acad Sci U S A 97:12457-62 LEFT-TO-RIGHT Rnd1 interacts with Plexin-B1:Sema4D Rnd1 is constitutively active and stably associates with Plexin-B1 and regulates the R-Ras GAP activity of the C1 and C2 domains of the Plexin-B1 cytoplasmic tail. These domains interact with each other and in this closed conformation cannot associate with active R-Ras-GTP. Rnd1 binds to the region between C1 and C2 domains and disrupts this interaction, allowing the receptor to associate with GTP-bound R-Ras. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 RND1:GTP Rnd1-GTP Reactome DB_ID: 421104 1 RND1 Rho-related GTP-binding protein Rho6 (Rnd1) RND1_HUMAN RHO6 Reactome DB_ID: 396949 UniProt:Q92730 RND1 RND1 RHO6 FUNCTION Lacks intrinsic GTPase activity. Has a low affinity for GDP, and constitutively binds GTP. Controls rearrangements of the actin cytoskeleton. Induces the Rac-dependent neuritic process formation in part by disruption of the cortical actin filaments. Causes the formation of many neuritic processes from the cell body with disruption of the cortical actin filaments.SUBUNIT Binds GRB7 and PLXNB1. Interacts with UBXD5. Interacts with PLXNA2.TISSUE SPECIFICITY Mostly expressed in brain and liver.SIMILARITY Belongs to the small GTPase superfamily. Rho family. UniProt Q92730 1 EQUAL 229 EQUAL Reactome Database ID Release 79 396949 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=396949 Reactome R-HSA-396949 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-396949.2 1 Reactome Database ID Release 79 421104 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=421104 Reactome R-HSA-421104 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-421104.3 Sema4D:pPlexin-B1:Met:Rnd1 SEMA4D:MET:p-Y-PLXNB1:RND1:GTP Reactome DB_ID: 416587 1 1 Reactome Database ID Release 79 416587 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416587 Reactome R-HSA-416587 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416587.2 Reactome Database ID Release 79 400677 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400677 Reactome R-HSA-400677 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400677.1 12730235 Pubmed 2003 Direct interaction of Rnd1 with Plexin-B1 regulates PDZ-RhoGEF-mediated Rho activation by Plexin-B1 and induces cell contraction in COS-7 cells Oinuma, I Katoh, H Harada, A Negishi, M J Biol Chem 278:25671-7 LEFT-TO-RIGHT Inactivation of R-Ras by Sema4D-Plexin-B1 GAP activity Plexin-B1 functions as an R-Ras GTPase-activating protein (GAP) and directly and specifically down regulates R-Ras activity in response to Sema4D, inducing growth cone collapse. R-Ras inactivation promotes PI3K and Akt inactivation followed by GSK-3beta activation and CRMP inactivation. R-Ras inactivation also inhibits cell migration by regulating beta1 integrin activity. <br> Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 R-Ras-GTP Reactome DB_ID: 399865 1 RRAS Ras-related protein R-Ras (p23) RRAS_HUMAN Reactome DB_ID: 396959 UniProt:P10301 RRAS RRAS FUNCTION Regulates the organization of the actin cytoskeleton (PubMed:16537651, PubMed:18270267). With OSPBL3, modulates integrin beta-1 (ITGB1) activity (PubMed:18270267).SUBUNIT Interacts with PLCE1 (PubMed:16537651). Interacts (active GTP-bound form preferentially) with RGS14 (By similarity). Interacts with OSBPL3 (PubMed:18270267, PubMed:16537651, PubMed:20074548) (By similarity). Interacts with ZDHHC19 (PubMed:20074548).PTM S-palmitoylated by ZDHHC19, leading to increased association with membranes and with rafts/caveolae as well as enhanced cell viability.SIMILARITY Belongs to the small GTPase superfamily. Ras family. UniProt P10301 1 EQUAL 215 EQUAL Reactome Database ID Release 79 396959 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=396959 Reactome R-HSA-396959 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-396959.1 1 Reactome Database ID Release 79 399865 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399865 Reactome R-HSA-399865 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399865.2 Pi Orthophosphate hydrogenphosphate Phosphate Inorganic Phosphate Reactome DB_ID: 29372 hydrogenphosphate [ChEBI:43474] hydrogenphosphate hydrogen phosphate phosphate [PO3(OH)](2-) INORGANIC PHOSPHATE GROUP HYDROGENPHOSPHATE ION HPO4(2-) [P(OH)O3](2-) ChEBI CHEBI:43474 Reactome Database ID Release 79 29372 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29372 Reactome R-ALL-29372 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29372.4 COMPOUND C00009 R-Ras-GDP Reactome DB_ID: 399866 1 GDP Guanosine 5'-diphosphate Guanosine diphosphate Reactome DB_ID: 114549 GDP [ChEBI:17552] GDP Guanosine 5'-diphosphate Guanosine diphosphate ChEBI CHEBI:17552 Reactome Database ID Release 79 114549 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114549 Reactome R-ALL-114549 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-114549.2 COMPOUND C00035 1 Reactome Database ID Release 79 399866 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399866 Reactome R-HSA-399866 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399866.1 ACTIVATION activeUnit: #Protein1 GENE ONTOLOGY GO:0005096 Reactome Database ID Release 79 416583 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416583 Reactome Database ID Release 79 416546 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416546 Reactome R-HSA-416546 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416546.1 16702230 Pubmed 2006 Semaphorin 4D/Plexin-B1-mediated R-Ras GAP activity inhibits cell migration by regulating beta(1) integrin activity Oinuma, I Katoh, H Negishi, M J Cell Biol 173:601-13 16799460 Pubmed 2006 Sema4D/plexin-B1 activates GSK-3beta through R-Ras GAP activity, inducing growth cone collapse Ito, Y Oinuma, I Katoh, H Kaibuchi, K Negishi, M EMBO Rep 7:704-9 LEFT-TO-RIGHT p190RhoGAP binds Plexin-B1 Plexin-B1 can mediate inhibition of RhoA via the Sema4D-dependent recruitment of p190RhoGAP into the semaphorin receptor complex. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 ARHGAP35 GRLF1/p190-A variant 1 p190RhoGAP Reactome DB_ID: 195118 UniProt:Q9NRY4 ARHGAP35 ARHGAP35 GRF1 GRLF1 KIAA1722 P190A p190ARHOGAP FUNCTION Rho GTPase-activating protein (GAP) (PubMed:19673492, PubMed:28894085). Binds several acidic phospholipids which inhibits the Rho GAP activity to promote the Rac GAP activity (PubMed:19673492). This binding is inhibited by phosphorylation by PRKCA (PubMed:19673492). Involved in cell differentiation as well as cell adhesion and migration, plays an important role in retinal tissue morphogenesis, neural tube fusion, midline fusion of the cerebral hemispheres and mammary gland branching morphogenesis (By similarity). Transduces signals from p21-ras to the nucleus, acting via the ras GTPase-activating protein (GAP) (By similarity). Transduces SRC-dependent signals from cell-surface adhesion molecules, such as laminin, to promote neurite outgrowth. Regulates axon outgrowth, guidance and fasciculation (By similarity). Modulates Rho GTPase-dependent F-actin polymerization, organization and assembly, is involved in polarized cell migration and in the positive regulation of ciliogenesis and cilia elongation (By similarity). During mammary gland development, is required in both the epithelial and stromal compartments for ductal outgrowth (By similarity). Represses transcription of the glucocorticoid receptor by binding to the cis-acting regulatory sequence 5'-GAGAAAAGAAACTGGAGAAACTC-3'; this function is however unclear and would need additional experimental evidences (PubMed:1894621).ACTIVITY REGULATION Binding of acidic phospholipids inhibits the Rho GAP activity and promotes the Rac GAP activity.SUBUNIT Interacts with RASA1 (By similarity). Interacts with the general transcription factor GTF2I, the interaction sequesters GTF2I in the cytoplasm (PubMed:19393245).TISSUE SPECIFICITY Detected in neutrophils (at protein level).DOMAIN N-terminal part (1-266) has GTPase activity. Required for proper cellular localization.DOMAIN The pG1 pseudoGTPase domain does not bind GTP.PTM Phosphorylation of Tyr-1105 by PTK6 promotes the association with RASA1, inactivating RHOA while activating RAS. Phosphorylation at Tyr-308 by PDGFRA inhibits binding to GTF2I (PubMed:18829532, PubMed:19393245). Phosphorylated by PRKCA at Ser-1221 and Thr-1226, induces relocalization from the cytoplasm to regions of plasma membrane ruffling and prevents the binding and substrate specificity regulation by phospholipids (PubMed:19673492). In brain, phosphorylated by FYN and SRC (By similarity). During focal adhesion formation, phosphorylated by MAPK1 and MAPK3 at the C-terminal region, probably at Ser-1451, Ser-1476, Thr-1480 and Ser-1483. Phosphorylation by MAPK1 and MAPK3 inhibits GAP function and localizes ARGHAP35 away from newly forming focal adhesions and stress fibers in cells spreading on fibronectin (By similarity). Phosphorylation at Ser-1476 and Thr-1480 by GSK3B requires priming by MAPK and inhibits RhoGAP activity and modulates polarized cell migration (By similarity). UniProt Q9NRY4 1 EQUAL 1499 EQUAL Reactome Database ID Release 79 195118 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195118 Reactome R-HSA-195118 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195118.2 Sema4D:Plexin-B1:p190RhoGAP:Rac:Rnd1 SEMA4D:MET:p-Y-PLXNB1:RND1:GTP:ARHGAP35 Reactome DB_ID: 416601 1 1 Reactome Database ID Release 79 416601 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416601 Reactome R-HSA-416601 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416601.2 Reactome Database ID Release 79 416562 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416562 Reactome R-HSA-416562 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416562.1 16188938 Pubmed 2005 p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling Barberis, D Casazza, A Sordella, R Corso, S Artigiani, S Settleman, J Comoglio, PM Tamagnone, L J Cell Sci 118:4689-700 LEFT-TO-RIGHT Inactivation of Rho-GTP by p190RhoGAP p190RhoGAP complexed with Plexin-B1 stimulates GTP hydrolysis by RhoA. The resulting lower levels of Rho-GTP may account for F-actin depolymerization and cytoskeletal rearrangements. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 H2O water Reactome DB_ID: 29356 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 79 29356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29356 Reactome R-ALL-29356 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29356.5 COMPOUND C00001 RHOA:GTP Reactome DB_ID: 5665993 RHOA RhoA Transforming protein RhoA RHOA_HUMAN Reactome DB_ID: 194510 UniProt:P61586 RHOA RHOA ARH12 ARHA RHO12 FUNCTION Small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. Mainly associated with cytoskeleton organization, in active state binds to a variety of effector proteins to regulate cellular responses such as cytoskeletal dynamics, cell migration and cell cycle. Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers (PubMed:8910519, PubMed:9121475, PubMed:31570889). Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis (PubMed:16236794, PubMed:12900402). Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion (PubMed:20974804, PubMed:23940119). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization (PubMed:20937854). Regulates KCNA2 potassium channel activity by reducing its location at the cell surface in response to CHRM1 activation; promotes KCNA2 endocytosis (PubMed:9635436, PubMed:19403695). Acts as an allosteric activator of guanine nucleotide exchange factor ECT2 by binding in its activated GTP-bound form to the PH domain of ECT2 which stimulates the release of PH inhibition and promotes the binding of substrate RHOA to the ECT2 catalytic center (PubMed:31888991). May be an activator of PLCE1 (PubMed:16103226). In neurons, involved in the inhibiton of the initial spine growth. Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling (By similarity). Acts as a regulator of platelet alpha-granule release during activation and aggregation of platelets (By similarity).FUNCTION (Microbial infection) Serves as a target for the yopT cysteine peptidase from Yersinia pestis, vector of the plague.ACTIVITY REGULATION Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. Activated by GEFs such as ARHGEF2, ARHGEF3, ARHGEF28 and BCR (PubMed:23940119, PubMed:12221096). Inhibited by GAPs such as ARHGAP30 (PubMed:21565175). Inhibited by GDP dissociation inhibitors such as ARHGDIA (PubMed:20400958).SUBUNIT Interacts with ARHGEF28 (By similarity). Interacts (via GTP-bound form) with RIPOR1 (via N-terminus); this interaction links RHOA to STK24 and STK26 kinases (PubMed:27807006). Interacts with RIPOR2 (via active GTP- or inactive GDP-bound forms) isoform 1 and isoform 2; these interactions are direct, block the loading of GTP to RHOA and decrease upon chemokine CCL19 stimulation in primary T lymphocytes (PubMed:25588844). Binds PRKCL1, ROCK1 and ROCK2 (PubMed:10388627, PubMed:8617235, PubMed:8641286). Interacts with ARHGEF2, ARHGEF3, NET1 and RTKN (PubMed:10940294, PubMed:12221096, PubMed:9857026). Interacts with PLCE1 and AKAP13 (PubMed:11696353, PubMed:12900402). Interacts with DIAPH1 (PubMed:23325789). Interacts (in the constitutively activated, GTP-bound form) with DGKQ (PubMed:10066731). Interacts with RACK1; enhances RHOA activation (PubMed:20499158). Interacts with PKP4; the interaction is detected at the midbody (PubMed:17115030). Interacts (GTP-bound form preferentially) with PKN2; the interaction stimulates autophosphorylation and phosphorylation of PKN2 (PubMed:20974804, PubMed:9121475). Interacts with ARHGDIA; this interaction inactivates and stabilizes RHOA (PubMed:20400958). Interacts with ARHGDIB. Interacts (GTP-bound form) with KCNA2 (via cytoplasmic N-terminal domain) (PubMed:9635436). Interacts (GTP-bound form) with ECT2; the interaction results in allosteric activation of ECT2 (PubMed:31888991).SUBUNIT (Microbial infection) Interacts with yopT from Yersinia pestis.SUBUNIT (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein F; this interaction facilitates virus-induced syncytium formation.DOMAIN The basic-rich region is essential for yopT recognition and cleavage.PTM (Microbial infection) Substrate for botulinum ADP-ribosyltransferase.PTM (Microbial infection) Cleaved by yopT protease when the cell is infected by some Yersinia pathogens. This removes the lipid attachment, and leads to its displacement from plasma membrane and to subsequent cytoskeleton cleavage.PTM (Microbial infection) AMPylation at Tyr-34 and Thr-37 are mediated by bacterial enzymes in case of infection by H.somnus and V.parahaemolyticus, respectively. AMPylation occurs in the effector region and leads to inactivation of the GTPase activity by preventing the interaction with downstream effectors, thereby inhibiting actin assembly in infected cells. It is unclear whether some human enzyme mediates AMPylation; FICD has such ability in vitro but additional experiments remain to be done to confirm results in vivo.PTM (Microbial infection) Glycosylated at Tyr-34 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rho and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-37 by C.difficile toxins TcdA and TcdB in the colonic epithelium (PubMed:7777059, PubMed:7775453, PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7777059, PubMed:7775453).PTM (Microbial infection) Glycosylated (O-GlcNAcylated) at Thr-37 by C.novyi toxin TcdA (PubMed:8810274). O-GlcNAcylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:8810274).PTM Phosphorylation by PRKG1 at Ser-188 inactivates RHOA signaling (PubMed:11162591). Phosphorylation by SLK at Ser-188 in response to AGTR2 activation (By similarity).PTM Ubiquitinated by the BCR(KCTD13) and BCR(TNFAIP1) E3 ubiquitin ligase complexes, leading to its degradation by the proteasome, thereby regulating the actin cytoskeleton and synaptic transmission in neurons.PTM Serotonylation of Gln-63 by TGM2 during activation and aggregation of platelets leads to constitutive activation of GTPase activity.SIMILARITY Belongs to the small GTPase superfamily. Rho family. UniProt P61586 1 EQUAL 190 EQUAL Reactome Database ID Release 79 194510 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194510 Reactome R-HSA-194510 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194510.1 1 1 Reactome Database ID Release 79 5665993 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665993 Reactome R-HSA-5665993 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665993.1 RHOA:GDP Reactome DB_ID: 8964174 1 GDP Guanosine 5'-diphosphate Guanosine diphosphate GDP(3-) Reactome DB_ID: 29420 GDP(3-) [ChEBI:58189] GDP(3-) 5'-O-[(phosphonatooxy)phosphinato]guanosine guanosine 5'-diphosphate(3-) GDP guanosine 5'-diphosphate trianion guanosine 5'-diphosphate GDP trianion ChEBI CHEBI:58189 Reactome Database ID Release 79 29420 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29420 Reactome R-ALL-29420 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29420.3 COMPOUND C00035 1 Reactome Database ID Release 79 8964174 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8964174 Reactome R-HSA-8964174 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8964174.1 ACTIVATION activeUnit: #Protein8 Reactome Database ID Release 79 416593 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416593 Reactome Database ID Release 79 416559 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416559 Reactome R-HSA-416559 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416559.2 Reactome Database ID Release 79 416550 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416550 Reactome R-HSA-416550 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416550.2 16314868 Pubmed 2005 Semaphorins command cells to move Kruger, RP Aurandt, J Guan, KL Nat Rev Mol Cell Biol 6:789-800 18374575 Pubmed 2008 Semaphorin signaling: progress made and promises ahead Zhou, Y Gunput, RA Pasterkamp, RJ Trends Biochem Sci 33:161-70 14770294 Pubmed 2004 Biological functions and signaling of a transmembrane semaphorin, CD100/Sema4D Kumanogoh, Atsushi Kikutani, Hitoshi Cell Mol Life Sci 61:292-300 Sema4D induced cell migration and growth-cone collapse Sema4D-mediated attraction of endothelial cells requires Rho, but not R-Ras, signaling. Sema4D-mediated plexinB1 activation activates Rho and its downstream effector ROCK. ROCK then phosphorylates MLC to induce actomyosin stress fiber contraction and to direct the assembly of focal adhesion complexes and integrin-mediated adhesion. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:38 LEFT-TO-RIGHT 2.7.10.2 SEMA4D interacts with Plexin-B1:ErbB2 Sema4D binds Plexin-B1 to induce repulsive or attractive effects in neuronal and nonneuronal cells. Plexins constitute a large family of transmembrane proteins that function as receptors for semaphorins and their interaction governs cell adhesion and migration in a variety of tissues. All B-class plexins can interact with the receptor tyrosine kinases Met and ErbB2. Upon binding of Sema4D to plexin-B1, the kinase activity of ErbB2 is increased resulting in tyrosine phosphorylation of both Plexin-B1 and ErbB2. ErbB2 has been shown to mediate Sema4D-induced growth cone collapse in hippocampal neurons by the activation of RhoA via plexinB1 and PDZRhoGEF/LARG.<br>Sequence alignment reveals the presence of 13 conserved tyrosine residues (highly conserved sites 1918, 1953, 2038) but the specific tyrosine residues phosphorylated in the cytoplasmic domain of plexins in response to semaphorin stimulation have not yet been identified. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 Plexin-B1:ErbB2 Reactome DB_ID: 419629 ERBB2 ErbB2 Reactome DB_ID: 372889 UniProt:P04626 ERBB2 ERBB2 HER2 MLN19 NEU NGL FUNCTION Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization.FUNCTION In the nucleus is involved in transcriptional regulation. Associates with the 5'-TCAAATTC-3' sequence in the PTGS2/COX-2 promoter and activates its transcription. Implicated in transcriptional activation of CDKN1A; the function involves STAT3 and SRC. Involved in the transcription of rRNA genes by RNA Pol I and enhances protein synthesis and cell growth.ACTIVITY REGULATION Activated by dimerization. Not activated by EGF, TGF-alpha and amphiregulin. Interaction with PTK6 increases its intrinsic kinase activity.SUBUNIT Homodimer (PubMed:21454582). Heterodimer with EGFR, ERBB3 and ERBB4 (PubMed:10358079, PubMed:15093539, PubMed:21190959, PubMed:16978839). Part of a complex with EGFR and either PIK3C2A or PIK3C2B. May interact with PIK3C2B when phosphorylated on Tyr-1196 (PubMed:10805725). Interacts with PLXNB1 (PubMed:15210733). Interacts (when phosphorylated on Tyr-1248) with MEMO1 (PubMed:15156151). Interacts with MUC1; the interaction is enhanced by heregulin (HRG) (PubMed:12939402). Interacts (when phosphorylated on Tyr-1139) with GRB7 (via SH2 domain) (PubMed:12975581). Interacts (when phosphorylated on Tyr-1248) with ERBIN (PubMed:12444095). Interacts with KPNB1, RANBP2, EEA1, CRM1 and CLTC (PubMed:16314522). Interacts with PTK6 (PubMed:18719096). Interacts with RPA194 and ACTB (PubMed:21555369). Interacts with PRKCABP, SRC and MYOC (By similarity). Interacts (preferentially with the tyrosine phosphorylated form) with CPNE3; this interaction occurs at the cell membrane and is increased in a growth factor heregulin-dependent manner (PubMed:20010870). Interacts with HSP90AA1 and HSP90AB1 in an ATP-dependent manner; the interaction suppresses ERBB2 kinase activity (PubMed:26517842). Interacts with SORL1; this interaction regulates ERBB2 subcellular distribution by promoting its recycling after internalization from endosomes back to the plasma membrane, hence stimulates ERBB2-mediated signaling (PubMed:31138794).TISSUE SPECIFICITY Expressed in a variety of tumor tissues including primary breast tumors and tumors from small bowel, esophagus, kidney and mouth.PTM Autophosphorylated. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit (Probable). Ligand-binding increases phosphorylation on tyrosine residues (PubMed:27134172). Signaling via SEMA4C promotes phosphorylation at Tyr-1248 (PubMed:17554007). Dephosphorylated by PTPN12 (PubMed:27134172).POLYMORPHISM There are four alleles due to the variations in positions 654 and 655. Allele B1 (Ile-654/Ile-655) has a frequency of 0.782; allele B2 (Ile-654/Val-655) has a frequency of 0.206; allele B3 (Val-654/Val-655) has a frequency of 0.012.DISEASE Chromosomal aberrations involving ERBB2 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with CDK12, leading to CDK12-ERBB2 fusion leading to truncated CDK12 protein not in-frame with ERBB2.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily. UniProt P04626 23 EQUAL 1255 EQUAL Reactome Database ID Release 79 372889 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=372889 Reactome R-HSA-372889 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-372889.1 1 1 Reactome Database ID Release 79 419629 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419629 Reactome R-HSA-419629 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419629.1 SEMA4D:ERBB2:p-Y-PLXNB1 SEMA4D:pPlexin-B1:ErbB2 complex Reactome DB_ID: 373695 ERBB2:p-Y-PLXNB1 pPlexin-B1:ErbB2 Reactome DB_ID: 419627 1 1 Reactome Database ID Release 79 419627 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419627 Reactome R-HSA-419627 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419627.2 1 1 Reactome Database ID Release 79 373695 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=373695 Reactome R-HSA-373695 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-373695.2 ACTIVATION activeUnit: #Protein10 Reactome Database ID Release 79 419656 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419656 Reactome Database ID Release 79 373750 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=373750 Reactome R-HSA-373750 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-373750.1 15210733 Pubmed 2004 Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2 Swiercz, JM Kuner, R Offermanns, S J Cell Biol 165:869-80 LEFT-TO-RIGHT LARG and PDZ-RhoGEF binds to Plexin-B1 Plexin-B1 activates RhoA and induces growth cone collapse and and cytoskeletal reorganization through Rho-specific guanine nucleotide exchange factors PDZ-RhoGEF (ARHGEF11) and leukemia-associated RhoGEF (LARG, ARHGEF12). Plexin-B1 directly interacts with PDZ-RhoGEF through its c-terminal PDZ domain binding motif. It has been suggested that Rnd1, which binds to the cytoplasmic part of plexin-B1, can promote the interaction between plexin-B1 and PDZ-RhoGEF. The PDZ domain of LARG is directly involved in the interaction with the c-terminal sequence of Plexin-B1. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 SEMA4D:ERBB2:p-Y-PLXNB1:RND1 Reactome DB_ID: 419626 1 1 Reactome Database ID Release 79 419626 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419626 Reactome R-HSA-419626 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419626.2 Converted from EntitySet in Reactome ARHGEF11,ARHGEF12 LARG and PDZ-RhoGEF Reactome DB_ID: 416544 ARHGEF11 PDZ-RhoGEF Reactome DB_ID: 195102 UniProt:O15085 ARHGEF11 ARHGEF11 KIAA0380 FUNCTION May play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13). Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase and may act as GTPase-activating protein (GAP) for GNA12 and GNA13. Involved in neurotrophin-induced neurite outgrowth.SUBUNIT Interacts with GNA12 and GNA13 through the RGS domain. Interacts with RHOA, PLXNB1 and PLXNB2. Interacts with SLC1A6 (By similarity). Interacts (via DH domain) with GCSAM (via C-terminus).TISSUE SPECIFICITY Ubiquitously expressed.DOMAIN The poly-Pro region is essential for plasma membrane localization upon stimulation.PTM Phosphorylated by MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14).PTM Ubiquitinated by the BCR(KLHL20) E3 ubiquitin ligase complex when previously phosphorylated by MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14), leading to its degradation, thereby restricting RhoA activity and facilitating growth cone spreading and neurite outgrowth. UniProt O15085 1 EQUAL 1522 EQUAL Reactome Database ID Release 79 195102 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195102 Reactome R-HSA-195102 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195102.1 LARG ARHGEF12 Rho guanine nucleotide exchange factor 12 ARHGC_HUMAN Reactome DB_ID: 416560 UniProt:Q9NZN5 ARHGEF12 ARHGEF12 KIAA0382 LARG FUNCTION May play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13). Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase and may act as GTPase-activating protein (GAP) for GNA12 and GNA13.SUBUNIT Interacts with GNA12 and GNA13, probably through the RGS-like domain. Interacts with RHOA, PLXNB1 and PLXNB2. Interacts through its PDZ domain with IGF1R beta subunit. Interacts with GCSAM.TISSUE SPECIFICITY Ubiquitously expressed. Isoform 2 is found in jejunum and testis.DISEASE A chromosomal aberration involving ARHGEF12 may be a cause of acute leukemia. Translocation t(11;11)(q23;23) with KMT2A/MLL1. UniProt Q9NZN5 1 EQUAL 1544 EQUAL Reactome Database ID Release 79 416560 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416560 Reactome R-HSA-416560 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416560.1 Reactome Database ID Release 79 416544 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416544 Reactome R-HSA-416544 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416544.2 Sema4D:Plexin-B1:Rac-Rnd1:LARG/PDZ-RhoGEF SEMA4D:ERBB2:p-Y-PLXNB1:RND1:ARHGEF11,ARHGEF12 Reactome DB_ID: 416580 1 1 Reactome Database ID Release 79 416580 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416580 Reactome R-HSA-416580 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416580.2 Reactome Database ID Release 79 416594 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416594 Reactome R-HSA-416594 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416594.1 12196628 Pubmed 2002 The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG Aurandt, J Vikis, HG Gutkind, JS Ahn, N Guan, KL Proc Natl Acad Sci U S A 99:12085-90 12220504 Pubmed 2002 Interaction of plexin-B1 with PDZ domain-containing Rho guanine nucleotide exchange factors Hirotani, M Ohoka, Y Yamamoto, T Nirasawa, H Furuyama, T Kogo, M Matsuya, T Inagaki, S Biochem Biophys Res Commun 297:32-7 LEFT-TO-RIGHT Activation of Rho by LARG and PDZ-RhoGEF The RhoGEFs LARG and PDZ-RhoGEF complexed with Plexin-B1 stimulate the exchange of GDP for GTP on RhoA through their DH and PH domains. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 RhoA,B,C:GDP Reactome DB_ID: 419164 1 Converted from EntitySet in Reactome RHOA/B/C Reactome DB_ID: 419160 RHOB RhoB Reactome DB_ID: 194891 UniProt:P62745 RHOB RHOB ARH6 ARHB FUNCTION Mediates apoptosis in neoplastically transformed cells after DNA damage. Not essential for development but affects cell adhesion and growth factor signaling in transformed cells. Plays a negative role in tumorigenesis as deletion causes tumor formation. Involved in intracellular protein trafficking of a number of proteins. Targets PKN1 to endosomes and is involved in trafficking of the EGF receptor from late endosomes to lysosomes. Also required for stability and nuclear trafficking of AKT1/AKT which promotes endothelial cell survival during vascular development. Serves as a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Required for genotoxic stress-induced cell death in breast cancer cells.SUBUNIT Binds ROCK1 and ROCK2 (By similarity). Also binds PKN1/PRK1 (PubMed:9478917). Interacts with ARGGEF3 (PubMed:12221096). Interacts with RTKN (By similarity). Interacts with AKAP13 (PubMed:11546812). Interacts with RIPOR1 (PubMed:27807006).INDUCTION Up-regulated by DNA damaging agents like H(2)O(2) or ionizing radiation (IR).PTM Prenylation specifies the subcellular location of RHOB. The farnesylated form is localized to the plasma membrane while the geranylgeranylated form is localized to the endosome.PTM (Microbial infection) Glycosylated at Tyr-34 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rho and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-37 by C.difficile toxins TcdA and TcdB in the colonic epithelium (PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:24905543).MISCELLANEOUS RHOB is one of the targets of farnesyltransferase inhibitors which are currently under investigation as cancer therapeutics. These elevate the levels of geranylgeranylated RHOB and cause mislocalization, leading to apoptosis and antineoplastic effects.SIMILARITY Belongs to the small GTPase superfamily. Rho family. UniProt P62745 1 EQUAL 193 EQUAL Reactome Database ID Release 79 194891 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194891 Reactome R-HSA-194891 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194891.1 RHOC RhoC Reactome DB_ID: 194870 UniProt:P08134 RHOC RHOC ARH9 ARHC FUNCTION Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers. Serves as a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Regulates apical junction formation in bronchial epithelial cells.SUBUNIT Interacts with RTKN (By similarity). Interacts with AKAP13 (PubMed:11546812). Interacts with DIAPH1 (PubMed:15864301). Interacts with PKN2 (PubMed:20974804). Interacts with ROCK1 and ROCK2 (PubMed:8816443). Interacts with ARHGDIA (PubMed:20400958). Interacts with RIPOR1 (PubMed:27807006).PTM (Microbial infection) Glycosylated at Tyr-34 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rho and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-37 by C.difficile toxins TcdA and TcdB in the colonic epithelium (PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:24905543).SIMILARITY Belongs to the small GTPase superfamily. Rho family. UniProt P08134 1 EQUAL 190 EQUAL Reactome Database ID Release 79 194870 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194870 Reactome R-HSA-194870 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194870.1 Reactome Database ID Release 79 419160 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419160 Reactome R-HSA-419160 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419160.1 1 Reactome Database ID Release 79 419164 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419164 Reactome R-HSA-419164 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419164.1 RHOA/B/C:GTP Reactome DB_ID: 419161 1 1 Reactome Database ID Release 79 419161 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419161 Reactome R-HSA-419161 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419161.2 ACTIVATION activeUnit: #Protein11 GENE ONTOLOGY GO:0005085 Reactome Database ID Release 79 416599 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416599 Reactome Database ID Release 79 416588 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416588 Reactome R-HSA-416588 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416588.1 LEFT-TO-RIGHT ROCK activation by RHO ROCKs are primarily known as downstream effectors of RHO, but they can also be activated by arachidonic acid, which binds to the pleckstrin homology domain, releasing an autoinhibitory loop within ROCK and allowing catalytic activity (Araki et al. 2001). Proteolytic cleavage at the C-terminus by caspase-3 and granzyme B also activates ROCK1 and ROCK2, causing plasma membrane blebbing during apoptosis (Coleman et al. 2001, Sebbagh et al. 2005). Multiple targets of ROCK contribute to the stabilization of actin filaments and the generation of actin-myosin contractile force. Authored: Akkerman, JW, 2009-06-03 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Reviewed: Rivero Crespo, Francisco, 2014-12-26 Edited: Jupe, S, 2009-05-20 09:50:28 Converted from EntitySet in Reactome ROCK1,ROCK2 Reactome DB_ID: 419057 ROCK1 Rock1 p160 ROCK Reactome DB_ID: 212509 UniProt:Q13464 ROCK1 ROCK1 FUNCTION Protein kinase which is a key regulator of the actin cytoskeleton and cell polarity (PubMed:10436159, PubMed:10652353, PubMed:11018042, PubMed:11283607, PubMed:17158456, PubMed:18573880, PubMed:19131646, PubMed:8617235, PubMed:9722579). Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of DAPK3, GFAP, LIMK1, LIMK2, MYL9/MLC2, TPPP, PFN1 and PPP1R12A (PubMed:10436159, PubMed:10652353, PubMed:11018042, PubMed:11283607, PubMed:17158456, PubMed:18573880, PubMed:19131646, PubMed:8617235, PubMed:9722579, PubMed:23093407, PubMed:23355470). Phosphorylates FHOD1 and acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane blebbing (PubMed:18694941). Phosphorylates JIP3 and regulates the recruitment of JNK to JIP3 upon UVB-induced stress (PubMed:19036714). Acts as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability (By similarity). Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation (PubMed:19181962). Required for centrosome positioning and centrosome-dependent exit from mitosis (By similarity). Plays a role in terminal erythroid differentiation (PubMed:21072057). Inhibits podocyte motility via regulation of actin cytoskeletal dynamics and phosphorylation of CFL1 (By similarity). Promotes keratinocyte terminal differentiation (PubMed:19997641). Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process, essential for osteoblast mineralization (By similarity). May regulate closure of the eyelids and ventral body wall by inducing the assembly of actomyosin bundles (By similarity).ACTIVITY REGULATION Activated by RHOA binding. Inhibited by Y-27632.SUBUNIT Homodimer. Interacts with RHOB, RHOC, MYLC2B and PTEN. Interacts with ITGB1BP1 (via N-terminus and PTB domain) (By similarity). Interacts with RHOA (activated by GTP), CHORDC1, DAPK3, GEM, JIP3, RHOE, PPP1R12A, PFN1, LIMK1, LIMK2 and TSG101. Interacts with FHOD1 in a Src-dependent manner. Interacts with SHROOM3 (PubMed:22493320).TISSUE SPECIFICITY Detected in blood platelets.DOMAIN The C-terminal auto-inhibitory domain interferes with kinase activity. RHOA binding leads to a conformation change and activation of the kinase. Truncated ROCK1 is constitutively activated.PTM Autophosphorylated on serine and threonine residues.PTM Cleaved by caspase-3 during apoptosis. This leads to constitutive activation of the kinase and membrane blebbing.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. UniProt Q13464 2 EQUAL 1354 EQUAL Reactome Database ID Release 79 212509 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212509 Reactome R-HSA-212509 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212509.1 ROCK2 Rho-associated protein kinase 2 ROCK2_HUMAN Reactome DB_ID: 419058 UniProt:O75116 ROCK2 ROCK2 KIAA0619 FUNCTION Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus. Plays an important role in generating the circadian rhythm of the aortic myofilament Ca(2+) sensitivity and vascular contractility by modulating the myosin light chain phosphorylation.ACTIVITY REGULATION Activated by RHOA binding. Inhibited by Y-27632 (By similarity).SUBUNIT Homodimer (By similarity). Interacts with IRS1 (By similarity). Interacts with RAF1 (By similarity). Interacts with RHOA (activated by GTP), RHOB and RHOC (By similarity). Interacts with PPP1R12A (PubMed:10579722, PubMed:19131646). Interacts with EP300 (PubMed:16574662). Interacts with CHORDC1 (PubMed:20230755). Interacts with BRCA2 (PubMed:21084279). Interacts with NPM1; this interaction enhances ROCK2 activity (PubMed:17015463). Interacts with SORL1 (PubMed:21147781). Interacts with PJVK (By similarity).TISSUE SPECIFICITY Expressed in the brain (at protein level).DOMAIN An interaction between Thr-414 and Asp-48 is essential for kinase activity and dimerization.PTM Phosphorylation at Tyr-722 reduces its binding to RHOA and is crucial for focal adhesion dynamics. Dephosphorylation by PTPN11 stimulates its RHOA binding activity.PTM Cleaved by granzyme B during apoptosis. This leads to constitutive activation of the kinase and membrane blebbing.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. UniProt O75116 1 EQUAL 1388 EQUAL Reactome Database ID Release 79 419058 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419058 Reactome R-HSA-419058 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419058.1 Reactome Database ID Release 79 419057 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419057 Reactome R-HSA-419057 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419057.1 Activated ROCK:RhoA/B/C:GTP Reactome DB_ID: 422483 1 1 Reactome Database ID Release 79 422483 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=422483 Reactome R-HSA-422483 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-422483.1 Reactome Database ID Release 79 419049 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419049 Reactome R-HSA-419049 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419049.2 15699075 Pubmed 2005 Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner Sebbagh, Michael Hamelin, Jocelyne Bertoglio, Jacques Solary, Eric Breard, Jacqueline J. Exp. Med. 201:465-71 11294240 Pubmed 2001 Arachidonic acid-induced Ca2+ sensitization of smooth muscle contraction through activation of Rho-kinase Araki, S Ito, M Kureishi, Y Feng, J Machida, H Isaka, N Amano, M Kaibuchi, K Hartshorne, D J Nakano, T Pflugers Arch. 441:596-603 8816443 Pubmed 1996 The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton Leung, T Chen, X Q Manser, E Lim, L Mol. Cell. Biol. 16:5313-27 9920927 Pubmed 1999 Rho-associated kinase of chicken gizzard smooth muscle Feng, J Ito, M Kureishi, Y Ichikawa, K Amano, M Isaka, N Okawa, K Iwamatsu, A Kaibuchi, K Hartshorne, DJ Nakano, T J Biol Chem 274:3744-52 12778124 Pubmed 2003 Rocks: multifunctional kinases in cell behaviour Riento, K Ridley, AJ Nat Rev Mol Cell Biol 4:446-56 8617235 Pubmed 1996 The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase Ishizaki, T Maekawa, M Fujisawa, K Okawa, K Iwamatsu, A Fujita, A Watanabe, Nobumoto Saito, Y Kakizuka, A Morii, N Narumiya, S EMBO J 15:1885-93 11283606 Pubmed 2001 Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I Coleman, M L Sahai, E A Yeo, M Bosch, M Dewar, A Olson, M F Nat. Cell Biol. 3:339-45 INHIBITION Reactome Database ID Release 79 9691180 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9691180 ROCK1,ROCK2:ROCKi Reactome DB_ID: 9680444 1 Converted from EntitySet in Reactome ROCKi ROCK inhibitors Reactome DB_ID: 9686558 ripasudil Glanatec&reg; K-115 (ripasudil hydrochloride dihydrate) Reactome DB_ID: 9680440 ripasudil [Guide to Pharmacology:10423] ripasudil Glanatec&reg; K-115 (ripasudil hydrochloride dihydrate) Guide to Pharmacology 10423 Reactome Database ID Release 79 9680440 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9680440 Reactome R-ALL-9680440 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9680440.1 netarsudil Reactome DB_ID: 9686545 netarsudil [Guide to Pharmacology:9322] netarsudil AR11324 AR-11324 ester 60 [PMID: 27072905] Rhokiinsa&reg; Rhopressa&reg; Guide to Pharmacology 9322 Reactome Database ID Release 79 9686545 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9686545 Reactome R-ALL-9686545 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9686545.1 Reactome Database ID Release 79 9686558 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9686558 Reactome R-ALL-9686558 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9686558.1 1 Reactome Database ID Release 79 9680444 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9680444 Reactome R-HSA-9680444 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9680444.1 LEFT-TO-RIGHT ROCK1,2 bind ROCKi Ripasudil (Glanatec), as its hydrochloride hydrate (K-115), is a specifc Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor (ROCKi) used for the treatment of glaucoma and ocular hypertension in Japan (Garnock-Jones 2014). Netarsudil is a USA-approved ROCKi used to treat glaucoma and ocular hypertenstion (Sturdivant et al. 2016, Tanna & Johnson 2018). Authored: Jassal, Bijay, 2020-03-27 Reviewed: Shoichet, Brian, 2020-05-14 Edited: Jassal, Bijay, 2020-03-27 Reactome Database ID Release 79 9680443 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9680443 Reactome R-HSA-9680443 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9680443.1 25414122 Pubmed 2014 Ripasudil: first global approval Garnock-Jones, Karly P Drugs 74:2211-5 30007591 Pubmed 2018 Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension Tanna, Angelo P Johnson, Mark Ophthalmology 125:1741-1756 27072905 Pubmed 2016 Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma Sturdivant, Jill M Royalty, Susan M Lin, Cheng-Wen Moore, Lori A Yingling, Jeffrey D Laethem, Carmen L Sherman, Bryan Heintzelman, Geoffrey R Kopczynski, Casey C deLong, Mitchell A Bioorg. Med. Chem. Lett. 26:2475-2480 LEFT-TO-RIGHT 2.7.11.1 Myosin regulatory light chain phosphorylation by ROCK Nonmuscle myosin II (NMM2) is an actin-based motor protein that plays a crucial role in a variety of cellular processes, including smooth muscle contraction, cell migration, polarity formation, and cytokinesis. NMM2 consists of two myosin heavy chains encoded by MYH9, MYH10, MYH14 (NMHC-IIA, B and C) or MYH11, two copies of MYL6 essential light chain protein, and two regulatory light chains (MRLCs), MYL9 and MYL12B. Myosin II activity is stimulated by phosphorylation of MRLC. Diphosphorylation at Thr-19 and Ser-20 (commonly referred in the literature as Thr-18 and Ser-19) increases both actin-activated Mg2+ ATPase activity and the stability of myosin II filaments; monophosphorylation at Ser-20 is less effective (Ikebe and Hartshorne 1985, Ikebe et al. 1988). Kinases responsible for the phosphorylation include myosin light chain kinase (MLCK), ROCK kinase, citron kinase, myotonic dystrophy kinase-related CDC42-binding protein kinase, and Zipper-interacting protein (ZIP) kinase. ROCK activity has been shown to regulate MRLC phosphorylation by directly mono- or diphosphorylating MRLC (Amano et al., 1996, Ueda et al., 2002, Watanabe et al. 2007). Authored: Akkerman, JW, 2009-06-03 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Reviewed: Rivero Crespo, Francisco, 2014-12-26 Edited: Jupe, S, 2009-05-20 09:50:28 Smooth muscle/non-muscle myosin II Reactome DB_ID: 419194 MYL6 Myosin light polypeptide 6 MYL6_HUMAN Reactome DB_ID: 419186 UniProt:P60660 MYL6 MYL6 FUNCTION Regulatory light chain of myosin. Does not bind calcium.SUBUNIT Myosin is a hexamer of 2 heavy chains and 4 light chains. Interacts with SPATA6. UniProt P60660 2 EQUAL 151 EQUAL Reactome Database ID Release 79 419186 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419186 Reactome R-HSA-419186 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419186.1 2 Converted from EntitySet in Reactome Smooth muscle/non-muscle myosin 2 regulatory light chains Reactome DB_ID: 420895 MYL9 Myosin regulatory light polypeptide 9 MYL9_HUMAN LC20 MLC2 Reactome DB_ID: 390753 UniProt:P24844 MYL9 MYL9 MLC2 MRLC1 MYRL2 FUNCTION Myosin regulatory subunit that plays an important role in regulation of both smooth muscle and nonmuscle cell contractile activity via its phosphorylation. Implicated in cytokinesis, receptor capping, and cell locomotion (PubMed:11942626, PubMed:2526655). In myoblasts, may regulate PIEZO1-dependent cortical actomyosin assembly involved in myotube formation (By similarity).SUBUNIT Myosin is a hexamer of 2 heavy chains and 4 light chains: interacts with myosin heavy chain MYO19.TISSUE SPECIFICITY Smooth muscle tissues and in some, but not all, nonmuscle cells.PTM Phosphorylation increases the actin-activated myosin ATPase activity and thereby regulates the contractile activity. It is required to generate the driving force in the migration of the cells but not necessary for localization of myosin-2 at the leading edge. Phosphorylation is required for myotube formation.MISCELLANEOUS This chain binds calcium. UniProt P24844 2 EQUAL 172 EQUAL Reactome Database ID Release 79 390753 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390753 Reactome R-HSA-390753 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390753.1 MYL12B MYLC2B Myosin regulatory light chain 2-B, smooth muscle isoform MRLC2_HUMAN Reactome DB_ID: 390727 UniProt:O14950 MYL12B MYL12B MRLC2 MYLC2B FUNCTION Myosin regulatory subunit that plays an important role in regulation of both smooth muscle and nonmuscle cell contractile activity via its phosphorylation. Phosphorylation triggers actin polymerization in vascular smooth muscle. Implicated in cytokinesis, receptor capping, and cell locomotion.SUBUNIT Myosin is a hexamer of 2 heavy chains and 4 light chains: interacts with myosin heavy chain MYO19.TISSUE SPECIFICITY Ubiquitously expressed in various hematopoietic cells.PTM Phosphorylation increases the actin-activated myosin ATPase activity and thereby regulates the contractile activity. It is required to generate the driving force in the migration of the cells but not necessary for localization of myosin-2 at the leading edge. Phosphorylation is reduced following epigallocatechin-3-O-gallate treatment.MISCELLANEOUS This chain binds calcium. UniProt O14950 1 EQUAL 172 EQUAL Reactome Database ID Release 79 390727 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390727 Reactome R-HSA-390727 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390727.1 Reactome Database ID Release 79 420895 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=420895 Reactome R-HSA-420895 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-420895.1 2 Converted from EntitySet in Reactome Smooth muscle/non-muscle myosin 2 heavy chains Reactome DB_ID: 419183 MYH10 Myosin-10 MYH10_HUMAN Reactome DB_ID: 419174 UniProt:P35580 MYH10 MYH10 FUNCTION Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping. Involved with LARP6 in the stabilization of type I collagen mRNAs for CO1A1 and CO1A2. During cell spreading, plays an important role in cytoskeleton reorganization, focal contacts formation (in the central part but not the margins of spreading cells), and lamellipodial extension; this function is mechanically antagonized by MYH9.SUBUNIT Myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2). Interacts with PLEKHG6 (PubMed:16721066). Interacts with ECPAS (PubMed:20682791). Interacts with KIF26B (By similarity). Interacts with LARP6 (PubMed:20603131). Interacts with MCC (PubMed:22480440). Interacts with C9orf135 (PubMed:28345668).TISSUE SPECIFICITY Isoform 1 is expressed in cerebellum and spinal chord. Isoform 2 is expressed in cerebrum and retina. Isoform 3 is expressed in the cerebrum and to a much lower extent in cerebellum.DOMAIN The rodlike tail sequence is highly repetitive, showing cycles of a 28-residue repeat pattern composed of 4 heptapeptides, characteristic for alpha-helical coiled coils.PTM Phosphorylated by ABL2.DISEASE Associated with severe intellectual disability, microcephaly, and feeding difficulties as well as cerebral atrophy.SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Myosin family.CAUTION Represents a conventional non-muscle myosin. This protein should not be confused with the unconventional myosin-10 (MYO10). UniProt P35580 1 EQUAL 1976 EQUAL Reactome Database ID Release 79 419174 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419174 Reactome R-HSA-419174 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419174.1 MYH14 Myosin-14 MYH14_HUMAN Reactome DB_ID: 419176 UniProt:Q7Z406 MYH14 MYH14 KIAA2034 FP17425 FUNCTION Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping.SUBUNIT Myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2).TISSUE SPECIFICITY High levels of expression are found in brain (highest in corpus callosum), heart, kidney, liver, lung, small intestine, colon and skeletal muscle. Expression is low in organs composed mainly of smooth muscle, such as aorta, uterus and urinary bladder. No detectable expression is found in thymus, spleen, placenta and lymphocytes.DOMAIN The rodlike tail sequence is highly repetitive, showing cycles of a 28-residue repeat pattern composed of 4 heptapeptides, characteristic for alpha-helical coiled coils.SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Myosin family. UniProt Q7Z406 2 EQUAL 1995 EQUAL Reactome Database ID Release 79 419176 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419176 Reactome R-HSA-419176 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419176.1 MYH9 Myosin-9 MYH9_HUMAN Reactome DB_ID: 419173 UniProt:P35579 MYH9 MYH9 FUNCTION Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping. Required for cortical actin clearance prior to oocyte exocytosis (By similarity). Promotes cell motility in conjunction with S100A4 (PubMed:16707441). During cell spreading, plays an important role in cytoskeleton reorganization, focal contact formation (in the margins but not the central part of spreading cells), and lamellipodial retraction; this function is mechanically antagonized by MYH10 (PubMed:20052411).SUBUNIT Myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2). Interacts with RASIP1 (By similarity). Interacts with DDR1 (By similarity). Interacts with PDLIM2 (By similarity). Interacts with SVIL (PubMed:12917436, PubMed:17925381). Interacts with HTRA3 (PubMed:22229724). Interacts with Myo7a (By similarity). Interacts with C9orf135 (PubMed:28345668). Interacts with LIMCH1; independently of the integration of MYH9 into the myosin complex (PubMed:28228547). Interacts with RAB3A (PubMed:27325790). Interacts with ZBED4 (PubMed:22693546). Interacts with S100A4; this interaction increases cell motility (PubMed:16707441).TISSUE SPECIFICITY In the kidney, expressed in the glomeruli. Also expressed in leukocytes.DOMAIN The rodlike tail sequence is highly repetitive, showing cycles of a 28-residue repeat pattern composed of 4 heptapeptides, characteristic for alpha-helical coiled coils.PTM ISGylated.PTM Ubiquitination.DISEASE Subjects with mutations in the motor domain of MYH9 present with severe thrombocytopenia and develop nephritis and deafness before the age of 40 years, while those with mutations in the tail domain have a much lower risk of noncongenital complications and significantly higher platelet counts. The clinical course of patients with mutations in the four most frequently affected residues of MYH9 (responsible for 70% of MYH9-related cases) were evaluated. Mutations at residue 1933 do not induce kidney damage or cataracts and cause deafness only in the elderly, those in position 702 result in severe thrombocytopenia and produce nephritis and deafness at a juvenile age, while alterations at residue 1424 or 1841 result in intermediate clinical pictures.DISEASE Genetic variations in MYH9 are associated with non-diabetic end stage renal disease (ESRD).SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Myosin family. UniProt P35579 2 EQUAL 1960 EQUAL Reactome Database ID Release 79 419173 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419173 Reactome R-HSA-419173 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419173.1 MYH11 Myosin-11 MYH11_HUMAN Reactome DB_ID: 420855 UniProt:P35749 MYH11 MYH11 KIAA0866 FUNCTION Muscle contraction.SUBUNIT Muscle myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2).TISSUE SPECIFICITY Smooth muscle; expressed in the umbilical artery, bladder, esophagus and trachea. Isoform 1 is mostly found in slowly contracting tonic muscles.DOMAIN The rodlike tail sequence is highly repetitive, showing cycles of a 28-residue repeat pattern composed of 4 heptapeptides, characteristic for alpha-helical coiled coils.DOMAIN Limited proteolysis of myosin heavy chain produces 1 light meromyosin (LMM) and 1 heavy meromyosin (HMM). HMM can be further cleaved into 2 globular subfragments (S1) and 1 rod-shaped subfragment (S2).DISEASE A chromosomal aberration involving MYH11 is found in acute myeloid leukemia of M4EO subtype. Pericentric inversion inv(16)(p13;q22). The inversion produces a fusion protein consisting of the 165 N-terminal residues of CBF-beta (PEPB2) and the tail region of MYH11.SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Myosin family. UniProt P35749 1 EQUAL 1972 EQUAL Reactome Database ID Release 79 420855 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=420855 Reactome R-HSA-420855 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-420855.1 Reactome Database ID Release 79 419183 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419183 Reactome R-HSA-419183 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419183.1 2 Reactome Database ID Release 79 419194 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419194 Reactome R-HSA-419194 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419194.1 p-T19,S20-MRLC-smooth muscle/non-muscle myosin II Phospho-activated smooth muscle/non-muscle myosin 2 Reactome DB_ID: 419195 2 Converted from EntitySet in Reactome Phosphorylated smooth muscle/non-muscle myosin 2 regulatory light chains Reactome DB_ID: 421613 p-T19,S20-MYL12B Phosphorylated Myosin regulatory light chain 2-B, smooth muscle isoform Reactome DB_ID: 390751 20 EQUAL O-phospho-L-serine MOD MOD:00046 19 EQUAL O-phospho-L-threonine MOD MOD:00047 1 EQUAL 172 EQUAL Reactome Database ID Release 79 390751 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390751 Reactome R-HSA-390751 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390751.1 p-MYL9 p-T19,S20-MYL9 p-S20,T19-MYL9 Phosphorylated Myosin regulatory light polypeptide 9 Reactome DB_ID: 390752 20 EQUAL 19 EQUAL 2 EQUAL 172 EQUAL Reactome Database ID Release 79 390752 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390752 Reactome R-HSA-390752 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390752.1 Reactome Database ID Release 79 421613 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=421613 Reactome R-HSA-421613 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-421613.1 2 2 Reactome Database ID Release 79 419195 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419195 Reactome R-HSA-419195 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419195.1 ACTIVATION GENE ONTOLOGY GO:0004674 Reactome Database ID Release 79 419084 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419084 Reactome Database ID Release 79 419197 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419197 Reactome R-HSA-419197 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419197.1 17151359 Pubmed 2007 Regulation of myosin II dynamics by phosphorylation and dephosphorylation of its light chain in epithelial cells Watanabe, T Hosoya, H Yonemura, S Mol Biol Cell 18:605-16 8702756 Pubmed 1996 Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase) Amano, M Ito, M Kimura, K Fukata, Y Chihara, K Nakano, T Matsuura, Y Kaibuchi, K J Biol Chem 271:20246-9 2966156 Pubmed 1988 Effects of phosphorylation of light chain residues threonine 18 and serine 19 on the properties and conformation of smooth muscle myosin Ikebe, M Koretz, J Hartshorne, D J J. Biol. Chem. 263:6432-7 12185584 Pubmed 2002 Rho-kinase contributes to diphosphorylation of myosin II regulatory light chain in nonmuscle cells Ueda, K Murata-Hori, M Tatsuka, M Hosoya, H Oncogene 21:5852-60 3839510 Pubmed 1985 Phosphorylation of smooth muscle myosin at two distinct sites by myosin light chain kinase Ikebe, M Hartshorne, D J J. Biol. Chem. 260:10027-31 LEFT-TO-RIGHT 2.7.11.1 LIM kinase phosphorylation by ROCK LIM kinases are serine protein kinases with a unique combination of two N-terminal LIM motifs, a central PDZ domain, and a C-terminal protein kinase domain. ROCK1 and ROCK2 phosphorylate and activate LIM kinases LIMK1 and LIMK2 at Thr508 and Thr505, respectively (Ohashi et al. 2000, Sumi et al. 2001). These threonine residues lay within the activation loop of the kinase domain. LIMKs phosphorylate and inactivate cofilin, an actin depolymerizing factor, resulting in stabilization of the actin cytoskeleton (Pandey et al. 2006). Authored: Akkerman, JW, 2009-06-03 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Reviewed: Rivero Crespo, Francisco, 2014-12-26 Edited: Jupe, S, 2009-04-28 12:55:15 Converted from EntitySet in Reactome LIM Kinases Reactome DB_ID: 419708 LIMK1 LIM domain kinase 1 (LIMK-1) LIMK1_HUMAN Reactome DB_ID: 397785 UniProt:P53667 LIMK1 LIMK1 LIMK FUNCTION Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways (PubMed:10436159, PubMed:11832213, PubMed:12807904, PubMed:15660133, PubMed:16230460, PubMed:18028908, PubMed:22328514, PubMed:23633677). Activated by upstream kinases including ROCK1, PAK1 and PAK4, which phosphorylate LIMK1 on a threonine residue located in its activation loop (PubMed:10436159). LIMK1 subsequently phosphorylates and inactivates the actin binding/depolymerizing factors cofilin-1/CFL1, cofilin-2/CFL2 and destrin/DSTN, thereby preventing the cleavage of filamentous actin (F-actin), and stabilizing the actin cytoskeleton (PubMed:11832213, PubMed:15660133, PubMed:16230460, PubMed:23633677). In this way LIMK1 regulates several actin-dependent biological processes including cell motility, cell cycle progression, and differentiation (PubMed:11832213, PubMed:15660133, PubMed:16230460, PubMed:23633677). Phosphorylates TPPP on serine residues, thereby promoting microtubule disassembly (PubMed:18028908). Stimulates axonal outgrowth and may be involved in brain development (PubMed:18028908).SUBUNIT Interacts (via LIM domain) with the cytoplasmic domain of NRG1. Interacts with NISCH. Interacts with RLIM and RNF6 (By similarity). Self-associates to form homodimers (PubMed:10196227). Interacts with HSP90AA1; this interaction promotes LIMK1 dimerization and subsequent transphosphorylation (PubMed:16641196). Interacts with CDKN1C (PubMed:14530263). Interacts with SSH1 (PubMed:15660133). Interacts with ROCK1 (PubMed:10436159, PubMed:10652353). Interacts (via LIM zinc-binding domains) with FAM89B/LRAP25 (via LRR repeat). Forms a tripartite complex with CDC42BPA, CDC42BPB and FAM89B/LRAP25 (By similarity).TISSUE SPECIFICITY Highest expression in both adult and fetal nervous system. Detected ubiquitously throughout the different regions of adult brain, with highest levels in the cerebral cortex. Expressed to a lesser extent in heart and skeletal muscle.PTM Autophosphorylated. Phosphorylated on Thr-508 by ROCK1 and PAK1, resulting in activation. Phosphorylated by PAK4 which increases the ability of LIMK1 to phosphorylate cofilin. Phosphorylated at Ser-323 by MAPKAPK2 during activation of VEGFA-induced signaling, which results in activation of LIMK1 and promotion of actin reorganization, cell migration, and tubule formation of endothelial cells. Dephosphorylated and inactivated by SSH1. Phosphorylated by CDC42BP.PTM Ubiquitinated. 'Lys-48'-linked polyubiquitination by RNF6 leads to proteasomal degradation through the 26S proteasome, modulating LIMK1 levels in the growth cone and its effect on axonal outgrowth. Also polyubiquitinated by RLIM (By similarity).DISEASE LIMK1 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. UniProt P53667 1 EQUAL 647 EQUAL Reactome Database ID Release 79 397785 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=397785 Reactome R-HSA-397785 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-397785.1 LIMK2 LIM domain kinase 2 LIMK2_HUMAN Reactome DB_ID: 419171 UniProt:P53671 LIMK2 LIMK2 FUNCTION Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics (PubMed:10436159, PubMed:11018042). Acts downstream of several Rho family GTPase signal transduction pathways (PubMed:10436159, PubMed:11018042). Involved in astral microtubule organization and mitotic spindle orientation during early stages of mitosis by mediating phosphorylation of TPPP (PubMed:22328514). Displays serine/threonine-specific phosphorylation of myelin basic protein and histone (MBP) in vitro (PubMed:8537403). Suppresses ciliogenesis via multiple pathways; phosphorylation of CFL1, suppression of directional trafficking of ciliary vesicles to the ciliary base, and by facilitating YAP1 nuclear localization where it acts as a transcriptional corepressor of the TEAD4 target genes AURKA and PLK1 (PubMed:25849865).SUBUNIT Binds ROCK1 and MARF1 (Ref.9, PubMed:11018042, PubMed:10436159). Interacts with NISCH (By similarity).PTM Phosphorylated on serine and/or threonine residues by ROCK1.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. UniProt P53671 1 EQUAL 638 EQUAL Reactome Database ID Release 79 419171 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419171 Reactome R-HSA-419171 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419171.1 Reactome Database ID Release 79 419708 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419708 Reactome R-HSA-419708 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419708.1 Converted from EntitySet in Reactome p-LIMK Reactome DB_ID: 419709 p-T508-LIMK1 Reactome DB_ID: 399816 508 EQUAL 1 EQUAL 647 EQUAL Reactome Database ID Release 79 399816 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399816 Reactome R-HSA-399816 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399816.1 LIMK2 p-T505-LIMK2 LIM domain kinase 2, phosphorylated (Thr-505) LIMK2_HUMAN Reactome DB_ID: 419711 505 EQUAL 1 EQUAL 638 EQUAL Reactome Database ID Release 79 419711 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419711 Reactome R-HSA-419711 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419711.1 Reactome Database ID Release 79 419709 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419709 Reactome R-HSA-419709 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419709.1 ACTIVATION Reactome Database ID Release 79 419087 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419087 Reactome R-HSA-419087 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419087.1 11018042 Pubmed 2001 Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase Sumi, T Matsumoto, K Nakamura, T J Biol Chem 276:670-6 10652353 Pubmed 2000 Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop Ohashi, Ken Nagata, K Maekawa, M Ishizaki, T Narumiya, S Mizuno, K J Biol Chem 275:3577-82 16219803 Pubmed 2006 Regulation of LIM-kinase 1 and cofilin in thrombin-stimulated platelets Pandey, D Goyal, P Bamburg, JR Siess, W Blood 107:575-83 Reactome Database ID Release 79 416572 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416572 Reactome R-HSA-416572 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416572.3 15818466 Pubmed 2005 Plexins: axon guidance and signal transduction Negishi, M Oinuma, I Katoh, H Cell Mol Life Sci 62:1363-71 Reactome Database ID Release 79 400685 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400685 Reactome R-HSA-400685 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400685.2 SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion Sema3A, a prototypical semaphorin, acts as a chemorepellent or a chemoattractant for axons by activating a receptor complex comprising neuropilin-1 as the ligand-binding subunit and plexin-A1 as the signal-transducing subunit. Sema3A inhibits cell migration by inhibiting integrin ligand-binding activity. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:38 LEFT-TO-RIGHT Plexin-A1-4 binds NRP1 The best characterized receptors for mediating semaphorin signaling are members of the neuropilin and plexin families of transmembrane proteins. Neuropilins form complexes with Plexin-A which in turn can act as a signaling moiety. Also, when complexed with neuropilin-1, plexin-A1 can associate directly with the FERM domain containing guanine nucleotide exchange factor (GEF) FARP2. FARP2 exerts GEF activity for Rac but not Cdc42 and Rho. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 FARP2 RhoGEF and pleckstrin domain-containing protein 2 (FARP2) FARP2_HUMAN Reactome DB_ID: 396935 UniProt:O94887 FARP2 FARP2 KIAA0793 PLEKHC3 FUNCTION Functions as guanine nucleotide exchange factor that activates RAC1. May have relatively low activity. Plays a role in the response to class 3 semaphorins and remodeling of the actin cytoskeleton. Plays a role in TNFSF11-mediated osteoclast differentiation, especially in podosome rearrangement and reorganization of the actin cytoskeleton. Regulates the activation of ITGB3, integrin signaling and cell adhesion (By similarity).SUBUNIT Interacts with PLXNA1. Interaction with PLXNA1 or PIP5K1C lowers its guanine nucleotide exchange activity. Dissociates from PLXNA1 when SEMA3A binds to the receptor. Interacts with PIP5K1C via its FERM domain. The interaction with PIP5K1C is enhanced by SEMA3A binding. Interacts with RAC1 (By similarity).DOMAIN Intramolecular interaction between the DH domain and the PH domains can stabilize the protein in an autoinhibited conformation. UniProt O94887 1 EQUAL 1054 EQUAL Reactome Database ID Release 79 396935 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=396935 Reactome R-HSA-396935 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-396935.1 Plexin-A1-4:FYN Reactome DB_ID: 399844 FYN Fyn Reactome DB_ID: 200917 UniProt:P06241 FYN FYN FUNCTION Non-receptor tyrosine-protein kinase that plays a role in many biological processes including regulation of cell growth and survival, cell adhesion, integrin-mediated signaling, cytoskeletal remodeling, cell motility, immune response and axon guidance. Inactive FYN is phosphorylated on its C-terminal tail within the catalytic domain. Following activation by PKA, the protein subsequently associates with PTK2/FAK1, allowing PTK2/FAK1 phosphorylation, activation and targeting to focal adhesions. Involved in the regulation of cell adhesion and motility through phosphorylation of CTNNB1 (beta-catenin) and CTNND1 (delta-catenin). Regulates cytoskeletal remodeling by phosphorylating several proteins including the actin regulator WAS and the microtubule-associated proteins MAP2 and MAPT. Promotes cell survival by phosphorylating AGAP2/PIKE-A and preventing its apoptotic cleavage. Participates in signal transduction pathways that regulate the integrity of the glomerular slit diaphragm (an essential part of the glomerular filter of the kidney) by phosphorylating several slit diaphragm components including NPHS1, KIRREL1 and TRPC6. Plays a role in neural processes by phosphorylating DPYSL2, a multifunctional adapter protein within the central nervous system, ARHGAP32, a regulator for Rho family GTPases implicated in various neural functions, and SNCA, a small pre-synaptic protein. Participates in the downstream signaling pathways that lead to T-cell differentiation and proliferation following T-cell receptor (TCR) stimulation. Phosphorylates PTK2B/PYK2 in response to T-cell receptor activation. Also participates in negative feedback regulation of TCR signaling through phosphorylation of PAG1, thereby promoting interaction between PAG1 and CSK and recruitment of CSK to lipid rafts. CSK maintains LCK and FYN in an inactive form. Promotes CD28-induced phosphorylation of VAV1. In mast cells, phosphorylates CLNK after activation of immunoglobulin epsilon receptor signaling (By similarity).ACTIVITY REGULATION Inhibited by phosphorylation of Tyr-531 by leukocyte common antigen and activated by dephosphorylation of this site.SUBUNIT Interacts (via its SH3 domain) with PIK3R1 and PRMT8. Interacts with FYB1, PAG1, and SH2D1A. Interacts with CD79A (tyrosine-phosphorylated form); the interaction increases FYN activity. Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated) (By similarity). Interacts with TOM1L1 (phosphorylated form). Interacts with KDR (tyrosine phosphorylated). Interacts (via SH3 domain) with KLHL2 (via N-terminus) (By similarity). Interacts with SH2D1A and SLAMF1. Interacts with ITCH; the interaction phosphorylates ITCH and negatively regulates its activity. Interacts with FASLG. Interacts with RUNX3. Interacts with KIT. Interacts with EPHA8; possible downstream effector of EPHA8 in regulation of cell adhesion. Interacts with PTK2/FAK1; this interaction leads to PTK2/FAK1 phosphorylation and activation. Interacts with CAV1; this interaction couples integrins to the Ras-ERK pathway. Interacts with UNC119. Interacts (via SH2 domain) with PTPRH (phosphorylated form) (By similarity). Interacts with PTPRO (phosphorylated form) (By similarity). Interacts with PTPRB (phosphorylated form) (By similarity). Interacts with FYB2 (PubMed:27335501). Interacts with DSCAM (By similarity). Interacts with SKAP1 and FYB1; this interaction promotes the phosphorylation of CLNK (By similarity).SUBUNIT (Microbial infection) Interacts (via its SH3 domain) with hepatitis E virus/HEV protein ORF3.TISSUE SPECIFICITY Isoform 1 is highly expressed in the brain. Isoform 2 is expressed in cells of hemopoietic lineages, especially T-lymphocytes.PTM Autophosphorylated at Tyr-420 (By similarity). Phosphorylation on the C-terminal tail at Tyr-531 by CSK maintains the enzyme in an inactive state (PubMed:1699196). PTPRC/CD45 dephosphorylates Tyr-531 leading to activation (PubMed:1533589). Ultraviolet B (UVB) strongly increase phosphorylation at Thr-12 and kinase activity, and promotes translocation from the cytoplasm to the nucleus (PubMed:15537652). Dephosphorylation at Tyr-420 by PTPN2 negatively regulates T-cell receptor signaling (PubMed:22080863). Phosphorylated at tyrosine residues, which can be enhanced by NTN1 (By similarity).PTM Palmitoylated. Palmitoylation at Cys-3 and Cys-6, probably by ZDHHC21, regulates subcellular location.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. UniProt P06241 2 EQUAL 537 EQUAL Reactome Database ID Release 79 200917 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200917 Reactome R-HSA-200917 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-200917.2 1 Converted from EntitySet in Reactome Plexin-A1-4 Reactome DB_ID: 399833 PLXNA1 Plexin-A1 PLXA1_HUMAN Reactome DB_ID: 396932 UniProt:Q9UIW2 PLXNA1 PLXNA1 NOV PLXN1 FUNCTION Coreceptor for SEMA3A, SEMA3C, SEMA3F and SEMA6D. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance, invasive growth and cell migration. Class 3 semaphorins bind to a complex composed of a neuropilin and a plexin. The plexin modulates the affinity of the complex for specific semaphorins, and its cytoplasmic domain is required for the activation of down-stream signaling events in the cytoplasm (By similarity).SUBUNIT Interacts directly with NRP1 and NRP2. Interacts with FARP2, RND1 and KDR/VEGFR2. Binding of SEMA3A leads to dissociation of FARP2 (By similarity).TISSUE SPECIFICITY Detected in fetal brain, lung, liver and kidney.SIMILARITY Belongs to the plexin family. UniProt Q9UIW2 27 EQUAL 1896 EQUAL Reactome Database ID Release 79 396932 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=396932 Reactome R-HSA-396932 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-396932.1 PLXNA2 Plexin-A2 PLXA2_HUMAN Reactome DB_ID: 396934 UniProt:O75051 PLXNA2 PLXNA2 KIAA0463 OCT PLXN2 UNQ209/PRO235 FUNCTION Coreceptor for SEMA3A and SEMA6A. Necessary for signaling by SEMA6A and class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance, invasive growth and cell migration. Class 3 semaphorins bind to a complex composed of a neuropilin and a plexin. The plexin modulates the affinity of the complex for specific semaphorins, and its cytoplasmic domain is required for the activation of down-stream signaling events in the cytoplasm (By similarity).SUBUNIT Homodimer. The PLXNA2 homodimer interacts with a SEMA6A homodimer, giving rise to a heterotetramer. Interacts directly with NRP1 and NRP2 (By similarity). Interacts with RND1.TISSUE SPECIFICITY Detected in fetal brain.SIMILARITY Belongs to the plexin family. UniProt O75051 35 EQUAL 1894 EQUAL Reactome Database ID Release 79 396934 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=396934 Reactome R-HSA-396934 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-396934.1 PLXNA3 Plexin-A3 PLXA3_HUMAN Reactome DB_ID: 399734 UniProt:P51805 PLXNA3 PLXNA3 PLXN4 SEX FUNCTION Coreceptor for SEMA3A and SEMA3F. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance in the developing nervous system. Regulates the migration of sympathetic neurons, but not of neural crest precursors. Required for normal dendrite spine morphology in pyramidal neurons. May play a role in regulating semaphorin-mediated programmed cell death in the developing nervous system. Class 3 semaphorins bind to a complex composed of a neuropilin and a plexin. The plexin modulates the affinity of the complex for specific semaphorins, and its cytoplasmic domain is required for the activation of down-stream signaling events in the cytoplasm.SUBUNIT Interacts with CBFA2T3/MTG16.SIMILARITY Belongs to the plexin family. UniProt P51805 20 EQUAL 1871 EQUAL Reactome Database ID Release 79 399734 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399734 Reactome R-HSA-399734 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399734.1 PLXNA4 Plexin-A4 PLXA4_HUMAN Reactome DB_ID: 399736 UniProt:Q9HCM2 PLXNA4 PLXNA4 KIAA1550 PLXNA4A PLXNA4B UNQ2820/PRO34003 FUNCTION Coreceptor for SEMA3A. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance in the developing nervous system. Class 3 semaphorins bind to a complex composed of a neuropilin and a plexin. The plexin modulates the affinity of the complex for specific semaphorins, and its cytoplasmic domain is required for the activation of down-stream signaling events in the cytoplasm (By similarity).SUBUNIT Interacts with NRP1 and NRP2.SIMILARITY Belongs to the plexin family. UniProt Q9HCM2 24 EQUAL 1894 EQUAL Reactome Database ID Release 79 399736 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399736 Reactome R-HSA-399736 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399736.1 Reactome Database ID Release 79 399833 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399833 Reactome R-HSA-399833 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399833.1 1 Reactome Database ID Release 79 399844 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399844 Reactome R-HSA-399844 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399844.1 NRP1 Neuropilin-1 NRP1_HUMAN Reactome DB_ID: 3008773 UniProt:O14786 NRP1 NRP1 NRP VEGF165R FUNCTION Cell-surface receptor involved in the development of the cardiovascular system, in angiogenesis, in the formation of certain neuronal circuits and in organogenesis outside the nervous system. Mediates the chemorepulsant activity of semaphorins (PubMed:9288753, PubMed:9529250, PubMed:10688880). Recognizes a C-end rule (CendR) motif R/KXXR/K on its ligands which causes cellular internalization and vascular leakage (PubMed:19805273). It binds to semaphorin 3A, the PLGF-2 isoform of PGF, the VEGF165 isoform of VEGFA and VEGFB (PubMed:9288753, PubMed:9529250, PubMed:10688880, PubMed:19805273). Coexpression with KDR results in increased VEGF165 binding to KDR as well as increased chemotaxis. Regulates VEGF-induced angiogenesis. Binding to VEGFA initiates a signaling pathway needed for motor neuron axon guidance and cell body migration, including for the caudal migration of facial motor neurons from rhombomere 4 to rhombomere 6 during embryonic development (By similarity). Regulates mitochondrial iron transport via interaction with ABCB8/MITOSUR (PubMed:30623799).FUNCTION (Microbial infection) Acts as a host factor for human coronavirus SARS-CoV-2 infection. Recognizes and binds to CendR motif RRAR on SARS-CoV-2 spike protein S1 which enhances SARS-CoV-2 infection.SUBUNIT Homodimer, and heterodimer with NRP2 (PubMed:17989695). Interacts with FER (By similarity). Interacts with PLXNB1 (PubMed:10520995). Interacts with VEGFA (PubMed:26503042, PubMed:19805273). Interacts with ABCB8/MITOSUR in mitochondria (PubMed:30623799).SUBUNIT (Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 spike protein S1 (via the CendR motif RRAR).DOMAIN The tandem CUB domains mediate binding to semaphorin, while the tandem F5/8 domains are responsible for heparin and VEGF binding. F5/8 domains mediate the recognition and binding to R/KXXR/K CendR motifs (PubMed:19805273, PubMed:33082294).SIMILARITY Belongs to the neuropilin family. UniProt O14786 22 EQUAL 923 EQUAL Reactome Database ID Release 79 3008773 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3008773 Reactome R-HSA-3008773 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3008773.1 NRP1:PlexinA1-4:FARP2:FYN Reactome DB_ID: 399837 Plexin-A1-4:FYN:FARP2 Reactome DB_ID: 421116 1 1 Reactome Database ID Release 79 421116 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=421116 Reactome R-HSA-421116 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-421116.1 1 1 Reactome Database ID Release 79 399837 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399837 Reactome R-HSA-399837 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399837.1 Reactome Database ID Release 79 399942 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399942 Reactome R-HSA-399942 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399942.1 10520994 Pubmed 1999 Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors Takahashi, T Fournier, A Nakamura, F Wang, LH Murakami, Y Kalb, RG Fujisawa, H Strittmatter, SM Cell 99:59-69 LEFT-TO-RIGHT Sema3A binds Nrp-1 bound to PlexinA Although neuropilin-1 is required for Sema-3A action, it is incapable of transmitting a Sema-3A signal to the growth cone interior. The function of Sema-3A is mediated by Plexins. Sema-3A binds with high affinity to Plexin when the latter is complexed with Neuropilin-1. <br>Plexin-A1 is known to act as an R-Ras GAP (GTPase activating protein) when bound by Sema-3A. Plexin's GAP activity is regulated by FARP2 mediated Rac1 activation. Sema-3A binding to neuropilin-1/Plexin-A1 seems to induce a conformational change of plexin-A1 necessary for releasing FARP2. This suggests that neuropilin1 is required not only for ligand binding, but also for signaling, by modulating the interaction of FARP2 with plexin-A1. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 Sema3A dimer Reactome DB_ID: 399861 extracellular region GENE ONTOLOGY GO:0005576 SEMA3A Semaphorin 3A SM3A_HUMAN Reactome DB_ID: 198235 UniProt:Q14563 SEMA3A SEMA3A SEMAD FUNCTION Involved in the development of the olfactory system and in neuronal control of puberty. Induces the collapse and paralysis of neuronal growth cones. Could serve as a ligand that guides specific growth cones by a motility-inhibiting mechanism. Binds to the complex neuropilin-1/plexin-1.SUBUNIT Interacts with PLXND1.TISSUE SPECIFICITY Expressed in the dorsal root ganglia.DOMAIN Strong binding to neuropilin is mediated by the carboxy third of the protein.SIMILARITY Belongs to the semaphorin family. UniProt Q14563 21 EQUAL 771 EQUAL Reactome Database ID Release 79 198235 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198235 Reactome R-HSA-198235 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198235.1 2 Reactome Database ID Release 79 399861 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399861 Reactome R-HSA-399861 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399861.1 Sema3A:Nrp-1:Plexin A:Fyn Reactome DB_ID: 399858 NRP1:Plexin-A1-4:FYN Reactome DB_ID: 399841 1 1 1 Reactome Database ID Release 79 399841 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399841 Reactome R-HSA-399841 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399841.1 1 1 Reactome Database ID Release 79 399858 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399858 Reactome R-HSA-399858 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399858.1 Reactome Database ID Release 79 399933 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399933 Reactome R-HSA-399933 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399933.1 10679438 Pubmed 2000 Semaphorins and their receptors in vertebrates and invertebrates Raper, JA Curr Opin Neurobiol 10:88-94 16286926 Pubmed 2005 FARP2 triggers signals for Sema3A-mediated axonal repulsion Toyofuku, T Yoshida, J Sugimoto, T Zhang, H Kumanogoh, Atsushi Hori, M Kikutani, Hitoshi Nat Neurosci 8:1712-9 LEFT-TO-RIGHT 2.7.10.2 Phosphorylation of Plexin-A Sema3A binding to Neuropilin-1:Plexin-A complex results in conformational change of plexin-A and this conformational change permits Fes nonreceptor tyrosine kinase to bind and phosphorylate Plexin-A. The specific tyrosine residues phosphorylated in the cytoplasmic domain of plexins in response to semaphorin stimulation have not yet been identified. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 FES Proto-oncogene tyrosine-protein kinase Fes/Fps FES_HUMAN Reactome DB_ID: 396937 UniProt:P07332 FES FES FPS FUNCTION Tyrosine-protein kinase that acts downstream of cell surface receptors and plays a role in the regulation of the actin cytoskeleton, microtubule assembly, cell attachment and cell spreading. Plays a role in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Acts down-stream of the activated FCER1 receptor and the mast/stem cell growth factor receptor KIT. Plays a role in the regulation of mast cell degranulation. Plays a role in the regulation of cell differentiation and promotes neurite outgrowth in response to NGF signaling. Plays a role in cell scattering and cell migration in response to HGF-induced activation of EZR. Phosphorylates BCR and down-regulates BCR kinase activity. Phosphorylates HCLS1/HS1, PECAM1, STAT3 and TRIM28.ACTIVITY REGULATION Kinase activity is tightly regulated. Activated in response to signaling from a cell surface receptor. Activation probably requires binding of a substrate via the SH2 domain, plus autophosphorylation at Tyr-713. Present in an inactive form in the absence of activating stimuli.SUBUNIT Homooligomer. Interacts with BCR. Interacts (when activated, via coiled coil domain) with TRIM28. Interacts (via SH2 domain) with phosphorylated EZR, MS4A2/FCER1B and HCLS1/HS1. Interacts with phosphorylated KIT. Interacts with FLT3. Interacts (via F-BAR domain) with soluble tubulin. Interacts (via SH2 domain) with microtubules.TISSUE SPECIFICITY Widely expressed. Detected in adult colon epithelium (at protein level) (PubMed:16455651, PubMed:19051325). Expressed in melanocytes (at protein level) (PubMed:28463229).DOMAIN The coiled coil domains are important for regulating the kinase activity. They mediate homooligomerization and probably also interaction with other proteins.DOMAIN The N-terminal region including the first coiled coil domain mediates interaction with phosphoinositide-containing membranes.PTM Autophosphorylated on Tyr-713. Phosphorylated by LYN in response to FCER1 activation. Phosphorylated by HCK.DISEASE Has been shown to act as proto-oncogene in some types of cancer, possibly due to abnormal activation of the kinase. Has been shown to act as tumor suppressor in other types of cancer. Expressed and present as activated kinase in a subset of acute myeloid leukemia patients; promotes survival of leukemia cells (PubMed:20111072). Expression is absent in K562 leukemia cells; ectopic expression of FSP/FES restores myeloid differentiation (PubMed:2656706). May function as tumor suppressor in colorectal cancer; expression is reduced or absent in samples from some colon cancer patients (PubMed:16455651). May function as tumor suppressor in melanoma by preventing melanoma cell proliferation; expression is reduced or absent in samples from some melanoma patients (PubMed:28463229). Ectopic expression of FSP/FES suppresses anchorage-independent growth in colon cancer cell lines (PubMed:16455651). Up-regulated in prostate cancer, and might be a predictor of recurrence after radical surgery (PubMed:16455651). May promote growth of renal carcinoma cells (PubMed:19082481).MISCELLANEOUS Cellular homolog of retroviral oncogenes. In contrast to the viral oncoproteins, the kinase activity of cellular FSP/FES is tightly regulated, and the kinase is inactive in normal cells in the absence of activating stimuli (PubMed:15485904).SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. Fes/fps subfamily. UniProt P07332 1 EQUAL 822 EQUAL Reactome Database ID Release 79 396937 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=396937 Reactome R-HSA-396937 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-396937.1 Sema3A:NRP-1:pPlexin-A:Fyn:Fes Reactome DB_ID: 399859 Sema3A:NRP-1:pPlexin-A:fyn Reactome DB_ID: 419622 1 NRP1:p-Plexin-A1-4:FYN Reactome DB_ID: 419625 Converted from EntitySet in Reactome p-Plexin-A1-4 Reactome DB_ID: 419620 p-Y-PLXNA1 phosphorylated Plexin-A1 Reactome DB_ID: 419614 27 EQUAL 1896 EQUAL Reactome Database ID Release 79 419614 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419614 Reactome R-HSA-419614 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419614.1 p-Y-PLXNA2 phosphorylated Plexin-A2 Reactome DB_ID: 419607 35 EQUAL 1894 EQUAL Reactome Database ID Release 79 419607 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419607 Reactome R-HSA-419607 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419607.1 p-Y-PLXNA3 phosphorylated Plexin-A3 Reactome DB_ID: 419604 20 EQUAL 1871 EQUAL Reactome Database ID Release 79 419604 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419604 Reactome R-HSA-419604 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419604.1 p-Y-PLXNA4 phosphorylated Plexin-A4 Reactome DB_ID: 419608 24 EQUAL 1894 EQUAL Reactome Database ID Release 79 419608 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419608 Reactome R-HSA-419608 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419608.1 Reactome Database ID Release 79 419620 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419620 Reactome R-HSA-419620 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419620.1 1 1 1 Reactome Database ID Release 79 419625 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419625 Reactome R-HSA-419625 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419625.1 1 Reactome Database ID Release 79 419622 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419622 Reactome R-HSA-419622 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419622.1 1 1 Reactome Database ID Release 79 399859 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399859 Reactome R-HSA-399859 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399859.1 ACTIVATION Reactome Database ID Release 79 421150 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=421150 Reactome Database ID Release 79 399934 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399934 Reactome R-HSA-399934 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399934.1 12093729 Pubmed 2002 Involvement of Fes/Fps tyrosine kinase in semaphorin3A signaling Mitsui, N Inatome, R Takahashi, S Goshima, Y Yamamura, H Yanagi, S EMBO J 21:3274-85 18660749 Pubmed 2008 Tyrosine phosphorylation in semaphorin signalling: shifting into overdrive Franco, M Tamagnone, L EMBO Rep 9:865-71 LEFT-TO-RIGHT Activation of Rac1 by FARP2 Sema3A-mediated dissociation of FARP2 from Plexin-A is followed by activation of Rac1 by the GEF activity of released FARP2.<br>FARP2 is critical for Sema3A-mediated axonal repulsion through two independent downstream signaling pathways. Sema3A mediated disassociation of FARP2 from Plexin-A is followed by activation of Rac by GEF activity of released FARP2, binding of Rnd1 to plexin-A and down regulation of R-Ras by GAP activity of plexin-A. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 RAC1:GDP Reactome DB_ID: 445010 1 RAC1 Ras-related C3 botulinum toxin substrate 1 RAC1_HUMAN Reactome DB_ID: 442615 1 EQUAL 189 EQUAL Reactome Database ID Release 79 442615 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442615 Reactome R-HSA-442615 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-442615.1 1 Reactome Database ID Release 79 445010 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=445010 Reactome R-HSA-445010 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-445010.1 ACTIVATION Reactome Database ID Release 79 399937 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399937 Reactome Database ID Release 79 399938 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399938 Reactome R-HSA-399938 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399938.1 17607942 Pubmed 2007 The CRMP family of proteins and their role in Sema3A signaling Schmidt, EF Strittmatter, SM Adv Exp Med Biol 600:1-11 LEFT-TO-RIGHT Rac1 binds PlexinA Active Rac1 associates directly with Plexin-A1 in the linker region separating Plexin-A1's cytoplasmic GAP domains. Rac1 association relieves an inhibitory intramolecular interaction between the two Plexin-A1 GAP domains C1 and C2. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 Sema3A:Nrp-1:pPlexinA:Fyn:Fes:Rac-1-GTP Reactome DB_ID: 399872 1 1 Reactome Database ID Release 79 399872 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399872 Reactome R-HSA-399872 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399872.1 Reactome Database ID Release 79 399941 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399941 Reactome R-HSA-399941 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399941.2 15187088 Pubmed 2004 The activity of the plexin-A1 receptor is regulated by Rac Turner, LJ Nicholls, S Hall, A J Biol Chem 279:33199-205 LEFT-TO-RIGHT Recruitment of Rnd1 to Plexin A Binding of Sema3A to the Neuropilin-1-Plexin-A receptor complex results in the recruitment of Rnd1 to the cytoplasmic linker region of Plexin-A. Rnd1 activates the cytoplasmic GTPase signaling domain of Plexin-A. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 Sema3A:Nrp-1:pPlexinA:Fyn:Fes:Rac-1-GTP:Rnd1 Reactome DB_ID: 399877 1 1 Reactome Database ID Release 79 399877 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399877 Reactome R-HSA-399877 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399877.1 Reactome Database ID Release 79 399928 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399928 Reactome R-HSA-399928 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399928.1 LEFT-TO-RIGHT Inactivation of R-Ras by Sema3A-Plexin-A GAP activity Plexin-A's are GAPs for the Ras family GTPase R-Ras. On stimulation with Rnd-1, plexin-A directly and specifically down regulates R-Ras activity. R-Ras activity is critical for PI3K activation and ECM-mediated beta1 integrin activation and cell migration. Inactivation of R-Ras by Sema3A/Plexin-A1 reduces integrin-mediated adhesions. It has been suggested that the final step in the Sema3A repulsive signaling pathway is inhibition of integrin activity. Reduced integrin activity allows detachment from the substratum and subsequent cell retraction. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 ACTIVATION activeUnit: #Protein40 Reactome Database ID Release 79 399929 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399929 Reactome Database ID Release 79 399935 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399935 Reactome R-HSA-399935 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399935.1 LEFT-TO-RIGHT Inhibition of integrin activation by sequestering PIP5KIgamma Sema3A also mediates integrin inhibition by a mechanism involving PIPKI gamma 661, a phosphatidylinositol kinase that participates in integrin mediated focal adhesion assembly. The binding of talin to beta-integrin is required for integrin activation and is strengthened by PtdIns(4,5)P(2). PIPKI gamma 661, an enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an association with talin. Sema3A induced dissociation of FARP2 from Plexin-A1 stimulates an interaction between FARP2 and PIPKI gamma 661. FARP2 inhibits PIPK gamma 661's kinase activity, and thus inhibits integrin mediated adhesion. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 PIP5K1gamma:Talin-1 Reactome DB_ID: 398218 PIP5K1C PIP5K1gamma Reactome DB_ID: 392427 UniProt:O60331 PIP5K1C PIP5K1C KIAA0589 FUNCTION Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2/PIP2), a lipid second messenger that regulates several cellular processes such as signal transduction, vesicle trafficking, actin cytoskeleton dynamics, cell adhesion, and cell motility (PubMed:12422219, PubMed:22942276). PtdIns(4,5)P2 can directly act as a second messenger or can be utilized as a precursor to generate other second messengers: inositol 1,4,5-trisphosphate (IP3), diacylglycerol (DAG) or phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3/PIP3) (Probable). PIP5K1A-mediated phosphorylation of PtdIns(4)P is the predominant pathway for PtdIns(4,5)P2 synthesis (By similarity). Together with PIP5K1A, is required for phagocytosis, both enzymes regulating different types of actin remodeling at sequential steps (By similarity). Promotes particle attachment by generating the pool of PtdIns(4,5)P2 that induces controlled actin depolymerization to facilitate Fc-gamma-R clustering. Mediates RAC1-dependent reorganization of actin filaments. Required for synaptic vesicle transport (By similarity). Controls the plasma membrane pool of PtdIns(4,5)P2 implicated in synaptic vesicle endocytosis and exocytosis (PubMed:12847086). Plays a role in endocytosis mediated by clathrin and AP-2 (adaptor protein complex 2) (PubMed:12847086). Required for clathrin-coated pits assembly at the synapse (PubMed:17261850). Participates in cell junction assembly (PubMed:17261850). Modulates adherens junctions formation by facilitating CDH1/cadherin trafficking (PubMed:17261850). Required for focal adhesion dynamics. Modulates the targeting of talins (TLN1 and TLN2) to the plasma membrane and their efficient assembly into focal adhesions (PubMed:12422219). Regulates the interaction between talins (TLN1 and TLN2) and beta-integrins (PubMed:12422219). Required for uropodium formation and retraction of the cell rear during directed migration (By similarity). Has a role in growth factor-stimulated directional cell migration and adhesion (By similarity). Required for talin assembly into nascent adhesions forming at the leading edge toward the direction of the growth factor (PubMed:17635937). Negative regulator of T-cell activation and adhesion (By similarity). Negatively regulates integrin alpha-L/beta-2 (LFA-1) polarization and adhesion induced by T-cell receptor (By similarity). Together with PIP5K1A has a role during embryogenesis and together with PIP5K1B may have a role immediately after birth (By similarity).SUBUNIT Interacts with TLN1 (By similarity). Interacts with TLN2; interaction stimulates 1-phosphatidylinositol-4-phosphate 5-kinase activity (PubMed:12422219). May compete with beta-integrins for the same binding site on TLN1 and TLN2. Interacts with ARF6; interaction stimulates 1-phosphatidylinositol-4-phosphate 5-kinase activity. Interacts with AP2B1. Interacts with AP2M1; phosphorylation of PIP5K1C by CSK disrupts the interaction; clathrin competes with PIP5K1C (By similarity). Interacts with CDH1. Interacts with CSK (By similarity). Interacts with PLCG1; interaction is abolished upon EGF stimulation (By similarity). Interacts with LAPTM4B; promotes SNX5 association with LAPTM4B; kinase activity of PIP5K1C is required; interaction is regulated by phosphatidylinositol 4,5-bisphosphate generated by PIP5K1C (PubMed:25588945).PTM Phosphorylation on Ser-650 negatively regulates binding to TLN2 and is strongly stimulated in mitosis. Phosphorylation on Tyr-649 is necessary for targeting to focal adhesions. Phosphorylation on Ser-650 and Tyr-649 are mutually exclusive. Phosphorylated by SYK and CSK (By similarity). Tyrosine phosphorylation is enhanced by PTK2 signaling. Phosphorylated at Tyr-639 upon EGF stimulation. Some studies suggest that phosphorylation on Tyr-649 enhances binding to tailins (TLN1 and TLN2). According to PubMed:15738269 phosphorylation at Tyr-649 does not directly enhance binding to tailins (TLN1 and TLN2) but may act indirectly by inhibiting phosphorylation at Ser-650.PTM Acetylation at Lys-265 and Lys-268 seems to decrease lipid 1-phosphatidylinositol-4-phosphate 5-kinase activity. Deacetylation of these sites by SIRT1 positively regulates the exocytosis of TSH-containing granules from pituitary cells. UniProt O60331 1 EQUAL 668 EQUAL Reactome Database ID Release 79 392427 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=392427 Reactome R-HSA-392427 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-392427.1 1 TLN1 Talin-1 Reactome DB_ID: 350713 UniProt:Q9Y490 TLN1 TLN1 KIAA1027 TLN FUNCTION Probably involved in connections of major cytoskeletal structures to the plasma membrane. High molecular weight cytoskeletal protein concentrated at regions of cell-substratum contact and, in lymphocytes, at cell-cell contacts (By similarity).SUBUNIT Part of a complex composed of THSD1, PTK2/FAK1, TLN1 and VCL (PubMed:29069646). Interacts with THSD1 (PubMed:27895300, PubMed:29069646); this promotes interaction with PTK2/FAK1 and VCL. Binds with high affinity to VCL and with low affinity to integrins (PubMed:15070891). Interacts with APBB1IP; this inhibits VCL binding. Interacts with PTK2/FAK1 (By similarity). Interacts with PIP5K1C and NRAP (PubMed:10320340, PubMed:12422220). Interacts with LAYN (By similarity). Interacts with SYNM (PubMed:18342854). Interacts with ITGB1; the interaction is prevented by competitive binding of ITGB1BP1 (PubMed:21768292, PubMed:12473654).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus protein UL135. UniProt Q9Y490 1 EQUAL 2541 EQUAL Reactome Database ID Release 79 350713 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=350713 Reactome R-HSA-350713 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-350713.1 1 Reactome Database ID Release 79 398218 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=398218 Reactome R-HSA-398218 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-398218.1 FARP2:PIP5KIgamma Reactome DB_ID: 399839 1 1 Reactome Database ID Release 79 399839 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399839 Reactome R-HSA-399839 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399839.1 Reactome Database ID Release 79 399936 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399936 Reactome R-HSA-399936 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399936.1 10934324 Pubmed 2000 Molecular basis of semaphorin-mediated axon guidance Nakamura, F Kalb, RG Strittmatter, SM J Neurobiol 44:219-29 12422220 Pubmed 2002 Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions Ling, K Doughman, RL Firestone, AJ Bunce, MW Anderson, RA Nature 420:89-93 16930978 Pubmed 2006 Repulsion or adhesion: receptors make the call Halloran, MC Wolman, MA Curr Opin Cell Biol 18:533-40 Reactome Database ID Release 79 399955 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399955 Reactome R-HSA-399955 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399955.2 18580951 Pubmed 2008 The semaphorins: versatile regulators of tumour progression and tumour angiogenesis Neufeld, G Kessler, O Nat Rev Cancer 8:632-45 Sema3A PAK dependent Axon repulsion Activated Rac1 bound to plexin-A might modulate actin dynamics through the sequential phosphorylation and activation of PAK, LIMK1 and cofilin. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:38 LEFT-TO-RIGHT Activation of PAK by Rac1 Plexin-bound Rac1 binds to and stimulates the kinase activity of PAK. PAK dimers are arranged in head-to-tail fashion, in which the catalytic domain binds the kinase inhibitory (KI) domain and is supported by associated PAK-interacting exchange factor (PIX) dimers. Upon Rac1 binding the kinase undergoes conformational change that allows autophosphorylation. Phosphorylation of serine residues disables the KI-domain-kinase interaction and thereby reduces the affinity of PIX. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 Converted from EntitySet in Reactome PAK1,2,3 dimer Reactome DB_ID: 399856 PAK1 dimer Reactome DB_ID: 445002 PAK1 p21-activated kinase Reactome DB_ID: 162629 UniProt:Q13153 PAK1 PAK1 FUNCTION Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes (PubMed:11896197, PubMed:30290153). Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2. Phosphorylates SNAI1 at 'Ser-246' promoting its transcriptional repressor activity by increasing its accumulation in the nucleus. In podocytes, promotes NR3C2 nuclear localization. Required for atypical chemokine receptor ACKR2-induced phosphorylation of LIMK1 and cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3, maybe through CFL1 phosphorylation and inactivation. Plays a role in RUFY3-mediated facilitating gastric cancer cells migration and invasion (PubMed:25766321). In response to DNA damage, phosphorylates MORC2 which activates its ATPase activity and facilitates chromatin remodeling (PubMed:23260667). In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in F-actin stabilization (By similarity). In hippocampal neurons, necessary for the formation of dendritic spines and excitatory synapses; this function is dependent on kinase activity and may be exerted by the regulation of actomyosin contractility through the phosphorylation of myosin II regulatory light chain (MLC) (By similarity). Along with GIT1, positively regulates microtubule nucleation during interphase (PubMed:27012601).ACTIVITY REGULATION Phosphorylation of Thr-84 by OXSR1 inhibits activation (By similarity). Activated by binding small G proteins. Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, and enables activation by phosphorylation of Thr-423.SUBUNIT Homodimer; homodimerization results in autoinhibition (PubMed:30290153). Active as monomer. Interacts with GIT1 (PubMed:27012601). Component of cytoplasmic complexes, which also contains PXN, ARHGEF7 and GIT1. Interacts with NISCH (By similarity). Interacts with DVL1; mediates the formation of a DVL1, MUSK and PAK1 ternary complex involved in AChR clustering (By similarity). Binds to the caspase-cleaved p110 isoform of CDC2L1 and CDC2L2, p110C, but not the full-length proteins (PubMed:12624090). Interacts with ARHGEF7 (PubMed:27012601, PubMed:16101281). Interacts tightly with GTP-bound but not GDP-bound CDC42/P21 and RAC1 (By similarity). Probably found in a ternary complex composed of DSCAM, PAK1 and RAC1. Interacts with DSCAM (via cytoplasmic domain); the interaction is direct and enhanced in presence of RAC1 (PubMed:15169762). Interacts with SCRIB (PubMed:18716323). Interacts with PDPK1 (PubMed:10995762). Interacts (via kinase domain) with RAF1 (PubMed:11733498). Interacts with NCK1 and NCK2 (PubMed:10026169). Interacts with TBCB (PubMed:15831477). Interacts with CRIPAK (PubMed:16278681). Interacts with BRSK2 (By similarity). Interacts with SNAI1 (PubMed:15833848). Interacts with CIB1 isoform 2 (PubMed:23503467). Interacts with CIB1 (via N-terminal region); the interaction is direct, promotes PAK1 activity and occurs in a calcium-dependent manner. Interacts with INPP5K (PubMed:26940976). Interacts with gamma-tubulin (PubMed:27012601).TISSUE SPECIFICITY Overexpressed in gastric cancer cells and tissues (at protein level) (PubMed:25766321).PTM Autophosphorylated in trans, meaning that in a dimer, one kinase molecule phosphorylates the other one. Activated by autophosphorylation at Thr-423 in response to a conformation change, triggered by interaction with GTP-bound CDC42 or RAC1. Activated by phosphorylation at Thr-423 by BRSK2 and by PDPK1. Phosphorylated by JAK2 in response to PRL; this increases PAK1 kinase activity. Phosphorylated at Ser-21 by PKB/AKT; this reduces interaction with NCK1 and association with focal adhesion sites. Upon DNA damage, phosphorylated at Thr-212 and translocates to the nucleoplasm (PubMed:23260667). Phosphorylated at tyrosine residues, which can be enhanced by NTN1 (By similarity).SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily. UniProt Q13153 1 EQUAL 545 EQUAL Reactome Database ID Release 79 162629 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=162629 Reactome R-HSA-162629 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-162629.1 2 Reactome Database ID Release 79 445002 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=445002 Reactome R-HSA-445002 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-445002.1 PAK2 dimer Reactome DB_ID: 2685645 PAK2 Reactome DB_ID: 211604 UniProt:Q13177 PAK2 PAK2 FUNCTION Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell motility, cell cycle progression, apoptosis or proliferation. Acts as downstream effector of the small GTPases CDC42 and RAC1. Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Full-length PAK2 stimulates cell survival and cell growth. Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. Phosphorylates JUN and plays an important role in EGF-induced cell proliferation. Phosphorylates many other substrates including histone H4 to promote assembly of H3.3 and H4 into nucleosomes, BAD, ribosomal protein S6, or MBP. Additionally, associates with ARHGEF7 and GIT1 to perform kinase-independent functions such as spindle orientation control during mitosis. On the other hand, apoptotic stimuli such as DNA damage lead to caspase-mediated cleavage of PAK2, generating PAK-2p34, an active p34 fragment that translocates to the nucleus and promotes cellular apoptosis involving the JNK signaling pathway. Caspase-activated PAK2 phosphorylates MKNK1 and reduces cellular translation.ACTIVITY REGULATION Activated by binding small G proteins. Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, enables phosphorylation of Thr-402 and allows the kinase domain to adopt an active structure (By similarity). Following caspase cleavage, autophosphorylated PAK-2p34 is constitutively active.SUBUNIT Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1. Interacts with SH3MD4. Interacts with SCRIB. Interacts with ARHGEF7 and GIT1. PAK-2p34 interacts with ARHGAP10 (PubMed:15471851, PubMed:16374509, PubMed:18716323, PubMed:19273597). Interacts with RAC1 (PubMed:20696164).SUBUNIT (Microbial infection) Interacts with and activated by HIV-1 Nef.TISSUE SPECIFICITY Ubiquitously expressed. Higher levels seen in skeletal muscle, ovary, thymus and spleen.PTM Full-length PAK2 is autophosphorylated when activated by CDC42/p21. Following cleavage, both peptides, PAK-2p27 and PAK-2p34, become highly autophosphorylated, with PAK-2p27 being phosphorylated on serine and PAK-2p34 on threonine residues, respectively. Autophosphorylation of PAK-2p27 can occur in the absence of any effectors and is dependent on phosphorylation of Thr-402, because PAK-2p27 is acting as an exogenous substrate.PTM During apoptosis proteolytically cleaved by caspase-3 or caspase-3-like proteases to yield active PAK-2p34.PTM Ubiquitinated, leading to its proteasomal degradation.PTM PAK-2p34 is myristoylated.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily. UniProt Q13177 2 EQUAL 524 EQUAL Reactome Database ID Release 79 211604 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211604 Reactome R-HSA-211604 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-211604.1 2 Reactome Database ID Release 79 2685645 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2685645 Reactome R-HSA-2685645 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2685645.1 PAK3 dimer Reactome DB_ID: 5669154 PAK3 Serine/threonine-protein kinase PAK 3 PAK3_HUMAN Reactome DB_ID: 428457 UniProt:O75914 PAK3 PAK3 OPHN3 FUNCTION Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, or cell cycle regulation. Plays a role in dendrite spine morphogenesis as well as synapse formation and plasticity. Acts as downstream effector of the small GTPases CDC42 and RAC1. Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. Additionally, phosphorylates TNNI3/troponin I to modulate calcium sensitivity and relaxation kinetics of thin myofilaments. May also be involved in early neuronal development. In hippocampal neurons, necessary for the formation of dendritic spines and excitatory synapses; this function is dependent on kinase activity and may be exerted by the regulation of actomyosin contractility through the phosphorylation of myosin II regulatory light chain (MLC) (By similarity).ACTIVITY REGULATION Activated by binding small G proteins. Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, enables phosphorylation of Thr-436 and allows the kinase domain to adopt an active structure (By similarity).SUBUNIT Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1. Shows highly specific binding to the SH3 domains of phospholipase C-gamma and of adapter protein NCK. Interacts with the C-terminal of APP (By similarity). Interacts with ARHGEF6 and ARHGEF7. Interacts with GIT1 and GIT2 (PubMed:10896954).TISSUE SPECIFICITY Restricted to the nervous system. Highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus.PTM Autophosphorylated when activated by CDC42/p21.PTM Neddylated.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily. UniProt O75914 1 EQUAL 559 EQUAL Reactome Database ID Release 79 428457 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428457 Reactome R-HSA-428457 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428457.1 2 Reactome Database ID Release 79 5669154 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5669154 Reactome R-HSA-5669154 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5669154.1 Reactome Database ID Release 79 399856 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399856 Reactome R-HSA-399856 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399856.1 Converted from EntitySet in Reactome PAK1,2,3 Reactome DB_ID: 390765 Reactome Database ID Release 79 390765 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390765 Reactome R-HSA-390765 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390765.1 Sema3A:Nrp-1:PlexinA:Rac1-GTP:PAK Reactome DB_ID: 399876 1 1 Reactome Database ID Release 79 399876 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399876 Reactome R-HSA-399876 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399876.1 Reactome Database ID Release 79 399930 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399930 Reactome R-HSA-399930 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399930.1 15548136 Pubmed 2005 PAK and other Rho-associated kinases--effectors with surprisingly diverse mechanisms of regulation Zhao, ZS Manser, E Biochem J 386:201-14 11604131 Pubmed 2001 Plexin signaling via off-track and rho family GTPases Whitford, KL Ghosh, A Neuron 32:1-3 LEFT-TO-RIGHT 2.7.11.1 Autophosphorylation of PAK PAK is autophosphorylated at several sites but S-144 flanking the kinase inhibitor region and T-423 (S-141/T-402 in PAK-gamma) within the catalytic domain are the two conserved sites that regulate the catalytic activity. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 2 2 Sema3A:Nrp-1:PlexinA:Rac1-GTP:pPAK Reactome DB_ID: 399874 1 Converted from EntitySet in Reactome p-S,T-PAK1,2,3 Reactome DB_ID: 399836 p-S144,T423-PAK1 Reactome DB_ID: 399819 144 EQUAL 423 EQUAL 1 EQUAL 545 EQUAL Reactome Database ID Release 79 399819 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399819 Reactome R-HSA-399819 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399819.1 p-S141,T402-PAK2 Reactome DB_ID: 399824 141 EQUAL 402 EQUAL 1 EQUAL 524 EQUAL Reactome Database ID Release 79 399824 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399824 Reactome R-HSA-399824 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399824.1 p-PAK3 p-S154,T436-PAK3 phospho-PAK3 Reactome DB_ID: 5357471 154 EQUAL 436 EQUAL 1 EQUAL 559 EQUAL Reactome Database ID Release 79 5357471 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357471 Reactome R-HSA-5357471 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357471.1 Reactome Database ID Release 79 399836 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399836 Reactome R-HSA-399836 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399836.1 1 Reactome Database ID Release 79 399874 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399874 Reactome R-HSA-399874 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399874.1 ACTIVATION activeUnit: #Protein59 Reactome Database ID Release 79 399940 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399940 Reactome Database ID Release 79 399939 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399939 Reactome R-HSA-399939 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399939.1 10075701 Pubmed 1999 Multisite autophosphorylation of p21-activated protein kinase gamma-PAK as a function of activation Gatti, A Huang, Z Tuazon, PT Traugh, JA J Biol Chem 274:8022-8 11278486 Pubmed 2001 The mechanism of PAK activation. Autophosphorylation events in both regulatory and kinase domains control activity Chong, C Tan, L Lim, L Manser, E J Biol Chem 276:17347-53 LEFT-TO-RIGHT 2.7.11.1 Phosphorylation of LIMK-1 by PAK LIM kinases are serine protein kinases with a unique combination of two N-terminal LIM motifs, a central PDZ domain, and a C-terminal protein kinase domain. LIMK1 is one of the downstream targets of PAK1 and is activated through phosphorylation by PAK1 on T508 within its activation loop (Edwards et al. 1999, Aizawa et al. 2001). LIM-kinase is responsible for the tight regulation of the activity of cofilin (a protein that depolymerizes actin filaments) and thus maintains the balance between actin assembly and disassembly. Phosphorylated cofilin is inactive, resulting in stabilization of the actin cytoskeleton. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 ACTIVATION activeUnit: #Protein60 Reactome Database ID Release 79 399948 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399948 Reactome Database ID Release 79 399952 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399952 Reactome R-HSA-399952 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399952.1 11276226 Pubmed 2001 Phosphorylation of cofilin by LIM-kinase is necessary for semaphorin 3A-induced growth cone collapse Aizawa, H Wakatsuki, S Ishii, A Moriyama, K Sasaki, Y Ohashi, Ken Sekine-Aizawa, Y Sehara-Fujisawa, A Mizuno, K Goshima, Y Yahara, I Nat Neurosci 4:367-73 10559936 Pubmed 1999 Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics Edwards, DC Sanders, LC Bokoch, GM Gill, GN Nat Cell Biol 1:253-9 LEFT-TO-RIGHT Dimerization of LIMK1 by Hsp90 After phosphorylation on Thr 508, LIMK undergoes homodimerization. Homodimer formation is promoted by the binding of heat shock protein 90 (Hsp90) to a short sequence in the kinase domain of LIMKs. LIMKs are further phosphorylated after homodimer formation and transphosphorylation of the kinase domain. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 Converted from EntitySet in Reactome HSP90AA1,HSP90AB1 Reactome DB_ID: 419619 HSP90 HSP90AA1 Reactome DB_ID: 192864 UniProt:P07900 HSP90AA1 HSP90AA1 HSP90A HSPC1 HSPCA FUNCTION Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity which is essential for its chaperone activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function (PubMed:11274138, PubMed:15577939, PubMed:15937123, PubMed:27353360, PubMed:29127155, PubMed:12526792). Engages with a range of client protein classes via its interaction with various co-chaperone proteins or complexes, that act as adapters, simultaneously able to interact with the specific client and the central chaperone itself (PubMed:29127155). Recruitment of ATP and co-chaperone followed by client protein forms a functional chaperone. After the completion of the chaperoning process, properly folded client protein and co-chaperone leave HSP90 in an ADP-bound partially open conformation and finally, ADP is released from HSP90 which acquires an open conformation for the next cycle (PubMed:27295069, PubMed:26991466). Plays a critical role in mitochondrial import, delivers preproteins to the mitochondrial import receptor TOMM70 (PubMed:12526792). Apart from its chaperone activity, it also plays a role in the regulation of the transcription machinery. HSP90 and its co-chaperones modulate transcription at least at three different levels (PubMed:25973397). In the first place, they alter the steady-state levels of certain transcription factors in response to various physiological cues(PubMed:25973397). Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment (PubMed:25973397). Third, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression (PubMed:25973397). Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:11276205). Antagonizes STUB1-mediated inhibition of TGF-beta signaling via inhibition of STUB1-mediated SMAD3 ubiquitination and degradation (PubMed:24613385). Mediates the association of TOMM70 with IRF3 or TBK1 in mitochodria outer membrane which promotes host antiviral response (PubMed:20628368, PubMed:25609812).ACTIVITY REGULATION In the resting state, through the dimerization of its C-terminal domain, HSP90 forms a homodimer which is defined as the open conformation (PubMed:18400751). Upon ATP-binding, the N-terminal domain undergoes significant conformational changes and comes in contact to form an active closed conformation (PubMed:18400751). After HSP90 finishes its chaperoning tasks of assisting the proper folding, stabilization and activation of client proteins under the active state, ATP molecule is hydrolyzed to ADP which then dissociates from HSP90 and directs the protein back to the resting state (PubMed:18400751). Co-chaperone TSC1 promotes ATP binding and inhibits HSP90AA1 ATPase activity (PubMed:29127155). Binding to phosphorylated AHSA1 promotes HSP90AA1 ATPase activity (PubMed:29127155). Inhibited by geldanamycin, Ganetespib (STA-9090) and SNX-2112 (PubMed:29127155, PubMed:12526792).SUBUNIT Homodimer (PubMed:7588731, PubMed:8289821, PubMed:18400751, PubMed:29127155). Identified in NR3C1/GCR steroid receptor-chaperone complexes formed at least by NR3C1, HSP90AA1 and a variety of proteins containing TPR repeats such as FKBP4, FKBP5, PPID, PPP5C or STIP1 (PubMed:15383005, PubMed:9195923). Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex (PubMed:29127155). The closed form interacts (via the middle domain and TPR repeat-binding motif) with co-chaperone TSC1 (via C-terminus) (PubMed:29127155). Interacts with TOM34 (PubMed:9660753). Interacts with TERT; the interaction, together with PTGES3, is required for correct assembly and stabilization of the TERT holoenzyme complex (PubMed:11274138, PubMed:9817749). Interacts with CHORDC1 and DNAJC7 (PubMed:12853476, PubMed:19875381). Interacts with STUB1 and UBE2N; may couple the chaperone and ubiquitination systems (PubMed:16307917, PubMed:27353360). Interacts (via TPR repeat-binding motif) with PPP5C (via TPR repeats); the interaction is direct and activates PPP5C phosphatase activity (PubMed:15383005, PubMed:15577939, PubMed:16531226, PubMed:27353360). Following LPS binding, may form a complex with CXCR4, GDF5 and HSPA8 (PubMed:11276205). Interacts with KSR1 (PubMed:10409742). Interacts with co-chaperone CDC37 (via C-terminus); the interaction inhibits HSP90AA1 ATPase activity (PubMed:23569206, PubMed:27353360). May interact with NWD1 (PubMed:24681825). Interacts with FNIP1 and FNIP2; the interaction inhibits HSP90AA1 ATPase activity (PubMed:17028174, PubMed:27353360). Interacts with co-chaperone AHSA1 (phosphorylated on 'Tyr-223'); the interaction activates HSP90AA1 ATPase activity and results in the dissociation of TSC1 from HSP90AA1 (PubMed:12604615, PubMed:27353360, PubMed:29127155). Interacts with FLCN in the presence of FNIP1 (PubMed:27353360). Interacts with HSP70, STIP1 and PTGES3 (PubMed:27353360). Interacts with SMYD3; this interaction enhances SMYD3 histone-lysine N-methyltransferase (PubMed:15235609, PubMed:25738358). Interacts with SGTA (via TPR repeats) (PubMed:15708368). Interacts with TTC1 (via TPR repeats) (PubMed:15708368). Interacts with HSF1 in an ATP-dependent manner (PubMed:11583998. PubMed:26517842). Interacts with MET; the interaction suppresses MET kinase activity (PubMed:26517842). Interacts with ERBB2 in an ATP-dependent manner; the interaction suppresses ERBB2 kinase activity (PubMed:26517842). Interacts with HIF1A, KEAP1 and RHOBTB2 (PubMed:26517842). Interacts with HSF1; this interaction is decreased in a IER5-dependent manner, promoting HSF1 accumulation in the nucleus, homotrimerization and DNA-binding activities (PubMed:26754925). Interacts with STUB1 and SMAD3 (PubMed:24613385). Interacts with HSP90AB1; interaction is constitutive (PubMed:20353823). Interacts with HECTD1 (via N-terminus) (By similarity). Interacts with NR3C1 (via domain NR LBD) and NR1D1 (via domain NR LBD) (By similarity). Interacts with NLPR12 (PubMed:30559449, PubMed:17947705). Interacts with PDCL3 (By similarity). Interacts with TOMM70; the interaction is required for preprotein mitochondrial import (PubMed:12526792). Interacts with TOMM70, IRF3 and TBK1; the interactions are direct and mediate the association of TOMM70 with IRF3 and TBK1 (PubMed:20628368).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein US11; this interaction inhibits TBK1-induced interferon production.DOMAIN The TPR repeat-binding motif mediates interaction with TPR repeat-containing proteins like the co-chaperone STUB1.PTM ISGylated.PTM S-nitrosylated; negatively regulates the ATPase activity and the activation of eNOS by HSP90AA1.PTM Ubiquitinated via 'Lys-63'-linked polyubiquitination by HECTD1. Ubiquitination promotes translocation into the cytoplasm away from the membrane and secretory pathways.SIMILARITY Belongs to the heat shock protein 90 family. UniProt P07900 2 EQUAL 732 EQUAL Reactome Database ID Release 79 192864 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=192864 Reactome R-HSA-192864 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-192864.1 HSP90AB1 Heat shock protein HSP 90-beta HS90B_HUMAN Reactome DB_ID: 419617 UniProt:P08238 HSP90AB1 HSP90AB1 HSP90B HSPC2 HSPCB FUNCTION Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function (PubMed:16478993, PubMed:19696785). Engages with a range of client protein classes via its interaction with various co-chaperone proteins or complexes, that act as adapters, simultaneously able to interact with the specific client and the central chaperone itself. Recruitment of ATP and co-chaperone followed by client protein forms a functional chaperone. After the completion of the chaperoning process, properly folded client protein and co-chaperone leave HSP90 in an ADP-bound partially open conformation and finally, ADP is released from HSP90 which acquires an open conformation for the next cycle (PubMed:27295069, PubMed:26991466). Apart from its chaperone activity, it also plays a role in the regulation of the transcription machinery. HSP90 and its co-chaperones modulate transcription at least at three different levels. They first alter the steady-state levels of certain transcription factors in response to various physiological cues. Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment. Third, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression (PubMed:25973397). Antagonizes STUB1-mediated inhibition of TGF-beta signaling via inhibition of STUB1-mediated SMAD3 ubiquitination and degradation (PubMed:24613385). Promotes cell differentiation by chaperoning BIRC2 and thereby protecting from auto-ubiquitination and degradation by the proteasomal machinery (PubMed:18239673). Main chaperone involved in the phosphorylation/activation of the STAT1 by chaperoning both JAK2 and PRKCE under heat shock and in turn, activates its own transcription (PubMed:20353823). Involved in the translocation into ERGIC (endoplasmic reticulum-Golgi intermediate compartment) of leaderless cargos (lacking the secretion signal sequence) such as the interleukin 1/IL-1; the translocation process is mediated by the cargo receptor TMED10 (PubMed:32272059).ACTIVITY REGULATION In the resting state, through the dimerization of its C-terminal domain, HSP90 forms a homodimer which is defined as the open conformation. Upon ATP-binding, the N-terminal domain undergoes significant conformational changes and comes in contact to form an active closed conformation. After HSP90 finishes its chaperoning tasks of assisting the proper folding, stabilization and activation of client proteins under the active state, ATP molecule is hydrolyzed to ADP which then dissociates from HSP90 and directs the protein back to the resting state.SUBUNIT Monomer (PubMed:24880080). Homodimer (PubMed:7588731, PubMed:18400751). Forms a complex with CDK6 and CDC37 (PubMed:9482106, PubMed:25486457). Interacts with UNC45A; binding to UNC45A involves 2 UNC45A monomers per HSP90AB1 dimer (PubMed:16478993). Interacts with CHORDC1 (By similarity). Interacts with DNAJC7 (PubMed:18620420). Interacts with FKBP4 (PubMed:15159550). May interact with NWD1 (PubMed:24681825). Interacts with SGTA (PubMed:16580629). Interacts with HSF1 in an ATP-dependent manner. Interacts with MET; the interaction suppresses MET kinase activity. Interacts with ERBB2 in an ATP-dependent manner; the interaction suppresses ERBB2 kinase activity. Interacts with HIF1A, KEAP1 and RHOBTB2 (PubMed:26517842). Interacts with STUB1 and SMAD3 (PubMed:24613385). Interacts with XPO1 and AHSA1 (PubMed:22022502, PubMed:25486457). Interacts with BIRC2 (PubMed:25486457). Interacts with KCNQ4; promotes cell surface expression of KCNQ4 (PubMed:23431407). Interacts with BIRC2; prevents auto-ubiquitination and degradation of its client protein BIRC2 (PubMed:18239673). Interacts with NOS3 (PubMed:23585225). Interacts with AHR; interaction is inhibited by HSP90AB1 phosphorylation on Ser-226 and Ser-255 (PubMed:15581363). Interacts with STIP1 and CDC37; upon SMYD2-dependent methylation (PubMed:24880080). Interacts with JAK2 and PRKCE; promotes functional activation in a heat shock-dependent manner (PubMed:20353823). Interacts with HSP90AA1; interaction is constitutive (PubMed:20353823). HSP90AB1-CDC37 chaperone complex interacts with inactive MAPK7 (via N-terminal half) in resting cells; the interaction is MAP2K5-independent and prevents from ubiquitination and proteasomal degradation (PubMed:23428871). Interacts with CDC25A; prevents heat shock-mediated CDC25A degradation and contributes to cell cycle progression (PubMed:22843495). Interacts with TP53 (via DNA binding domain); suppresses TP53 aggregation and prevents from irreversible thermal inactivation (PubMed:15358771). Interacts with TGFB1 processed form (LAP); inhibits latent TGFB1 activation (PubMed:20599762). Interacts with TRIM8; prevents nucleus translocation of phosphorylated STAT3 and HSP90AB1 (By similarity). Interacts with NR3C1 (via domain NR LBD) and NR1D1 (via domain NR LBD) (By similarity). Interacts with PDCL3 (By similarity). Interacts with TTC4 (via TPR repeats) (PubMed:18320024). Interacts with IL1B; the interaction facilitates cargo translocation into the ERGIC (PubMed:32272059).INDUCTION By heat shock.DOMAIN The TPR repeat-binding motif mediates interaction with TPR repeat-containing proteins.PTM Ubiquitinated in the presence of STUB1-UBE2D1 complex (in vitro).PTM ISGylated.PTM S-nitrosylated; negatively regulates the ATPase activity.PTM Phosphorylation at Tyr-301 by SRC is induced by lipopolysaccharide (PubMed:23585225). Phosphorylation at Ser-226 and Ser-255 inhibits AHR interaction (PubMed:15581363).PTM Methylated by SMYD2; facilitates dimerization and chaperone complex formation; promotes cancer cell proliferation.PTM Cleaved following oxidative stress resulting in HSP90AB1 protein radicals formation; disrupts the chaperoning function and the degradation of its client proteins.SIMILARITY Belongs to the heat shock protein 90 family. UniProt P08238 2 EQUAL 724 EQUAL Reactome Database ID Release 79 419617 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419617 Reactome R-HSA-419617 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419617.1 Reactome Database ID Release 79 419619 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419619 Reactome R-HSA-419619 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419619.1 2 pLIMK dimer:HSP-90 Reactome DB_ID: 419632 1 2 Reactome Database ID Release 79 419632 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419632 Reactome R-HSA-419632 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419632.1 Reactome Database ID Release 79 419645 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419645 Reactome R-HSA-419645 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419645.2 16641196 Pubmed 2006 Hsp90 increases LIM kinase activity by promoting its homo-dimerization Li, R Soosairajah, J Harari, D Citri, A Price, J Ng, HL Morton, CJ Parker, MW Yarden, Y Bernard, O FASEB J 20:1218-20 17188549 Pubmed 2007 Lim kinases, regulators of actin dynamics Bernard, O Int J Biochem Cell Biol 39:1071-6 LEFT-TO-RIGHT 2.7.11.1 Transphosphorylation of pLIMK1 Binding of Hsp90 to the LIMK proteins protects them from degradation and promotes their dimer formation and transphosphorylation. It is estimated that LIMK1 contains at least 5 phospho-amino acids primarily phospho-serines, in its kinase domain. The positions of these serine residues are not known. Transphosphorylation of these serine residues in LIMK1 increases its stability. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 09:59:28 Active LIMK1 Reactome DB_ID: 419630 p-S,T508-LIMK1 Transphosphorylated pLIMK-1 Reactome DB_ID: 419610 1 EQUAL 647 EQUAL Reactome Database ID Release 79 419610 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419610 Reactome R-HSA-419610 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419610.1 2 Reactome Database ID Release 79 419630 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419630 Reactome R-HSA-419630 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419630.1 ACTIVATION activeUnit: #Protein36 Reactome Database ID Release 79 419647 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419647 Reactome Database ID Release 79 419644 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419644 Reactome R-HSA-419644 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419644.2 7848918 Pubmed 1994 Kiz-1, a protein with LIM zinc finger and kinase domains, is expressed mainly in neurons Bernard, O Ganiatsas, S Kannourakis, G Dringen, R Cell Growth Differ 5:1159-71 LEFT-TO-RIGHT 2.7.11.1 Phosphorylation of cofilin by LIMK-1 The EPHB2-FAK pathway partially promotes dendritic spine stability through LIMK-mediated cofilin (CFL1) phosphorylation (Shi et al. 2009). CFL1 is a member of the ADF (actin-depolymerizing factor) protein family that is involved in regulating actin dynamics in the growth cone. It binds to actin in a one-to-one molar ratio, and stimulates both the severing of actin filaments and depolymerization of actin subunits from the actin filament end. Activated LIMK phosphorylates CFL1 on the conserved serine 3 residue located near the actin-binding site. After phosphorylation, CFL1 is inactive, loses its affinity for actin and dissociates from G-actin monomers. Once freed, ADP-actin monomers can exchange ADP with cytoplasmic ATP, ready for reincorporation at the barbed end of a growing filament (Gungabissoon & Bamburg 2003). Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 CFL1 Cofilin-1 COF1_HUMAN Reactome DB_ID: 350751 UniProt:P23528 CFL1 CFL1 CFL FUNCTION Binds to F-actin and exhibits pH-sensitive F-actin depolymerizing activity (PubMed:11812157). In conjunction with the subcortical maternal complex (SCMC), plays an essential role for zygotes to progress beyond the first embryonic cell divisions via regulation of actin dynamics (PubMed:15580268). Required for the centralization of the mitotic spindle and symmetric division of zygotes (By similarity). Plays a role in the regulation of cell morphology and cytoskeletal organization in epithelial cells (PubMed:21834987). Required for the up-regulation of atypical chemokine receptor ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation (PubMed:23633677). Required for neural tube morphogenesis and neural crest cell migration (By similarity).SUBUNIT Can bind G- and F-actin in a 1:1 ratio of cofilin to actin (PubMed:11812157). It is a major component of intranuclear and cytoplasmic actin rods (By similarity). Interacts with the subcortical maternal complex (SCMC) via interaction with TLE6 isoform 1 and NLRP5 (By similarity).SUBUNIT (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) matrix protein; this interaction probably facilitates viral replication.TISSUE SPECIFICITY Widely distributed in various tissues.INDUCTION Up-regulated in response to enterovirus 71 (EV71) infection (at protein level).PTM Inactivated by phosphorylation on Ser-3. Phosphorylated on Ser-3 in resting cells (By similarity). Dephosphorylated by PDXP/chronophin; this restores its activity in promoting actin filament depolymerization. The phosphorylation of Ser-24 may prevent recognition of the nuclear localization signal (By similarity). Phosphorylated via a ARRB1-RAC1-LIMK1-PAK1 cascade upon active ligand stimulation of atypical chemokine receptor ACKR2.SIMILARITY Belongs to the actin-binding proteins ADF family. UniProt P23528 2 EQUAL 166 EQUAL Reactome Database ID Release 79 350751 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=350751 Reactome R-HSA-350751 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-350751.1 pCofilin: Active LIMK-1 Reactome DB_ID: 399878 p-S3-CFL1 pCofilin-1(S3) Reactome DB_ID: 399813 3 EQUAL 2 EQUAL 166 EQUAL Reactome Database ID Release 79 399813 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399813 Reactome R-HSA-399813 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399813.1 1 1 Reactome Database ID Release 79 399878 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399878 Reactome R-HSA-399878 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399878.1 ACTIVATION Reactome Database ID Release 79 419883 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419883 Reactome Database ID Release 79 399950 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399950 Reactome R-HSA-399950 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399950.2 12642619 Pubmed 2003 Regulation of growth cone actin dynamics by ADF/cofilin Gungabissoon, RA Bamburg, JR J Histochem Cytochem 51:411-20 12593985 Pubmed 2003 Semaphorin junction: making tracks toward neural connectivity Pasterkamp, RJ Kolodkin, AL Curr Opin Neurobiol 13:79-89 Reactome Database ID Release 79 399954 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399954 Reactome R-HSA-399954 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399954.2 CRMPs in Sema3A signaling CRMPs are a small family of plexinA-interacting cytosolic phosphoproteins identified as mediators of Sema3A signaling and neuronal differentiation. After Sema3A activation Plexin-A bound CRMP's undergo phosphorylation by Cdk5, GSK3beta and Fes kinases. Phosphorylation of CRMPs by these kinases blocks the ability of CRMP to bind to tubulin dimers, subsequently induces depolymerization of F-actin, and ultimately leads to growth cone collapse. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:38 LEFT-TO-RIGHT Activation of Fyn PlexinA1 and A2 are constitutively bound to the src family tyrosine kinase, Fyn. Stimulation with Sema3A causes Fyn activation and leads to the recruitment of Cdk5 into the complex. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 NRP1:PlexinA1-4:FYN Reactome DB_ID: 399846 Plexin-A1-4:FYN Reactome DB_ID: 399847 1 1 Reactome Database ID Release 79 399847 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399847 Reactome R-HSA-399847 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399847.1 1 1 Reactome Database ID Release 79 399846 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399846 Reactome R-HSA-399846 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399846.1 Sema3A:Nrp-1:PlexinA:Fyn Reactome DB_ID: 399869 1 1 Reactome Database ID Release 79 399869 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399869 Reactome R-HSA-399869 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399869.1 Reactome Database ID Release 79 399931 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399931 Reactome R-HSA-399931 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399931.1 LEFT-TO-RIGHT 2.7.10.2 Recruitment and activation of Cdk5 Cyclin-dependent kinase 5 (CDK5), a member of the serine/threonine kinase Cdk family, is complexed with p35 a neuron specific activator of Cdk5. The complex CDK5:p35 is required for neurite outgrowth and cortical lamination. CDK5:p35 complex is recruited to the growth cone by associating with active Fyn. FYN promotes the kinase activity of CDK5 by phosphorylating CDK5 on tyrosine residue 15. Activation of CDK5 by FYN via Tyr15 phosphorylation might facilitate suppression of RAC-PAK signaling downstream of PlexinA. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 CDK5:p35 CDK5:MyrG-CDK5R1(2-307) Reactome DB_ID: 421107 CDK5 Reactome DB_ID: 180064 UniProt:Q00535 CDK5 CDK5 CDKN5 FUNCTION Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry. Interacts with D1 and D3-type G1 cyclins. Phosphorylates SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1, SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16, RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53, HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH and NEFM. Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39), especially in post-mitotic neurons, and promotes CDK5R1 (p35) expression in an autostimulation loop. Phosphorylates many downstream substrates such as Rho and Ras family small GTPases (e.g. PAK1, RAC1, RHOA, CDC42) or microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B), and modulates actin dynamics to regulate neurite growth and/or spine morphogenesis. Phosphorylates also exocytosis associated proteins such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1 as well as endocytosis associated proteins such as DNM1, AMPH and SYNJ1 at synaptic terminals. In the mature central nervous system (CNS), regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity; synaptic vesicle exocytosis, vesicles fusion with the presynaptic membrane, and endocytosis. Promotes cell survival by activating anti-apoptotic proteins BCL2 and STAT3, and negatively regulating of JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to genotoxic and oxidative stresses enhances its stabilization by preventing ubiquitin ligase-mediated proteasomal degradation, and induces transactivation of p53/TP53 target genes, thus regulating apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by preventing calpain-mediated proteolysis producing p25/CDK5R1 and avoiding ubiquitin ligase-mediated proteasomal degradation. During aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits cell-cycle activity and double-strand DNA breaks that precedes neuronal death by deregulating HDAC1. DNA damage triggered phosphorylation of huntingtin/HTT in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. Negative regulator of Wnt/beta-catenin signaling pathway. Activator of the GAIT (IFN-gamma-activated inhibitor of translation) pathway, which suppresses expression of a post-transcriptional regulon of proinflammatory genes in myeloid cells; phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase (EPRS) in a IFN-gamma-dependent manner, the initial event in assembly of the GAIT complex. Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5 in response to osmotic stress mediates its rapid nuclear localization. MEF2 is inactivated by phosphorylation in nucleus in response to neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-endodeoxyribonuclease is repressed by phosphorylation, resulting in accumulation of DNA damage and contributing to neuronal death. NOS3 phosphorylation down regulates NOS3-derived nitrite (NO) levels. SRC phosphorylation mediates its ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. May regulate endothelial cell migration and angiogenesis via the modulation of lamellipodia formation. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer in association with altered stability and subcellular distribution.ACTIVITY REGULATION Inhibited by 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine), 1-isopropyl-4-aminobenzyl-6-ether-linked benzimidazoles, resveratrol, AT-7519 and olomoucine. Activated by CDK5R1 (p35) and CDK5R2 (p39) during the development of the nervous system; degradation of CDK5R1 (p35) and CDK5R2 (p39) by proteasome result in down regulation of kinase activity, during this process, CDK5 phosphorylates p35 and induces its ubiquitination and subsequent degradation. Kinase activity is mainly determined by the amount of p35 available and subcellular location; reversible association to plasma membrane inhibits activity. Long-term inactivation as well as CDK5R1 (p25)-mediated hyperactivation of CDK5 triggers cell death. The pro-death activity of hyperactivated CDK5 is suppressed by membrane association of CDK5, via myristoylation of p35. Brain-derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor (NGF), retinoic acid, laminin and neuregulin promote activity. Neurotoxicity enhances nuclear activity, thus leading to MEF2 phosphorylation and inhibition prior to apoptosis of cortical neurons. Repression by GSTP1 via p25/p35 translocation prevents neurodegeneration.SUBUNIT Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1 (p25) and macromolecular complex composed of at least CDK5, CDK5R1 (p35) and CDK5RAP1 or CDK5RAP2 or CDK5RAP3. Only the heterodimer shows kinase activity. Under neurotoxic stress and neuronal injury conditions, p35 is cleaved by calpain to generate p25 that hyperactivates CDK5, that becomes functionally disabled and often toxic. Found in a trimolecular complex with CABLES1 and ABL1. Interacts with CABLES1 and CABLES2 (By similarity). Interacts with AATK and GSTP1. Binds to HDAC1 when in complex with p25. Interaction with myristoylation p35 promotes CDK5 association with membranes. Both isoforms 1 and 2 interacts with beta-catenin/CTNNB1. Interacts with delta-catenin/CTNND2 and APEX1. Interacts with P53/TP53 in neurons. Interacts with EPHA4; may mediate the activation of NGEF by EPHA4. Interacts with PTK2/FAK1 (By similarity). The complex p35/CDK5 interacts with CLOCK. Interacts with HTR6 (By similarity).TISSUE SPECIFICITY Isoform 1 is ubiquitously expressed. Accumulates in cortical neurons (at protein level). Isoform 2 has only been detected in testis, skeletal muscle, colon, bone marrow and ovary.PTM Phosphorylation on Tyr-15 by ABL1 and FYN, and on Ser-159 by casein kinase 1 promotes kinase activity. By contrast, phosphorylation at Thr-14 inhibits activity.PTM Phosphorylation at Ser-159 is essential for maximal catalytic activity.MISCELLANEOUS Dysregulation of CDK5 is associated with neurodegenerative disorders such as Alzheimer, Parkinson, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. UniProt Q00535 1 EQUAL 292 EQUAL Reactome Database ID Release 79 180064 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=180064 Reactome R-HSA-180064 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-180064.1 1 MyrG-p35 MyrG-CDK5R1(2-307) MyrG-CDK5R1 Cyclin-dependent kinase 5 activator 1 CD5R1_HUMAN Reactome DB_ID: 421083 UniProt:Q15078 CDK5R1 CDK5R1 CDK5R NCK5A FUNCTION p35 is a neuron specific activator of CDK5. The complex p35/CDK5 is required for neurite outgrowth and cortical lamination. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. Activator of TPKII. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer in association with altered stability and subcellular distribution.SUBUNIT Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1 (p25) and macromolecular complex composed of at least CDK5, CDK5R1 (p35) and CDK5RAP1 or CDK5RAP2 or CDK5RAP3. Only the heterodimer shows kinase activity. Interacts with EPHA4 and NGEF; may mediate the activation of NGEF by EPHA4 (By similarity). Interacts with RASGRF2. The complex p35/CDK5 interacts with CLOCK.TISSUE SPECIFICITY Brain and neuron specific.PTM The p35 form is proteolytically cleaved by calpain, giving rise to the p25 form. P35 has a 5 to 10 fold shorter half-life compared to p25. The conversion results in deregulation of the CDK5 kinase: p25/CDK5 kinase displays an increased and altered tau phosphorylation in comparison to the p35/CDK5 kinase in vivo (By similarity).PTM Myristoylated. A proper myristoylation signal is essential for the proper distribution of p35.PTM Ubiquitinated. Degradation of p35 by proteasome results in down-regulation of CDK5 activity. During this process, CDK5 phosphorylates p35 and induces its ubiquitination and subsequent degradation.PTM Phosphorylation at Ser-8 and Thr-138 by CDK5 prevents calpain-mediated proteolysis.MISCELLANEOUS Cleavage of p35 to p25 may be involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in neurodegenerative diseases. The p25 form accumulates in neurons in the brain of patients with Alzheimer disease, but not in normal brain. This accumulation correlates with an increase in CDK5 kinase activity. Application of amyloid beta peptide A-beta(1-42) induced the conversion of p35 to p25 in primary cortical neurons. Expression of the p25/Cdk5 complex in cultured primary neurons induces cytoskeletal disruption, morphological degeneration and apoptosis.SIMILARITY Belongs to the cyclin-dependent kinase 5 activator family. UniProt Q15078 2 EQUAL N-myristoylglycine MOD MOD:00068 2 EQUAL 307 EQUAL Reactome Database ID Release 79 421083 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=421083 Reactome R-HSA-421083 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-421083.2 1 Reactome Database ID Release 79 421107 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=421107 Reactome R-HSA-421107 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-421107.3 ComplexPortal CPX-2201 Sema3A:Nrp-1:PlexinA:Fyn:pCdk5 Reactome DB_ID: 399868 1 NRP1:PlexinA1-4:FYN:pCdk5:p53 Reactome DB_ID: 399845 PlexinA1-4:FYN:pCdk5:p35 Reactome DB_ID: 399854 Fyn:pCdk5:p35 Reactome DB_ID: 399838 pCdk5:p35 p-Y15-CDK5:p35 p-Y15-CDK5:MyrG-CDK5R1(2-307) Reactome DB_ID: 421098 1 p-Y15-CDK5 pCdk5 (Y15) Reactome DB_ID: 399809 15 EQUAL 1 EQUAL 292 EQUAL Reactome Database ID Release 79 399809 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399809 Reactome R-HSA-399809 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399809.1 1 Reactome Database ID Release 79 421098 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=421098 Reactome R-HSA-421098 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-421098.3 ComplexPortal CPX-2201 1 1 Reactome Database ID Release 79 399838 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399838 Reactome R-HSA-399838 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399838.2 1 1 Reactome Database ID Release 79 399854 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399854 Reactome R-HSA-399854 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399854.2 1 1 Reactome Database ID Release 79 399845 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399845 Reactome R-HSA-399845 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399845.1 1 Reactome Database ID Release 79 399868 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399868 Reactome R-HSA-399868 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399868.1 ACTIVATION activeUnit: #Protein39 Reactome Database ID Release 79 399949 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399949 Reactome Database ID Release 79 399946 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399946 Reactome R-HSA-399946 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399946.1 LEFT-TO-RIGHT 2.7.11.1 Phosphorylation of CRMPs by Cdk5 Cdk5:p35 complex is associated with Plexin-A through the actived form of Fyn. CRMPs are the downstream substrates for Cdk5. Cdk5 phosphorylates serine 522 of CRMPs. Phosphorylation of CRMPs mediates the Sema3A induced growth cone collapse.<br>Collapsin response mediator proteins (CRMPs) are five homologous cytosolic phosphoproteins (CRMP1–5) involved in neuronal differentiation and axonal guidance. These members oligomerize and exist as tetramers. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 4 CRMP's tetramers Reactome DB_ID: 399843 Converted from EntitySet in Reactome CRMP's 1-5 Reactome DB_ID: 399825 CRMP1 Dihydropyrimidinase-related protein 1 (CRMP-1) DPYL1_HUMAN DRP-1 Reactome DB_ID: 398120 UniProt:Q14194 CRMP1 CRMP1 DPYSL1 ULIP3 FUNCTION Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton (PubMed:25358863). Plays a role in axon guidance (PubMed:25358863). During the axon guidance process, acts downstream of SEMA3A to promote FLNA dissociation from F-actin which results in the rearrangement of the actin cytoskeleton and the collapse of the growth cone (PubMed:25358863). Involved in invasive growth and cell migration (PubMed:11562390). May participate in cytokinesis (PubMed:19799413).SUBUNIT Homotetramer, and heterotetramer with DPYSL2, DPYSL3, DPYSL4 or DPYSL5 (By similarity). Interacts with PLXNA1 (By similarity). Interacts with FLNA (via calponin-homology (CH) domain 1 and filamin repeat 24); the interaction alters FLNA ternary structure and thus promotes FLNA dissociation from F-actin (PubMed:25358863).TISSUE SPECIFICITY Brain.PTM Phosphorylation at Ser-522 enhances CRMP1-mediated alteration of FLNA ternary structure and FLNA dissociation from F-actin.SIMILARITY Belongs to the metallo-dependent hydrolases superfamily. Hydantoinase/dihydropyrimidinase family.CAUTION Lacks most of the conserved residues that are essential for binding the metal cofactor and hence for dihydropyrimidinase activity. Its enzyme activity is therefore unsure. UniProt Q14194 1 EQUAL 572 EQUAL Reactome Database ID Release 79 398120 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=398120 Reactome R-HSA-398120 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-398120.1 DPYSL2 CRMP-2 Dihydropyrimidinase-related protein 2 DPYL2_HUMAN Reactome DB_ID: 396943 UniProt:Q16555 DPYSL2 DPYSL2 CRMP2 ULIP2 FUNCTION Plays a role in neuronal development and polarity, as well as in axon growth and guidance, neuronal growth cone collapse and cell migration. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. May play a role in endocytosis.SUBUNIT Homotetramer, and heterotetramer with CRMP1, DPYSL3, DPYSL4 or DPYSL5. Interacts through its C-terminus with the C-terminus of CYFIP1/SRA1. Interacts with HTR4. Interacts with CLN6. Interacts with MICALL1.TISSUE SPECIFICITY Ubiquitous.PTM 3F4, a monoclonal antibody which strongly stains neurofibrillary tangles in Alzheimer disease brains, specifically labels DPYSL2 when phosphorylated on Ser-518, Ser-522 and Thr-509.PTM Phosphorylation at Thr-514 by GSK3B abolishes tubulin-binding leading to destabilization of microtubule assembly in axons and neurodegeneration (By similarity). Phosphorylation by DYRK2 at Ser-522 is required for subsequent phosphorylation by GSK3B.SIMILARITY Belongs to the metallo-dependent hydrolases superfamily. Hydantoinase/dihydropyrimidinase family.CAUTION Lacks most of the conserved residues that are essential for binding the metal cofactor and hence for dihydropyrimidinase activity. Its enzyme activity is therefore unsure. UniProt Q16555 1 EQUAL 572 EQUAL Reactome Database ID Release 79 396943 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=396943 Reactome R-HSA-396943 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-396943.1 DPYSL3 Dihydropyrimidinase-related protein 3 (CRMP-4) DPYL3_HUMAN Reactome DB_ID: 398124 UniProt:Q14195 DPYSL3 DPYSL3 CRMP4 DRP3 ULIP ULIP1 FUNCTION Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance, neuronal growth cone collapse and cell migration (By similarity).SUBUNIT Homotetramer, and heterotetramer with CRMP1, DPYSL2, DPYSL4 or DPYSL5 (By similarity). Interacts with synaptic vesicle protein 2 and SH3A domain of intersectin (By similarity). Interacts with FLNA (PubMed:25358863).TISSUE SPECIFICITY Mainly expressed in heart and skeletal muscle. Also strongly expressed in fetal brain and spinal cord.PTM Phosphorylation on Ser-522 by DYRK2 promotes subsequent phosphorylation on Thr-509, Thr-514 and Ser-518 by GSK3.SIMILARITY Belongs to the metallo-dependent hydrolases superfamily. Hydantoinase/dihydropyrimidinase family.CAUTION Lacks most of the conserved residues that are essential for binding the metal cofactor and hence for dihydropyrimidinase activity. Its enzyme activity is therefore unsure. UniProt Q14195 1 EQUAL 570 EQUAL Reactome Database ID Release 79 398124 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=398124 Reactome R-HSA-398124 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-398124.1 DPYSL4 Dihydropyrimidinase-related protein 4 (CRMP-3) DPYL4_HUMAN Reactome DB_ID: 398126 UniProt:O14531 DPYSL4 DPYSL4 CRMP3 ULIP4 FUNCTION Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance, neuronal growth cone collapse and cell migration (By similarity).SUBUNIT Homotetramer, and heterotetramer with CRMP1, DPYSL2, DPYSL3 or DPYSL5 (By similarity). Interacts with PLEXA1 (By similarity). Interacts with FLNA (PubMed:25358863).SIMILARITY Belongs to the metallo-dependent hydrolases superfamily. Hydantoinase/dihydropyrimidinase family.CAUTION Lacks most of the conserved residues that are essential for binding the metal cofactor and hence for dihydropyrimidinase activity. Its enzyme activity is therefore unsure. UniProt O14531 1 EQUAL 572 EQUAL Reactome Database ID Release 79 398126 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=398126 Reactome R-HSA-398126 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-398126.1 DPYSL5 Dihydropyrimidinase-related protein 5 (CRAM) DPYL5_HUMAN Reactome DB_ID: 398138 UniProt:Q9BPU6 DPYSL5 DPYSL5 CRMP5 ULIP6 FUNCTION May have a function in neuronal differentiation and/or axon growth.SUBUNIT Homotetramer, and heterotetramer with other DPYS-like proteins. Interacts with DPYSL2, DPYSL3 and DPYSL4 (By similarity).SIMILARITY Belongs to the metallo-dependent hydrolases superfamily. Hydantoinase/dihydropyrimidinase family.CAUTION Lacks most of the conserved residues that are essential for binding the metal cofactor and hence for dihydropyrimidinase activity. Its enzyme activity is therefore unsure. UniProt Q9BPU6 1 EQUAL 564 EQUAL Reactome Database ID Release 79 398138 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=398138 Reactome R-HSA-398138 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-398138.1 Reactome Database ID Release 79 399825 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399825 Reactome R-HSA-399825 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399825.1 4 Reactome Database ID Release 79 399843 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399843 Reactome R-HSA-399843 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399843.1 4 Sema3A:Nrp-1:PlexinA:Fyn:Cdk5:pCRMP's Reactome DB_ID: 399867 1 NRP1:PlexinA1-4:FYN:Cdk5:p53:p-CRMP tetramers Reactome DB_ID: 399855 PlexinA1-4:FYN:Cdk5:p35:p-CRMP tetramers Reactome DB_ID: 399852 1 1 p-CRMP tetramers Reactome DB_ID: 399850 Converted from EntitySet in Reactome Cdk5 phosphorylated CRMP1-5 Reactome DB_ID: 399827 p-S522-CRMP1 pCRMP-1 (S522) Reactome DB_ID: 399779 522 EQUAL 1 EQUAL 572 EQUAL Reactome Database ID Release 79 399779 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399779 Reactome R-HSA-399779 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399779.1 p-S522-DPYSL2 pCRMP-2 (S522) Reactome DB_ID: 399776 522 EQUAL 1 EQUAL 572 EQUAL Reactome Database ID Release 79 399776 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399776 Reactome R-HSA-399776 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399776.1 p-S544-DPYSL4 pCRMP-3 (S544) Reactome DB_ID: 399808 544 EQUAL 1 EQUAL 572 EQUAL Reactome Database ID Release 79 399808 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399808 Reactome R-HSA-399808 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399808.1 p-S522-DPYSL3 pCRMP-4 (S522) Reactome DB_ID: 399806 522 EQUAL 1 EQUAL 570 EQUAL Reactome Database ID Release 79 399806 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399806 Reactome R-HSA-399806 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399806.1 pCRAM-5 p-S534-DPYSL5 pCRAM (S534) Reactome DB_ID: 399793 534 EQUAL 1 EQUAL 564 EQUAL Reactome Database ID Release 79 399793 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399793 Reactome R-HSA-399793 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399793.1 Reactome Database ID Release 79 399827 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399827 Reactome R-HSA-399827 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399827.1 4 Reactome Database ID Release 79 399850 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399850 Reactome R-HSA-399850 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399850.1 1 Reactome Database ID Release 79 399852 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399852 Reactome R-HSA-399852 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399852.2 1 1 Reactome Database ID Release 79 399855 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399855 Reactome R-HSA-399855 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399855.1 1 Reactome Database ID Release 79 399867 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399867 Reactome R-HSA-399867 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399867.1 ACTIVATION activeUnit: #Protein72 Reactome Database ID Release 79 399943 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399943 Reactome Database ID Release 79 399944 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399944 Reactome R-HSA-399944 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399944.1 12372285 Pubmed 2002 Fyn and Cdk5 mediate semaphorin-3A signaling, which is involved in regulation of dendrite orientation in cerebral cortex Sasaki, Y Cheng, C Uchida, Y Nakajima, O Ohshima, T Yagi, T Taniguchi, M Nakayama, T Kishida, R Kudo, Y Ohno, S Nakamura, F Goshima, Y Neuron 35:907-20 14685275 Pubmed 2004 Structural bases for CRMP function in plexin-dependent semaphorin3A signaling Deo, RC Schmidt, EF Elhabazi, A Togashi, H Burley, SK Strittmatter, SM EMBO J 23:9-22 LEFT-TO-RIGHT 2.7.11.1 Phosphorylation of CRMPs by GSK3beta The phosphorylation of CRMPs at Ser522 allows the subsequent phosphorylation of CRMP1, CRMP2 and CRMP4 at Ser518, Thr509, and Thr514 mediated by serine/threonine kinase GSK3beta. Phosphorylation of CRMP by GSK3beta results in decreased CRMP affinity for beta-tubulin and changes in microtubule dynamics. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 9 9 Sema3A:Nrp-1:PlexinA:Fyn:Cdk5:pCRMP's Reactome DB_ID: 399870 1 Nrp-1:PlexinA:Fyn:Cdk5:pCRMP's (S522,S518,T509,T514) Reactome DB_ID: 399853 PlexinA1-4:FYN:CDK5:p-CRMPs (S522,S518,T509,T514) Reactome DB_ID: 399851 pCRMP's tetramers (S522,S518,T509,T514) Reactome DB_ID: 399848 Converted from EntitySet in Reactome GSK3beta phosphorylated CRMP's 1-5 Reactome DB_ID: 399832 p-T509,T514,S518,S522-CRMP1 p-S518,S522,T509,T514-CRMP1 pCRMP-1 (S522,S518,T509,T514) Reactome DB_ID: 399777 518 EQUAL 509 EQUAL 514 EQUAL 1 EQUAL 572 EQUAL Reactome Database ID Release 79 399777 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399777 Reactome R-HSA-399777 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399777.1 p-T509,T514,S518,S522-DPYSL2 p-S518,S522,T509,T514-DPYSL2 pCRMP-2 (S522,S518,T509,T514) Reactome DB_ID: 399778 518 EQUAL 509 EQUAL 514 EQUAL 1 EQUAL 572 EQUAL Reactome Database ID Release 79 399778 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399778 Reactome R-HSA-399778 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399778.1 p-T509,T514,S518,S522-DPYSL3 p-S518,S522,T509,T514-DPYSL3 pCRMP-4 (S522,S518,T509,T514) Reactome DB_ID: 399798 518 EQUAL 509 EQUAL 514 EQUAL 1 EQUAL 570 EQUAL Reactome Database ID Release 79 399798 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399798 Reactome R-HSA-399798 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399798.1 Reactome Database ID Release 79 399832 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399832 Reactome R-HSA-399832 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399832.1 4 Reactome Database ID Release 79 399848 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399848 Reactome R-HSA-399848 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399848.1 1 1 1 Reactome Database ID Release 79 399851 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399851 Reactome R-HSA-399851 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399851.1 1 1 Reactome Database ID Release 79 399853 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399853 Reactome R-HSA-399853 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399853.1 1 Reactome Database ID Release 79 399870 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399870 Reactome R-HSA-399870 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399870.1 ACTIVATION GSK3B Glycogen synthase kinase-3 beta GSK3B_HUMAN Reactome DB_ID: 2997551 UniProt:P49841 GSK3B GSK3B FUNCTION Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation. Phosphorylates SFPQ at 'Thr-687' upon T-cell activation. Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including ARNTL/BMAL1, CLOCK and PER2 (PubMed:19946213, PubMed:28903391). Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation (PubMed:19946213). Phosphorylates ARNTL/BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation (PubMed:28903391). Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (PubMed:24391509). Regulates the circadian rhythmicity of hippocampal long-term potentiation and ARNTL/BMLA1 and PER2 expression (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, leading to activate KAT5/TIP60 acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (PubMed:18846110).ACTIVITY REGULATION Activated by phosphorylation at Tyr-216. In response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1 and RPS6KA3; phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. Inhibited by lithium.SUBUNIT Monomer. Interacts with ARRB2, DISC1 and ZBED3 (By similarity). Interacts with CABYR, MMP2, MUC1, NIN and PRUNE1. Interacts with AXIN1; the interaction mediates hyperphosphorylation of CTNNB1 leading to its ubiquitination and destruction. Interacts with and phosphorylates SNAI1. Interacts with DNM1L (via a C-terminal domain). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B (By similarity). Interacts with SGK3. Interacts with DAB2IP (via C2 domain); the interaction stimulates GSK3B kinase activation. Interacts (via C2 domain) with PPP2CA. Interacts with the CLOCK-ARNTL/BMAL1 heterodimer (PubMed:19946213). Interacts with the ARNTL/BMAL1 (PubMed:28903391). Interacts with CTNND2 (PubMed:19706605). Interacts with NCYM (PubMed:24391509). The complex composed, at least, of APC, CTNNB1 and GSK3B interacts with JPT1; the interaction requires the inactive form of GSK3B (phosphorylated at 'Ser-9') (PubMed:25169422). Forms a complex composed of PRKAR2A or PRKAR2B, GSK3B and GSKIP through GSKIP interaction; facilitates PKA-induced phosphorylation and regulates GSK3B activity (PubMed:27484798, PubMed:20007971, PubMed:25920809). Interacts with GSKIP (PubMed:16981698). Interacts with GID8 (PubMed:28829046). Interacts with PIWIL2 (By similarity). Interacts with LMBR1L (PubMed:31073040). Interacts with DDX3X (PubMed:18846110). Interacts with BIRC2 (PubMed:18846110). Interacts with TNFRSF10B; TNFRSF10B stimulation inhibits GSK3B kinase activity (PubMed:18846110).TISSUE SPECIFICITY Expressed in testis, thymus, prostate and ovary and weakly expressed in lung, brain and kidney. Colocalizes with EIF2AK2/PKR and TAU in the Alzheimer disease (AD) brain.PTM Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and desactivates GSK3B, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-216 (PubMed:25169422). Inactivated by phosphorylation at Ser-9 (Probable). Phosphorylated in a circadian manner in the hippocampus (By similarity).PTM Mono-ADP-ribosylation by PARP10 negatively regulates kinase activity.MISCELLANEOUS Higher expression and activity of GSK3B are found in the skeletal muscle (vastus lateralis) of patients with type 2 diabetes (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B) inhibitors have been identified and characterized in preclinical models for treatments of type 2 diabetes (PubMed:19366350).SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. GSK-3 subfamily. UniProt P49841 1 EQUAL 420 EQUAL Reactome Database ID Release 79 2997551 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2997551 Reactome R-HSA-2997551 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2997551.1 Reactome Database ID Release 79 208885 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=208885 Reactome Database ID Release 79 399951 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399951 Reactome R-HSA-399951 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399951.1 15652488 Pubmed 2005 GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity Yoshimura, T Kawano, Y Arimura, N Kawabata, S Kikuchi, A Kaibuchi, K Cell 120:137-49 15676027 Pubmed 2005 Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer's disease Uchida, Y Ohshima, T Sasaki, Y Suzuki, H Yanai, S Yamashita, N Nakamura, F Takei, K Ihara, Y Mikoshiba, K Kolattukudy, P Honnorat, J Goshima, Y Genes Cells 10:165-79 LEFT-TO-RIGHT 2.7.10.2 Tyrosine phosphorylation of CRMPs by Fes Fes bound to Plexin-A is able to phosphorylate all five forms of CRMP, though neither specific sites nor the consequence of tyrosine phosphorylation in CRMP's have yet been investigated directly. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 5 5 Sema3A:NP-1:Plexin-A:Fes:CRMP Reactome DB_ID: 399860 pCRMP's tertramers (Y499) Reactome DB_ID: 399863 Converted from EntitySet in Reactome Fes phosphorylated CRMP's 1-5 Reactome DB_ID: 399829 p-Y-CRMP1 Tyrosine phosphorylated CRMP-1 Reactome DB_ID: 399784 1 EQUAL 572 EQUAL Reactome Database ID Release 79 399784 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399784 Reactome R-HSA-399784 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399784.1 p-Y-DPYSL2 Tyrosine phosphorylated CRMP-2 Reactome DB_ID: 399804 1 EQUAL 572 EQUAL Reactome Database ID Release 79 399804 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399804 Reactome R-HSA-399804 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399804.1 p-Y-DPYSL4 Tyrosine phosphorylated CRMP-3 Reactome DB_ID: 399794 1 EQUAL 572 EQUAL Reactome Database ID Release 79 399794 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399794 Reactome R-HSA-399794 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399794.1 p-Y-DPYSL3 Tyrosine phosphorylated CRMP-4 Reactome DB_ID: 399795 1 EQUAL 570 EQUAL Reactome Database ID Release 79 399795 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399795 Reactome R-HSA-399795 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399795.1 p-Y-DPYSL5 Tyrosine phosphorylated CRAM Reactome DB_ID: 399786 1 EQUAL 564 EQUAL Reactome Database ID Release 79 399786 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399786 Reactome R-HSA-399786 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399786.1 Reactome Database ID Release 79 399829 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399829 Reactome R-HSA-399829 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399829.1 4 Reactome Database ID Release 79 399863 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399863 Reactome R-HSA-399863 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399863.1 1 1 Reactome Database ID Release 79 399860 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399860 Reactome R-HSA-399860 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399860.1 ACTIVATION Reactome Database ID Release 79 399947 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399947 Reactome R-HSA-399947 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399947.1 17607944 Pubmed 2007 Intracellular kinases in semaphorin signaling Ahmed, A Eickholt, BJ Adv Exp Med Biol 600:24-37 Reactome Database ID Release 79 399956 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399956 Reactome R-HSA-399956 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399956.1 Other semaphorin interactions There are eight classes of semaphorins and four types of plexins. Semaphorin (SEMA) classes 1 and 2 are found in invertebrates and classes 3-7 are vertebrate sempahorines. Sempahorin class 3 is secreted, whereas the other classes are synthesised as transmembrane proteins. Vertebrate plexins (PLXNs) are classified into four subfamilies plexin-A to -D. There are four A-type plexins, three B-type, one C-type and D-type. Interactions between different subfamilies of plexins and semaphorins show differential specificity, which trigger different sets of biological functions. Another level of functional specificity specificity is attained by plexins by coupling with various coreceptors expressed in a cell- or tissue-specific manner, such as neuropilins (NRP), L1CAM, c-MET proto-oncogene, ERB2, CD72 and CD45 (Kruger et al. 2005, Law & Lee 2012). Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:38 LEFT-TO-RIGHT SEMA3E binds to PLXND1 SEMA3E binds to neither neuropilin but instead binds directly to plexin-D1. This interaction controls endothelial cell positioning and the patterning of the developing vasculature. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 PLXND1 Plexin-D1 PXD1_HUMAN Reactome DB_ID: 209637 UniProt:Q9Y4D7 PLXND1 PLXND1 KIAA0620 FUNCTION Cell surface receptor for SEMA4A and for class 3 semaphorins, such as SEMA3A, SEMA3C and SEMA3E. Plays an important role in cell-cell signaling, and in regulating the migration of a wide spectrum of cell types. Regulates the migration of thymocytes in the medulla. Regulates endothelial cell migration. Plays an important role in ensuring the specificity of synapse formation. Required for normal development of the heart and vasculature (By similarity). Mediates anti-angiogenic signaling in response to SEMA3E.SUBUNIT Interacts with NRP1 and SEMA4A (By similarity). Interacts with SH3BP1; they dissociate upon SEMA3E binding to PLXND1 allowing SH3BP1 to transduce downstream signal through RAC1 inactivation (PubMed:24841563).TISSUE SPECIFICITY Detected at low levels in heart, placenta, lung, skeletal muscle, kidney, thymus and liver. Detected at very low levels in brain, colon, spleen, small intestine and peripheral blood leukocytes.SIMILARITY Belongs to the plexin family. UniProt Q9Y4D7 47 EQUAL 1925 EQUAL Reactome Database ID Release 79 209637 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=209637 Reactome R-HSA-209637 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-209637.1 SEMA3E Semaphorin 3E precursor SM3E_HUMAN Reactome DB_ID: 198226 UniProt:O15041 SEMA3E SEMA3E KIAA0331 SEMAH FUNCTION Plays an important role in signaling via the cell surface receptor PLXND1. Mediates reorganization of the actin cytoskeleton, leading to the retraction of cell projections. Promotes focal adhesion disassembly and inhibits adhesion of endothelial cells to the extracellular matrix. Regulates angiogenesis, both during embryogenesis and after birth. Can down-regulate sprouting angiogenesis. Required for normal vascular patterning during embryogenesis. Plays an important role in ensuring the specificity of synapse formation (By similarity).SUBUNIT Interacts with PLXND1.SIMILARITY Belongs to the semaphorin family. UniProt O15041 26 EQUAL 775 EQUAL Reactome Database ID Release 79 198226 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198226 Reactome R-HSA-198226 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198226.1 SEMA3A:PLXND1 Reactome DB_ID: 209639 1 1 Reactome Database ID Release 79 209639 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=209639 Reactome R-HSA-209639 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-209639.1 Reactome Database ID Release 79 416683 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416683 Reactome R-HSA-416683 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416683.1 15550623 Pubmed 2005 Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins Gu, C Yoshida, Y Livet, J Reimert, DV Mann, F Merte, J Henderson, CE Jessell, TM Kolodkin, AL Ginty, DD Science 307:265-8 LEFT-TO-RIGHT SEMA4A binds to PLXND1 Sema4A binds plexinD1 to inhibit angiogenesis. Sema4A–plexinD1 interactions modulate VEGF-mediated endothelial cell migration and proliferation at the intracellular level by suppressing VEGF–VEGFR2-induced activation of Rac1, Akt and integrins. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 SEMA4A Semaphorin 4A precursor SM4A_HUMAN Reactome DB_ID: 198232 UniProt:Q9H3S1 SEMA4A SEMA4A SEMAB SEMB UNQ783/PRO1317 FUNCTION Cell surface receptor for PLXNB1, PLXNB2, PLXNB3 and PLXND1 that plays an important role in cell-cell signaling (By similarity). Regulates glutamatergic and GABAergic synapse development (By similarity). Promotes the development of inhibitory synapses in a PLXNB1-dependent manner and promotes the development of excitatory synapses in a PLXNB2-dependent manner (By similarity). Plays a role in priming antigen-specific T-cells, promotes differentiation of Th1 T-helper cells, and thereby contributes to adaptive immunity (By similarity). Promotes phosphorylation of TIMD2 (By similarity). Inhibits angiogenesis (By similarity). Promotes axon growth cone collapse (By similarity). Inhibits axonal extension by providing local signals to specify territories inaccessible for growing axons (By similarity).SUBUNIT Interacts with PLXNB1, PLXNB2, PLXNB3, PLXND1 and TIMD2 (By similarity).SIMILARITY Belongs to the semaphorin family.CAUTION Variant Gln-713 was originally reported as mutation causing retinitis pigmentosa (PubMed:16199541). Subsequently, it has been shown to be a likely benign variant (PubMed:22956603, PubMed:28805479). UniProt Q9H3S1 33 EQUAL 761 EQUAL Reactome Database ID Release 79 198232 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198232 Reactome R-HSA-198232 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198232.1 SEMA4A:PLXND1 Reactome DB_ID: 416694 1 1 Reactome Database ID Release 79 416694 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416694 Reactome R-HSA-416694 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416694.1 Reactome Database ID Release 79 416690 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416690 Reactome R-HSA-416690 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416690.1 17318185 Pubmed 2007 Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-D1 Toyofuku, T Yabuki, M Kamei, J Kamei, M Makino, N Kumanogoh, Atsushi Hori, M EMBO J 26:1373-84 LEFT-TO-RIGHT SEMA4D interacts with CD45 SEMA4D also associates with CD45, a cell surface protein tyrosine phosphatase (PTP) considered a key molecule in the T-cell receptor (TCR) activation process. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 PTPRC Leukocyte common antigen precursor CD45_HUMAN Reactome DB_ID: 197931 UniProt:P08575 PTPRC PTPRC CD45 FUNCTION Protein tyrosine-protein phosphatase required for T-cell activation through the antigen receptor. Acts as a positive regulator of T-cell coactivation upon binding to DPP4. The first PTPase domain has enzymatic activity, while the second one seems to affect the substrate specificity of the first one. Upon T-cell activation, recruits and dephosphorylates SKAP1 and FYN. Dephosphorylates LYN, and thereby modulates LYN activity (By similarity).FUNCTION (Microbial infection) Acts as a receptor for human cytomegalovirus protein UL11 and mediates binding of UL11 to T-cells, leading to reduced induction of tyrosine phosphorylation of multiple signaling proteins upon T-cell receptor stimulation and impaired T-cell proliferation.SUBUNIT Binds GANAB and PRKCSH (By similarity). Interacts with SKAP1 (PubMed:11909961). Interacts with DPP4; the interaction is enhanced in an interleukin-12-dependent manner in activated lymphocytes (PubMed:12676959).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus protein UL11; the interaction is required for binding of UL11 to T-cells.TISSUE SPECIFICITY Isoform 1: Detected in thymocytes. Isoform 2: Detected in thymocytes. Isoform 3: Detected in thymocytes. Isoform 4: Not detected in thymocytes. Isoform 5: Detected in thymocytes. Isoform 6: Not detected in thymocytes. Isoform 7: Detected in thymocytes. Isoform 8: Not detected in thymocytes.DEVELOPMENTAL STAGE Isoform 1: During T-cell development, expressed at the CD3-CD4-CD8- and CD3+CD4+CD8- stages but barely detectable at the CD3-CD4+CD8+ stage. Isoform 2: During T-cell development, expressed at low levels at the CD3-CD4-CD8- and CD3-CD4+CD8- stages but up-regulated at the CD3+CD4+CD8+ and CD3+CD4+CD8- stages. Isoform 3: During T-cell development, expressed at the CD3-CD4-CD8- and CD3+CD4+CD8- stages but barely detectable at the CD3-CD4+CD8+ stage. Isoform 5: During T-cell development, expressed at the CD3-CD4-CD8- and CD3+CD4+CD8- stages but barely detectable at the CD3-CD4+CD8+ stage. Isoform 7: Consistently expressed at high levels at all stages of T-cell development.DOMAIN The first PTPase domain interacts with SKAP1.PTM Heavily N- and O-glycosylated.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Receptor class 1/6 subfamily.CAUTION It is uncertain whether Met-1 or Met-3 is the initiator. UniProt P08575 24 EQUAL 1304 EQUAL Reactome Database ID Release 79 197931 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197931 Reactome R-HSA-197931 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197931.1 SEMA4D:PTPRC Reactome DB_ID: 373689 1 1 Reactome Database ID Release 79 373689 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=373689 Reactome R-HSA-373689 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-373689.1 Reactome Database ID Release 79 373746 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=373746 Reactome R-HSA-373746 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-373746.1 8955171 Pubmed 1996 CD100 is associated with CD45 at the surface of human T lymphocytes. Role in T cell homotypic adhesion Herold, C Elhabazi, A Bismuth, G Bensussan, A Boumsell, L J Immunol 157:5262-8 10648410 Pubmed 2000 Switch in the protein tyrosine phosphatase associated with human CD100 semaphorin at terminal B-cell differentiation stage Billard, C Delaire, S Raffoux, E Bensussan, A Boumsell, L Blood 95:965-72 LEFT-TO-RIGHT SEMA4D interacts with CD72 In the immune system, Sema4D/CD100 binds CD72 to mediate B-cell-B-cell, B-cell-T-cell and T-cell-dendritic cell interactions and there by regulates B-cell and T-cell activation. In B-cells, this interaction directs the dissociation of SHP-1 from the CD72 cytoplasmic domain and enhances their activation.<br> Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 CD72 B-cell differentiation antigen CD72 CD72_HUMAN Reactome DB_ID: 198121 UniProt:P21854 CD72 CD72 FUNCTION Plays a role in B-cell proliferation and differentiation.SUBUNIT Homodimer; disulfide-linked. Associates with CD5. Interacts (tyrosine phosphorylated) with PTPN6/SHP-1 (By similarity).TISSUE SPECIFICITY Pre-B-cells and B-cells but not terminally differentiated plasma cells.PTM Phosphorylated upon engagement of the B-cell receptor, probably by LYN or SYK. Phosphorylation at Tyr-7 is important for interaction with PTPN6/SHP-1 (By similarity). UniProt P21854 1 EQUAL 359 EQUAL Reactome Database ID Release 79 198121 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198121 Reactome R-HSA-198121 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198121.1 SEMA4D:CD72 Reactome DB_ID: 373697 1 1 Reactome Database ID Release 79 373697 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=373697 Reactome R-HSA-373697 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-373697.1 Reactome Database ID Release 79 373748 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=373748 Reactome R-HSA-373748 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-373748.1 12882840 Pubmed 2003 Involvement of CD100, a lymphocyte semaphorin, in the activation of the human immune system via CD72: implications for the regulation of immune and inflammatory responses Ishida, I Kumanogoh, Atsushi Suzuki, K Akahani, S Noda, K Kikutani, Hitoshi Int Immunol 15:1027-34 11114375 Pubmed 2000 Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling Kumanogoh, Atsushi Watanabe, C Lee, I Wang, X Shi, W Araki, H Hirata, H Iwahori, K Uchida, J Yasui, T Matsumoto, M Yoshida, K Yakura, H Pan, C Parnes, JR Kikutani, Hitoshi Immunity 13:621-31 LEFT-TO-RIGHT SEMA5A binds to PLXNB3 Sema5s have been implicated in invasive growth, vascular patterning and axon guidance. Plexin-B3 is the specific and high-affinity receptor for Sema5A, and their interaction triggers the collapsing response. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 SEMA5A Semaphorin 5A SM5A_HUMAN Reactome DB_ID: 198222 UniProt:Q13591 SEMA5A SEMA5A SEMAF FUNCTION Bifunctional axonal guidance cue regulated by sulfated proteoglycans; attractive effects result from interactions with heparan sulfate proteoglycans (HSPGs), while the inhibitory effects depend on interactions with chondroitin sulfate proteoglycans (CSPGs) (By similarity). Ligand for receptor PLXNB3. In glioma cells, SEMA5A stimulation of PLXNB3 results in the disassembly of F-actin stress fibers, disruption of focal adhesions and cellular collapse as well as inhibition of cell migration and invasion through ARHGDIA-mediated inactivation of RAC1. May promote angiogenesis by increasing endothelial cell proliferation and migration and inhibiting apoptosis.SUBUNIT Binds PLXNB3.SIMILARITY Belongs to the semaphorin family. UniProt Q13591 23 EQUAL 1074 EQUAL Reactome Database ID Release 79 198222 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198222 Reactome R-HSA-198222 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198222.1 PLXNB3 Plexin-B3 PLXB3_HUMAN Reactome DB_ID: 416675 UniProt:Q9ULL4 PLXNB3 PLXNB3 KIAA1206 PLXN6 FUNCTION Receptor for SEMA5A that plays a role in axon guidance, invasive growth and cell migration. Stimulates neurite outgrowth and mediates Ca(2+)/Mg(2+)-dependent cell aggregation. In glioma cells, SEMA5A stimulation of PLXNB3 results in the disassembly of F-actin stress fibers, disruption of focal adhesions and cellular collapse as well as inhibition of cell migration and invasion through ARHGDIA-mediated inactivation of RAC1.SUBUNIT Interacts (via cytoplasmic domain) with RAC1 and ARHGDIA (By similarity). Binds MET and MST1R. Interacts (via cytoplasmic domain) with FSCN1. Interacts with RIT2/RIN. May form homodimers (via Sema domain).TISSUE SPECIFICITY Expression detected in Purkinje and granular cells in cerebellum, and in brain neocortex but not in corpus callosum. Expressed in glioma cells and embryonic kidney cells (at protein level). Expressed in brain, liver, pancreas and placenta, with weak expression detected also in lung and kidney. Expressed in several glioma cell lines.SIMILARITY Belongs to the plexin family. UniProt Q9ULL4 45 EQUAL 1909 EQUAL Reactome Database ID Release 79 416675 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416675 Reactome R-HSA-416675 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416675.1 SEMA5A:PLXNB3 Reactome DB_ID: 416696 1 1 Reactome Database ID Release 79 416696 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416696 Reactome R-HSA-416696 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416696.1 Reactome Database ID Release 79 416698 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416698 Reactome R-HSA-416698 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416698.1 15218527 Pubmed 2004 Plexin-B3 is a functional receptor for semaphorin 5A Artigiani, S Conrotto, P Fazzari, P Gilestro, GF Barberis, D Giordano, S Comoglio, PM Tamagnone, L EMBO Rep 5:710-4 LEFT-TO-RIGHT SEMA6A binds to PLXNA2 and PLXNA4 Sema6A binds plexinA2 and plexinA4 to establish lamina-restricted axon projection in the hippocampus. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 Converted from EntitySet in Reactome PLXNA2,PLXNA4 Reactome DB_ID: 416718 Reactome Database ID Release 79 416718 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416718 Reactome R-HSA-416718 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416718.1 SEMA6A Semaphorin-6A SEM6A_HUMAN Reactome DB_ID: 416714 UniProt:Q9H2E6 SEMA6A SEMA6A KIAA1368 SEMAQ FUNCTION Cell surface receptor for PLXNA2 that plays an important role in cell-cell signaling. Required for normal granule cell migration in the developing cerebellum. Promotes reorganization of the actin cytoskeleton and plays an important role in axon guidance in the developing central nervous system. Can act as repulsive axon guidance cue. Has repulsive action towards migrating granular neurons. May play a role in channeling sympathetic axons into the sympathetic chains and controlling the temporal sequence of sympathetic target innervation.FUNCTION (Microbial infection) Acts as a receptor for P.sordellii toxin TcsL in the in the vascular endothelium.SUBUNIT Active as a homodimer or oligomer (By similarity). The SEMA6A homodimer interacts with a PLXNA2 homodimer, giving rise to a heterotetramer (By similarity). Interacts with EVL (PubMed:10993894).SUBUNIT (Microbial infection) Interacts with P.sordellii toxin TcsL; semaphorins SEMA6A and SEMA6B constitute the major host receptors for TcsL in the vascular endothelium.SIMILARITY Belongs to the semaphorin family. UniProt Q9H2E6 19 EQUAL 1030 EQUAL Reactome Database ID Release 79 416714 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416714 Reactome R-HSA-416714 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416714.1 SEMA6A:PLXNA2,PLXNA4 Reactome DB_ID: 416728 1 1 Reactome Database ID Release 79 416728 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416728 Reactome R-HSA-416728 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416728.1 Reactome Database ID Release 79 416723 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416723 Reactome R-HSA-416723 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416723.1 17296555 Pubmed 2007 Interactions between plexin-A2, plexin-A4, and semaphorin 6A control lamina-restricted projection of hippocampal mossy fibers Suto, F Tsuboi, M Kamiya, H Mizuno, H Kiyama, Y Komai, S Shimizu, M Sanbo, M Yagi, T Hiromi, Y Chédotal, A Mitchell, KJ Manabe, T Fujisawa, H Neuron 53:535-47 LEFT-TO-RIGHT SEMA6D binds to PLXNA1:TREM2:DAP12 Plexin-A1 is a receptor for the transmembrane semaphorin, Sema6D. Plexin-A1 associates with the triggering receptor expressed on myeloid cells-2 (Trem-2), linking semaphorin-signalling to the immuno-receptor tyrosine-based activation motif (ITAM)-bearing adaptor protein, DAP12. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 SEMA6D Semaphorin-6D SEM6D_HUMAN Reactome DB_ID: 416706 UniProt:Q8NFY4 SEMA6D SEMA6D KIAA1479 FUNCTION Shows growth cone collapsing activity on dorsal root ganglion (DRG) neurons in vitro. May be a stop signal for the DRG neurons in their target areas, and possibly also for other neurons. May also be involved in the maintenance and remodeling of neuronal connections.SIMILARITY Belongs to the semaphorin family. UniProt Q8NFY4 21 EQUAL 1073 EQUAL Reactome Database ID Release 79 416706 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416706 Reactome R-HSA-416706 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416706.1 PLXNA1:TREM2:DAP12 Reactome DB_ID: 416707 1 DAP12 dimer:TREM2 Reactome DB_ID: 210245 DAP12 dimer Reactome DB_ID: 548940 DAP12 TYROBP TYRO protein tyrosine kinase-binding protein precursor TYBP_HUMAN Reactome DB_ID: 198087 UniProt:O43914 TYROBP TYROBP DAP12 KARAP FUNCTION Adapter protein which non-covalently associates with activating receptors found on the surface of a variety of immune cells to mediate signaling and cell activation following ligand binding by the receptors (PubMed:9490415, PubMed:9655483, PubMed:10604985). TYROBP is tyrosine-phosphorylated in the ITAM domain following ligand binding by the associated receptors which leads to activation of additional tyrosine kinases and subsequent cell activation (PubMed:9490415). Also has an inhibitory role in some cells (PubMed:21727189). Non-covalently associates with activating receptors of the CD300 family to mediate cell activation (PubMed:15557162, PubMed:16920917, PubMed:17928527; PubMed:26221034). Also mediates cell activation through association with activating receptors of the CD200R family (By similarity). Required for neutrophil activation mediated by integrin (By similarity). Required for the activation of myeloid cells mediated by the CLEC5A/MDL1 receptor (PubMed:10449773). Associates with natural killer (NK) cell receptors such as KIR2DS2 and the KLRD1/KLRC2 heterodimer to mediate NK cell activation (PubMed:9490415, PubMed:9655483, PubMed:23715743). Also enhances trafficking and cell surface expression of NK cell receptors KIR2DS1, KIR2DS2 and KIR2DS4 and ensures their stability at the cell surface (PubMed:23715743). Associates with SIRPB1 to mediate activation of myeloid cells such as monocytes and dendritic cells (PubMed:10604985). Associates with TREM1 to mediate activation of neutrophils and monocytes (PubMed:10799849). Associates with TREM2 on monocyte-derived dendritic cells to mediate up-regulation of chemokine receptor CCR7 and dendritic cell maturation and survival (PubMed:11602640). Association with TREM2 mediates cytokine-induced formation of multinucleated giant cells which are formed by the fusion of macrophages (PubMed:18957693). Stabilizes the TREM2 C-terminal fragment (TREM2-CTF) produced by TREM2 ectodomain shedding which suppresses the release of pro-inflammatory cytokines (PubMed:25957402). In microglia, required with TREM2 for phagocytosis of apoptotic neurons (By similarity). Required with ITGAM/CD11B in microglia to control production of microglial superoxide ions which promote the neuronal apoptosis that occurs during brain development (By similarity). Promotes proinflammatory responses in microglia following nerve injury which accelerates degeneration of injured neurons (By similarity). Positively regulates the expression of the IRAK3/IRAK-M kinase and IL10 production by liver dendritic cells and inhibits their T cell allostimulatory ability (By similarity). Negatively regulates B cell proliferation (PubMed:21727189). Required for CSF1-mediated osteoclast cytoskeletal organization (By similarity). Positively regulates multinucleation during osteoclast development (By similarity).SUBUNIT Homodimer; disulfide-linked (PubMed:20890284). Homotrimer; disulfide-linked (PubMed:25981043). Homotetramer; disulfide-linked (PubMed:25981043). Homotrimers and homotetramers form when low levels of partner receptors are available and are competitive with assembly with interacting receptors (PubMed:25981043). They may represent alternative oligomerization states or may be intermediates in the receptor assembly process (PubMed:25981043). Binding of a metal cation aids in homooligomerization through coordination of the metal ion by the subunits of the oligomer (PubMed:25981043). Interacts with TREM1 (PubMed:10799849). Interacts with TREM2 (PubMed:11602640, PubMed:25957402). Interacts with SIRPB1 (PubMed:10604985). Interacts with CLECSF5 (PubMed:10449773). Interacts with SIGLEC14 (PubMed:17012248). Interacts with CD300LB and CD300E (PubMed:15557162, PubMed:16920917, PubMed:17928527). Interacts with CD300C2 (By similarity). Interacts (via ITAM domain) with SYK (via SH2 domains); activates SYK mediating neutrophil and macrophage integrin-mediated activation (By similarity). Interacts with KLRC2, KIR2DS3 and KIR2DS5 (PubMed:18624290, PubMed:20890284). Interacts with CD300H (PubMed:26221034). Interacts with KIR2DS1 (PubMed:23715743). Interacts with KLRD1 (PubMed:9655483, PubMed:15940674).TISSUE SPECIFICITY Expressed at low levels in the early development of the hematopoietic system and in the promonocytic stage and at high levels in mature monocytes. Expressed in hematological cells and tissues such as peripheral blood leukocytes and spleen. Also found in bone marrow, lymph nodes, placenta, lung and liver. Expressed at lower levels in different parts of the brain especially in the basal ganglia and corpus callosum.PTM Following ligand binding by associated receptors, tyrosine phosphorylated in the ITAM domain which leads to activation of additional tyrosine kinases and subsequent cell activation.SIMILARITY Belongs to the TYROBP family. UniProt O43914 22 EQUAL 113 EQUAL Reactome Database ID Release 79 198087 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198087 Reactome R-HSA-198087 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198087.1 2 Reactome Database ID Release 79 548940 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548940 Reactome R-HSA-548940 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548940.1 1 TREM2 Triggering receptor expressed on myeloid cells 2 precursor TMR2_HUMAN Reactome DB_ID: 197664 UniProt:Q9NZC2 TREM2 TREM2 FUNCTION Forms a receptor signaling complex with TYROBP which mediates signaling and cell activation following ligand binding (PubMed:10799849). Acts as a receptor for amyloid-beta protein 42, a cleavage product of the amyloid-beta precursor protein APP, and mediates its uptake and degradation by microglia (PubMed:27477018, PubMed:29518356). Binding to amyloid-beta 42 mediates microglial activation, proliferation, migration, apoptosis and expression of pro-inflammatory cytokines, such as IL6R and CCL3, and the anti-inflammatory cytokine ARG1 (By similarity). Acts as a receptor for lipoprotein particles such as LDL, VLDL, and HDL and for apolipoproteins such as APOA1, APOA2, APOB, APOE, APOE2, APOE3, APOE4, and CLU and enhances their uptake in microglia (PubMed:27477018). Binds phospholipids (preferably anionic lipids) such as phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and sphingomyelin (PubMed:29794134). Regulates microglial proliferation by acting as an upstream regulator of the Wnt/beta-catenin signaling cascade (By similarity). Required for microglial phagocytosis of apoptotic neurons (PubMed:24990881). Also required for microglial activation and phagocytosis of myelin debris after neuronal injury and of neuronal synapses during synapse elimination in the developing brain (By similarity). Regulates microglial chemotaxis and process outgrowth, and also the microglial response to oxidative stress and lipopolysaccharide (By similarity). It suppresses PI3K and NF-kappa-B signaling in response to lipopolysaccharide; thus promoting phagocytosis, suppressing pro-inflammatory cytokine and nitric oxide production, inhibiting apoptosis and increasing expression of IL10 and TGFB (By similarity). During oxidative stress, it promotes anti-apoptotic NF-kappa-B signaling and ERK signaling (By similarity). Plays a role in microglial MTOR activation and metabolism (By similarity). Regulates age-related changes in microglial numbers (PubMed:29752066). Triggers activation of the immune responses in macrophages and dendritic cells (PubMed:10799849). Mediates cytokine-induced formation of multinucleated giant cells which are formed by the fusion of macrophages (By similarity). In dendritic cells, it mediates up-regulation of chemokine receptor CCR7 and dendritic cell maturation and survival (PubMed:11602640). Involved in the positive regulation of osteoclast differentiation (PubMed:12925681).SUBUNIT Monomer (PubMed:27995897). After ectodomain shedding, the extracellular domain oligomerizes, which is enhanced and stabilized by binding of phosphatidylserine (PubMed:29794134). Interacts with TYROBP/DAP12 (PubMed:11602640, PubMed:25957402). Interaction with TYROBP is required for stabilization of the TREM2 C-terminal fragment (TREM2-CTF) which is produced by proteolytic processing (PubMed:25957402).TISSUE SPECIFICITY Expressed in the brain, specifically in microglia and in the fusiform gyrus (at protein level) (PubMed:28802038, PubMed:28855300, PubMed:27477018, PubMed:29752066). Expressed on macrophages and dendritic cells but not on granulocytes or monocytes (PubMed:10799849, PubMed:28855301). In the CNS strongest expression seen in the basal ganglia, corpus callosum, medulla oblongata and spinal cord (PubMed:12080485).PTM Undergoes ectodomain shedding through proteolytic cleavage by ADAM10 and ADAM17 to produce a transmembrane segment, the TREM2 C-terminal fragment (TREM2-CTF), which is subsequently cleaved by gamma-secretase. UniProt Q9NZC2 19 EQUAL 230 EQUAL Reactome Database ID Release 79 197664 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197664 Reactome R-HSA-197664 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197664.1 1 Reactome Database ID Release 79 210245 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=210245 Reactome R-HSA-210245 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-210245.1 1 Reactome Database ID Release 79 416707 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416707 Reactome R-HSA-416707 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416707.1 SEMA6D:PLXNA1:TREM2:DAP12 Reactome DB_ID: 416720 1 1 Reactome Database ID Release 79 416720 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416720 Reactome R-HSA-416720 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416720.1 Reactome Database ID Release 79 416725 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416725 Reactome R-HSA-416725 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416725.1 16715077 Pubmed 2006 Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis Takegahara, N Takamatsu, H Toyofuku, T Tsujimura, T Okuno, T Yukawa, K Mizui, M Yamamoto, M Prasad, DV Suzuki, K Ishii, M Terai, K Moriya, M Nakatsuji, Y Sakoda, S Sato, S Akira, Shizuo Takeda, K Inui, M Takai, T Ikawa, M Okabe, M Kumanogoh, Atsushi Kikutani, Hitoshi Nat Cell Biol 8:615-22 LEFT-TO-RIGHT SEMA7A binds to PLXNC1 Sema7A signals through two unrelated receptors, an RGD-dependent alpha1beta1-integrin and a member of the plexin family, plexinC1. Sema7A-plexinC1 interactions have been implicated in immune system function and also participate in neuronal network formation. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 PLXNC1 Plexin-C1 PLXC1_HUMAN Reactome DB_ID: 434899 UniProt:O60486 PLXNC1 PLXNC1 VESPR FUNCTION Receptor for SEMA7A, for smallpox semaphorin A39R, vaccinia virus semaphorin A39R and for herpesvirus Sema protein. Binding of semaphorins triggers cellular responses leading to the rearrangement of the cytoskeleton and to secretion of IL6 and IL8 (By similarity).SUBUNIT Monomer. Homodimer. Interacts with SEMA7A.TISSUE SPECIFICITY Detected in heart, brain, lung, spleen and placenta.PTM N-glycosylated.SIMILARITY Belongs to the plexin family. UniProt O60486 35 EQUAL 1568 EQUAL Reactome Database ID Release 79 434899 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434899 Reactome R-HSA-434899 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-434899.1 SEMA7A Semaphorin 7A SM7A_HUMAN Reactome DB_ID: 198229 UniProt:O75326 SEMA7A SEMA7A CD108 SEMAL FUNCTION Plays an important role in integrin-mediated signaling and functions both in regulating cell migration and immune responses. Promotes formation of focal adhesion complexes, activation of the protein kinase PTK2/FAK1 and subsequent phosphorylation of MAPK1 and MAPK3. Promotes production of proinflammatory cytokines by monocytes and macrophages. Plays an important role in modulating inflammation and T-cell-mediated immune responses. Promotes axon growth in the embryonic olfactory bulb. Promotes attachment, spreading and dendrite outgrowth in melanocytes.SUBUNIT Interacts with ITGA1 and ITGB1 (Probable). Interacts with PLXNC1.TISSUE SPECIFICITY Detected in skin keratinocytes and on endothelial cells from skin blood vessels (at protein level). Expressed in fibroblasts, keratinocytes, melanocytes, placenta, testis, ovary, spleen, brain, spinal chord, lung, heart, adrenal gland, lymph nodes, thymus, intestine and kidney.INDUCTION Up-regulated in UV-irradiated fibroblasts, but not in UV-irradiated keratinocytes.POLYMORPHISM Genetic variations in SEMA7A define the John Milton Hagen blood group system (JMH) [MIM:614745]. Three different JMH phenotypes have been identified based on the presence or absence of the high-frequency JMH antigen: JMH-weak, JMH-negative, and JMH-variant. The JMH-weak and -negative phenotypes can be either acquired or inherited and are characterized by a reduction or complete loss of JMH expression on red blood cells. Individuals with the JMH-variant phenotype are usually JMH-positive and have alloantibodies compatible with JMH-negative red blood cells. The JMH-variant phenotype results from rare SEMA7A missense variants.SIMILARITY Belongs to the semaphorin family. UniProt O75326 45 EQUAL 648 EQUAL Reactome Database ID Release 79 198229 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198229 Reactome R-HSA-198229 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198229.1 SEMA7A:PLXNC1 Reactome DB_ID: 434928 1 1 Reactome Database ID Release 79 434928 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434928 Reactome R-HSA-434928 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-434928.1 Reactome Database ID Release 79 434989 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434989 Reactome R-HSA-434989 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-434989.1 10520995 Pubmed 1999 Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates Tamagnone, L Artigiani, S Chen, H He, Z Ming, GI Song, H Chédotal, A Winberg, ML Goodman, CS Poo, M Tessier-Lavigne, M Comoglio, PM Cell 99:71-80 LEFT-TO-RIGHT SEMA7A binds to integrin alpha1beta1 Sema7A has a RGD-motif in the extracellular region and interacts with alpha1beta1 integrin in both olfactory nerves and monocytes/macrophages. This interaction stimulates cytokine production in monocytes and macrophages, and is critical for the effector phase of the inflammatory immune response. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 ITGA1:ITGB1 Integrin alpha1beta1 Reactome DB_ID: 215982 ITGB1 Integrin beta-1 Fibronectin receptor beta subunit CD29 antigen Integrin VLA-4 beta subunit Reactome DB_ID: 57596 UniProt:P05556 ITGB1 ITGB1 FNRB MDF2 MSK12 FUNCTION Integrins alpha-1/beta-1, alpha-2/beta-1, alpha-10/beta-1 and alpha-11/beta-1 are receptors for collagen. Integrins alpha-1/beta-1 and alpha-2/beta-2 recognize the proline-hydroxylated sequence G-F-P-G-E-R in collagen. Integrins alpha-2/beta-1, alpha-3/beta-1, alpha-4/beta-1, alpha-5/beta-1, alpha-8/beta-1, alpha-10/beta-1, alpha-11/beta-1 and alpha-V/beta-1 are receptors for fibronectin. Alpha-4/beta-1 recognizes one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. Integrin alpha-5/beta-1 is a receptor for fibrinogen. Integrin alpha-1/beta-1, alpha-2/beta-1, alpha-6/beta-1 and alpha-7/beta-1 are receptors for lamimin. Integrin alpha-6/beta-1 (ITGA6:ITGB1) is present in oocytes and is involved in sperm-egg fusion (By similarity). Integrin alpha-4/beta-1 is a receptor for VCAM1. It recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha-9/beta-1 is a receptor for VCAM1, cytotactin and osteopontin. It recognizes the sequence A-E-I-D-G-I-E-L in cytotactin. Integrin alpha-3/beta-1 is a receptor for epiligrin, thrombospondin and CSPG4. Alpha-3/beta-1 may mediate with LGALS3 the stimulation by CSPG4 of endothelial cells migration. Integrin alpha-V/beta-1 is a receptor for vitronectin. Beta-1 integrins recognize the sequence R-G-D in a wide array of ligands. When associated with alpha-7 integrin, regulates cell adhesion and laminin matrix deposition. Involved in promoting endothelial cell motility and angiogenesis. Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process and the formation of mineralized bone nodules. May be involved in up-regulation of the activity of kinases such as PKC via binding to KRT1. Together with KRT1 and RACK1, serves as a platform for SRC activation or inactivation. Plays a mechanistic adhesive role during telophase, required for the successful completion of cytokinesis. Integrin alpha-3/beta-1 provides a docking site for FAP (seprase) at invadopodia plasma membranes in a collagen-dependent manner and hence may participate in the adhesion, formation of invadopodia and matrix degradation processes, promoting cell invasion. ITGA4:ITGB1 binds to fractalkine (CX3CL1) and may act as its coreceptor in CX3CR1-dependent fractalkine signaling (PubMed:23125415, PubMed:24789099). ITGA4:ITGB1 and ITGA5:ITGB1 bind to PLA2G2A via a site (site 2) which is distinct from the classical ligand-binding site (site 1) and this induces integrin conformational changes and enhanced ligand binding to site 1 (PubMed:18635536, PubMed:25398877). ITGA5:ITGB1 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1 (PubMed:12807887, PubMed:17158881). ITGA5:ITGB1 is a receptor for IL1B and binding is essential for IL1B signaling (PubMed:29030430). ITGA5:ITGB3 is a receptor for soluble CD40LG and is required for CD40/CD40LG signaling (PubMed:31331973).FUNCTION (Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human echoviruses 1 and 8.FUNCTION (Microbial infection) Acts as a receptor for Cytomegalovirus/HHV-5.FUNCTION (Microbial infection) Acts as a receptor for Epstein-Barr virus/HHV-4.FUNCTION (Microbial infection) Integrin ITGA5:ITGB1 acts as a receptor for Human parvovirus B19.FUNCTION (Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human rotavirus.FUNCTION (Microbial infection) Acts as a receptor for Mammalian reovirus.FUNCTION (Microbial infection) In case of HIV-1 infection, integrin ITGA5:ITGB1 binding to extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.SUBUNIT Heterodimer of an alpha and a beta subunit. Beta-1 associates with either alpha-1, alpha-2, alpha-3, alpha-4, alpha-5, alpha-6, alpha-7, alpha-8, alpha-9, alpha-10, alpha-11 or alpha-V. ITGA6:ITGB1 is found in a complex with CD9; interaction takes place in oocytes and is involved in sperm-egg fusion (By similarity). Interacts with seprase FAP (seprase); the interaction occurs at the cell surface of invadopodia membrane in a collagen-dependent manner. Binds LGALS3BP and NMRK2, when associated with alpha-7, but not with alpha-5. Interacts with FGR and HCK. Interacts (via the cytoplasmic region) with RAB25 (via the hypervariable C-terminal region). Interacts with RAB21. Interacts with KRT1 in the presence of RACK1 and SRC. Interacts with JAML; integrin alpha-4/beta-1 may regulate leukocyte to endothelial cells adhesion by controlling JAML homodimerization. Interacts with FLNA, FLNB and RANBP9. Interacts with MYO10. Interacts with DAB2. Interacts with FERMT2; the interaction is inhibited in presence of ITGB1BP1. Interacts with ITGB1BP1 (via C-terminal region); the interaction is a prerequisite for focal adhesion disassembly. Interacts with TLN1; the interaction is prevented by competitive binding of ITGB1BP1. Interacts with ACAP1; required for ITGB1 recycling. Interacts with ASAP3. Interacts with EMP2; the interaction may be direct or indirect and ITGB1 has a heterodimer form (By similarity). ITGA5:ITGB1 interacts with CCN3. ITGA4:ITGB1 is found in a ternary complex with CX3CR1 and CX3CL1 (PubMed:23125415). ITGA5:ITGB1 interacts with FBN1 (PubMed:12807887, PubMed:17158881). ITGA5:ITGB1 interacts with IL1B (PubMed:29030430). ITGA4:ITGB1 interacts with MDK; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation (PubMed:15466886). ITGA6:ITGB1 interacts with MDK; this interaction mediates MDK-induced neurite-outgrowth (PubMed:15466886). ITGA5:ITGB1 interacts with ACE2 (PubMed:33102950).SUBUNIT (Microbial infection) Integrin ITGA2:ITGB1 interacts with human echoviruses 1 and 8 capsid proteins.SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 envelope glycoprotein B/gB.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus/HHV-4 gB protein.SUBUNIT (Microbial infection) Integrin ITGA5:ITGB1 interacts with human parvovirus B19 capsid protein.SUBUNIT (Microbial infection) Integrin ITGA2:ITGB1 interacts with human rotavirus VP4 protein.SUBUNIT (Microbial infection) Interacts with mammalian reovirus capsid proteins.SUBUNIT (Microbial infection) Integrin ITGA5:ITGB1 interacts with HIV-1 Tat.SUBUNIT (Microbial infection) ITGA5:ITGB1 interacts with SARS coronavirus-2/SARS-CoV-2 spike protein.PTM The cysteine residues are involved in intrachain disulfide bonds.SIMILARITY Belongs to the integrin beta chain family. UniProt P05556 21 EQUAL 798 EQUAL Reactome Database ID Release 79 57596 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=57596 Reactome R-HSA-57596 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-57596.1 1 ITGA1 Integrin alpha-1 ITA1_HUMAN Reactome DB_ID: 215939 UniProt:P56199 ITGA1 ITGA1 FUNCTION Integrin alpha-1/beta-1 is a receptor for laminin and collagen. It recognizes the proline-hydroxylated sequence G-F-P-G-E-R in collagen. Involved in anchorage-dependent, negative regulation of EGF-stimulated cell growth.SUBUNIT Heterodimer of an alpha and a beta subunit. Alpha-1 associates with beta-1. Interacts with RAB21. Interacts (via cytoplasmic domain) with PTPN2; activates PTPN2 phosphatase activity towards EGFR and negatively regulates EGF signaling.DOMAIN The integrin I-domain (insert) is a VWFA domain. Integrins with I-domains do not undergo protease cleavage.SIMILARITY Belongs to the integrin alpha chain family. UniProt P56199 29 EQUAL 1179 EQUAL Reactome Database ID Release 79 215939 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=215939 Reactome R-HSA-215939 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-215939.1 1 Reactome Database ID Release 79 215982 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=215982 Reactome R-HSA-215982 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-215982.2 ComplexPortal CPX-1798 SEMA7A:Integrin alpha1beta1 Reactome DB_ID: 434927 1 1 Reactome Database ID Release 79 434927 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434927 Reactome R-HSA-434927 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-434927.1 Reactome Database ID Release 79 434990 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434990 Reactome R-HSA-434990 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-434990.1 17377534 Pubmed 2007 Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin Suzuki, K Okuno, T Yamamoto, M Pasterkamp, RJ Takegahara, N Takamatsu, H Kitao, T Takagi, J Rennert, PD Kolodkin, AL Kumanogoh, Atsushi Kikutani, Hitoshi Nature 446:680-4 12879062 Pubmed 2003 Semaphorin 7A promotes axon outgrowth through integrins and MAPKs Pasterkamp, RJ Peschon, JJ Spriggs, MK Kolodkin, AL Nature 424:398-405 Reactome Database ID Release 79 416700 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=416700 Reactome R-HSA-416700 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-416700.1 23050142 Pubmed 2012 The role of semaphorins and their receptors in gliomas Law, Janice Wai Sze Lee, Alan Yiu Wah J Signal Transduct 2012:902854 Reactome Database ID Release 79 373755 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=373755 Reactome R-HSA-373755 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-373755.1 12471249 Pubmed 2002 Molecular mechanisms of axon guidance Dickson, BJ Science 298:1959-64 18269210 Pubmed 2007 Role of semaphorins during axon growth and guidance Koncina, E Roth, L Gonthier, B Bagnard, D Adv Exp Med Biol 621:50-64 16939971 Pubmed 2006 Semaphorins in axon regeneration: developmental guidance molecules gone wrong? Pasterkamp, RJ Verhaagen, J Philos Trans R Soc Lond B Biol Sci 361:1499-511 NCAM signaling for neurite out-growth The neural cell adhesion molecule, NCAM, is a member of the immunoglobulin (Ig) superfamily and is involved in a variety of cellular processes of importance for the formation and maintenance of the nervous system. The role of NCAM in neural differentiation and synaptic plasticity is presumed to depend on the modulation of intracellular signal transduction cascades. NCAM based signaling complexes can initiate downstream intracellular signals by at least two mechanisms: (1) activation of FGFR and (2) formation of intracellular signaling complexes by direct interaction with cytoplasmic interaction partners such as Fyn and FAK. Tyrosine kinases Fyn and FAK interact with NCAM and undergo phosphorylation and this transiently activates the MAPK, ERK 1 and 2, cAMP response element binding protein (CREB) and transcription factors ELK and NFkB. CREB activates transcription of genes which are important for axonal growth, survival, and synaptic plasticity in neurons.<br><br>NCAM1 mediated intracellular signal transduction is represented in the figure below. The Ig domains in NCAM1 are represented in orange ovals and Fn domains in green squares. The tyrosine residues susceptible to phosphorylation are represented in red circles and their positions are numbered. Phosphorylation is represented by red arrows and dephosphorylation by yellow. Ig, Immunoglobulin domain; Fn, Fibronectin domain; Fyn, Proto-oncogene tyrosine-protein kinase Fyn; FAK, focal adhesion kinase; RPTPalpha, Receptor-type tyrosine-protein phosphatase; Grb2, Growth factor receptor-bound protein 2; SOS, Son of sevenless homolog; Raf, RAF proto-oncogene serine/threonine-protein kinase; MEK, MAPK and ERK kinase; ERK, Extracellular signal-regulated kinase; MSK1, Mitogen and stress activated protein kinase 1; CREB, Cyclic AMP-responsive element-binding protein; CRE, cAMP response elements. Authored: Garapati, P V, 2009-02-24 10:31:41 Reviewed: Maness, PF, Walmod, PS, 2009-05-25 Edited: Garapati, P V, 2009-02-24 10:31:41 LEFT-TO-RIGHT NCAM1 cis-homophilic interaction NCAM1 located on the cell membrane can participate in parallel cis and antiparallel trans-homophilic interactions. The cis-interaction is mediated by reciprocal IgI-IgII interactions: the IgI domain of one NCAM1 molecule interacts with the IgII domain of a second. Authored: Garapati, P V, 2009-02-24 10:31:15 Reviewed: Maness, PF, Walmod, PS, 2009-05-25 Edited: Garapati, P V, 2009-02-24 10:58:20 NCAM1 Neural cell adhesion molecule 1, 140 kDa isoform NCA1_HUMAN Reactome DB_ID: 190987 UniProt:P13591 NCAM1 NCAM1 NCAM FUNCTION This protein is a cell adhesion molecule involved in neuron-neuron adhesion, neurite fasciculation, outgrowth of neurites, etc.FUNCTION (Microbial infection) Acts as a receptor for rabies virus.FUNCTION (Microbial infection) Acts as a receptor for Zika virus.SUBUNIT (Microbial infection) Interacts with rabies virus glycoprotein.SUBUNIT (Microbial infection) Interacts with Zika virus envelope protein E.SUBUNIT Interacts with MDK. UniProt P13591 20 EQUAL 858 EQUAL Reactome Database ID Release 79 190987 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=190987 Reactome R-HSA-190987 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-190987.1 2 NCAM1 cis-homodimer Reactome DB_ID: 190988 2 Reactome Database ID Release 79 190988 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=190988 Reactome R-HSA-190988 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-190988.1 Reactome Database ID Release 79 391872 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=391872 Reactome R-HSA-391872 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-391872.1 14527396 Pubmed 2003 Structure and interactions of NCAM Ig1-2-3 suggest a novel zipper mechanism for homophilic adhesion Soroka, V Kolkova, K Kastrup, JS Diederichs, K Breed, J Kiselyov, VV Poulsen, FM Larsen, IK Welte, W Berezin, V Bock, E Kasper, C Structure 11:1291-301 15662836 Pubmed 2004 Zippers make signals: NCAM-mediated molecular interactions and signal transduction Walmod, Peter Schledermann Kolkova, K Berezin, V Bock, E Neurochem Res 29:2015-35 15353284 Pubmed 2004 Molecular mechanisms of NCAM function Hinsby, AM Berezin, V Bock, E Front Biosci 9:2227-44 LEFT-TO-RIGHT NCAM1 trans-homophilic interaction Antiparallel NCAM interactions involve trans-interactions of NCAM molecules on opposed cell membranes. Based on structural and functional studies a 'double zipper' model has been proposed to describe these interactions. The first model - the 'flat zipper'- formed between NCAM1 cis-dimers from one cell surface interacting in trans through IgII-IgIII contacts with NCAM1 cis-dimers from another cell surface. The second model - the 'compact zipper'- is formed between NCAM1 cis-dimers from one cell surface interacting in trans through IgI-IgIII and IgII-IgII contacts with cis-dimers from another cell surface.<p>Abrogation of cis-dimerization inhibits NCAM mediated neurite outgrowth, and cis-dimerization of NCAM1 may be a necessary prerequisite for subsequent trans-interactions. Authored: Garapati, P V, 2009-02-24 10:31:15 Reviewed: Maness, PF, Walmod, PS, 2009-05-25 Edited: Garapati, P V, 2009-02-24 10:58:20 2 NCAM1:NCAM1 trans-homotetramer Reactome DB_ID: 375103 2 Reactome Database ID Release 79 375103 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=375103 Reactome R-HSA-375103 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-375103.1 Reactome Database ID Release 79 375161 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=375161 Reactome R-HSA-375161 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-375161.1 LEFT-TO-RIGHT NCAM1 binds FGFR-1 FGFR is one of the heterophilic interactors of NCAM. The FG loop region of the second Fn3 module of NCAM binds to Ig domains 2 and 3 of FGFR. The FGFR binding site to NCAM overlaps with the site of NCAM-ATP interaction, and ATP is capable of disrupting NCAM-FGFR binding and signaling. <br>The interaction of NCAM activates FGFR and NCAM might merely mimic FGF's in FGFR stimulation, but there is a difference in the activation pattern induced by NCAM and FGF-2. NCAM activated FGFR stimulates neurite outgrowth by stimulating PLCgamma and DAG lipase leading to generation of arachidonic acid. Authored: Garapati, P V, 2009-02-24 10:31:15 Reviewed: Maness, PF, Walmod, PS, 2009-05-25 Edited: Garapati, P V, 2009-02-24 10:58:20 FGFR1c homodimer Reactome DB_ID: 190222 FGFR1c FGFR1-1 Fibroblast growth factor receptor 1c FGR1_HUMAN FGFR1 isoform 1 Reactome DB_ID: 189897 UniProt:P11362-1 FGFR1 FGFR1 BFGFR CEK FGFBR FLG FLT2 HBGFR FUNCTION Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation.ACTIVITY REGULATION Present in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by sequential autophosphorylation on tyrosine residues. Inhibited by ARQ 069; this compound maintains the kinase in an inactive conformation and inhibits autophosphorylation. Inhibited by PD173074.SUBUNIT Monomer. Homodimer after ligand binding. Interacts predominantly with FGF1 and FGF2, but can also interact with FGF3, FGF4, FGF5, FGF6, FGF8, FGF10, FGF19, FGF21, FGF22 and FGF23 (in vitro) (PubMed:1697263, PubMed:1722683, PubMed:8663044, PubMed:9655399, PubMed:12181353, PubMed:16597617, PubMed:17623664). Ligand specificity is determined by tissue-specific expression of isoforms, and differences in the third Ig-like domain are crucial for ligand specificity. Affinity for fibroblast growth factors (FGFs) is increased by heparan sulfate glycosaminoglycans that function as coreceptors. Likewise, KLB increases the affinity for FGF19, FGF21 and FGF23 (PubMed:19966287). Interacts (phosphorylated on Tyr-766) with PLCG1 (via SH2 domains) (PubMed:1656221, PubMed:1379697, PubMed:21765395). Interacts with FRS2 (PubMed:21765395). Interacts with RPS6KA1 (PubMed:15117958). Interacts (via C-terminus) with NEDD4 (via WW3 domain) (PubMed:21765395). Interacts with KL (By similarity). Interacts with SHB (via SH2 domain) (PubMed:12181353). Interacts with GRB10 (PubMed:10454568). Interacts with ANOS1; this interaction does not interfere with FGF2-binding to FGFR1, but prevents binding of heparin-bound FGF2 (PubMed:19696444). Interacts with SOX2 and SOX3. Interacts with FLRT1, FLRT2 and FLRT3 (By similarity). Found in a ternary complex with FGF1 and ITGAV:ITGB3 (PubMed:20422052, PubMed:18441324).TISSUE SPECIFICITY Detected in astrocytoma, neuroblastoma and adrenal cortex cell lines. Some isoforms are detected in foreskin fibroblast cell lines, however isoform 17, isoform 18 and isoform 19 are not detected in these cells.DOMAIN The second and third Ig-like domains directly interact with fibroblast growth factors (FGF) and heparan sulfate proteoglycans. Isoforms lacking the first Ig-like domain have higher affinity for fibroblast growth factors (FGF) and heparan sulfate proteoglycans than isoforms with all three Ig-like domains.PTM Autophosphorylated. Binding of FGF family members together with heparan sulfate proteoglycan or heparin promotes receptor dimerization and autophosphorylation on tyrosine residues. Autophosphorylation occurs in trans between the two FGFR molecules present in the dimer and proceeds in a highly ordered manner. Initial autophosphorylation at Tyr-653 increases the kinase activity by a factor of 50 to 100. After this, Tyr-583 becomes phosphorylated, followed by phosphorylation of Tyr-463, Tyr-766, Tyr-583 and Tyr-585. In a third stage, Tyr-654 is autophosphorylated, resulting in a further tenfold increase of kinase activity. Phosphotyrosine residues provide docking sites for interacting proteins and so are crucial for FGFR1 function and its regulation.PTM Ubiquitinated. FGFR1 is rapidly ubiquitinated by NEDD4 after autophosphorylation, leading to internalization and lysosomal degradation. CBL is recruited to activated FGFR1 via FRS2 and GRB2, and mediates ubiquitination and subsequent degradation of FGFR1.PTM N-glycosylated in the endoplasmic reticulum. The N-glycan chains undergo further maturation to an Endo H-resistant form in the Golgi apparatus.DISEASE Chromosomal aberrations involving FGFR1 are a cause of chromosome 8p11 myeloproliferative syndrome. Translocation t(8;13)(p11;q12) with ZMYM2. Translocation t(6;8)(q27;p11) with CEP43. Insertion ins(12;8)(p11;p11p22) with FGFR1OP2. Translocation t(8;9)(p12;q33) with CNTRL. Translocation t(2;8)(q12;p11) with RANBP2. Chromosome 8p11 myeloproliferative syndrome is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion proteins FGFR1OP2-FGFR1, CEP43-FGFR1 or FGFR1-CEP43 may exhibit constitutive kinase activity and be responsible for the transforming activity. The fusion protein CNTRL-FGFR1 is found in the cytoplasm, exhibits constitutive kinase activity and may be responsible for the transforming activity.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily. UniProt Isoform P11362-1 22 EQUAL 822 EQUAL Reactome Database ID Release 79 189897 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=189897 Reactome R-HSA-189897 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-189897.1 2 Reactome Database ID Release 79 190222 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=190222 Reactome R-HSA-190222 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-190222.1 NCAM1:FGFR-1 Reactome DB_ID: 419028 1 1 Reactome Database ID Release 79 419028 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419028 Reactome R-HSA-419028 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419028.1 Reactome Database ID Release 79 419033 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419033 Reactome R-HSA-419033 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419033.2 12791257 Pubmed 2003 Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP Kiselyov, VV Skladchikova, G Hinsby, AM Jensen, PH Kulahin, N Soroka, V Pedersen, N Tsetlin, V Poulsen, FM Berezin, V Bock, E Structure 11:691-701 16045455 Pubmed 2005 Structural biology of NCAM homophilic binding and activation of FGFR Kiselyov, VV Soroka, V Berezin, V Bock, E J Neurochem 94:1169-79 INHIBITION activeUnit: #SmallMolecule10 Reactome Database ID Release 79 500284 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=500284 Reactome R-HSA-500284 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-500284.2 NCAM-1:ATP Reactome DB_ID: 375093 1 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 114570 Reactome Database ID Release 79 114570 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114570 Reactome R-ALL-114570 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-114570.3 COMPOUND C00002 1 Reactome Database ID Release 79 375093 Database identifier. Use this URL to connect to the web page of th