BioPAX pathway converted from "Sema3A PAK dependent Axon repulsion" in the Reactome database. Sema3A PAK dependent Axon repulsion 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 Activation of PAK by Rac1 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 Reactome DB_ID: 399872 1 plasma membrane GO 0005886 Sema3A:Nrp-1:pPlexinA:Fyn:Fes:Rac-1-GTP [plasma membrane] Sema3A:Nrp-1:pPlexinA:Fyn:Fes:Rac-1-GTP Reactome DB_ID: 442641 1 RAC1:GTP [plasma membrane] RAC1:GTP Reactome DB_ID: 29438 1 cytosol GO 0005829 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) Reactome http://www.reactome.org ChEBI 37565 Reactome DB_ID: 351141 1 UniProt:P63000 RAC1 RAC1 TC25 RAC1 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).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. 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). Interacts with RAP1GDS1 (PubMed:20709748, PubMed:12551911).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 GTP-bound active form is ubiquitinated by HACE1, leading to its degradation by the proteasome.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 (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).PTM (Microbial infection) Palmitoylated by the N-epsilon-fatty acyltransferase F2 chain of V.cholerae toxin RtxA (PubMed:29074776). Palmitoylation inhibits activation by guanine nucleotide exchange factors (GEFs), preventing Rho GTPase signaling (PubMed:29074776).SIMILARITY Belongs to the small GTPase superfamily. Rho family.CAUTION The interaction between DSCAM, PAK1 and RAC1 has been described. This article has been withdrawn by the authors. Homo sapiens NCBI Taxonomy 9606 UniProt P63000 Chain Coordinates 1 EQUAL 189 EQUAL Reactome Database ID Release 83 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 Reactome DB_ID: 399859 1 Sema3A:NRP-1:pPlexin-A:Fyn:Fes [plasma membrane] Sema3A:NRP-1:pPlexin-A:Fyn:Fes Reactome DB_ID: 396937 1 UniProt:P07332 FES 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 DB_ID: 419622 1 Sema3A:NRP-1:pPlexin-A:fyn [plasma membrane] Sema3A:NRP-1:pPlexin-A:fyn Reactome DB_ID: 419625 1 NRP1:p-Plexin-A1-4:FYN [plasma membrane] NRP1:p-Plexin-A1-4:FYN Reactome DB_ID: 200917 1 UniProt:P06241 FYN 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). Interacts with NEDD9; in the presence of PTK2 (PubMed:9360983).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 DB_ID: 3008773 1 UniProt:O14786 NRP1 NRP1 NRP1 VEGF165R NRP 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 Converted from EntitySet in Reactome Reactome DB_ID: 419620 1 p-Plexin-A1-4 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-Y-PLXNA2 [plasma membrane] p-Y-PLXNA3 [plasma membrane] p-Y-PLXNA1 [plasma membrane] p-Y-PLXNA4 [plasma membrane] UniProt O75051 UniProt P51805 UniProt Q9UIW2 UniProt Q9HCM2 Reactome Database ID Release 83 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 Reactome DB_ID: 399861 1 extracellular region GO 0005576 Sema3A dimer [extracellular region] Sema3A dimer Reactome DB_ID: 198235 2 UniProt:Q14563 SEMA3A 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 83 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 Reactome Database ID Release 83 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 Reactome Database ID Release 83 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 Reactome Database ID Release 83 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 Converted from EntitySet in Reactome Reactome DB_ID: 399856 1 PAK1,2,3 dimer [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 390765 1 PAK1,2,3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PAK2 [cytosol] PAK1 [cytosol] PAK3 [cytosol] UniProt Q13177 UniProt Q13153 UniProt O75914 Reactome DB_ID: 399876 1 Sema3A:Nrp-1:PlexinA:Rac1-GTP:PAK [plasma membrane] Sema3A:Nrp-1:PlexinA:Rac1-GTP:PAK Converted from EntitySet in Reactome Reactome DB_ID: 390765 1 Reactome DB_ID: 399872 1 Reactome Database ID Release 83 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 83 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 2.7.11.1 Autophosphorylation of PAK 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 Reactome DB_ID: 399876 1 Reactome DB_ID: 113592 2 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 399874 1 Sema3A:Nrp-1:PlexinA:Rac1-GTP:pPAK [plasma membrane] Sema3A:Nrp-1:PlexinA:Rac1-GTP:pPAK Converted from EntitySet in Reactome Reactome DB_ID: 399836 1 p-S,T-PAK1,2,3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-S144,T423-PAK1 [cytosol] p-S154,T436-PAK3 [cytosol] p-S141,T402-PAK2 [cytosol] Reactome DB_ID: 399872 1 Reactome Database ID Release 83 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 Reactome DB_ID: 29370 2 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5'-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 399876 GO 0004674 GO molecular function Reactome Database ID Release 83 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 83 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 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 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 2.7.11.1 Phosphorylation of LIMK-1 by PAK 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 Reactome DB_ID: 397785 1 UniProt:P53667 LIMK1 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 DB_ID: 113592 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 399816 1 O-phospho-L-threonine at 508 508 EQUAL O-phospho-L-threonine [MOD:00047] 1 EQUAL 647 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 399874 Reactome Database ID Release 83 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 83 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 Dimerization of LIMK1 by Hsp90 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 Reactome DB_ID: 399816 2 O-phospho-L-threonine at 508 508 EQUAL 1 EQUAL 647 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 419619 1 HSP90AA1,HSP90AB1 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity HSP90AA1 [cytosol] HSP90AB1 [cytosol] UniProt P07900 UniProt P08238 Reactome DB_ID: 419632 1 pLIMK dimer:HSP-90 [cytosol] pLIMK dimer:HSP-90 Reactome DB_ID: 399816 2 O-phospho-L-threonine at 508 508 EQUAL 1 EQUAL 647 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 419619 1 Reactome Database ID Release 83 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 83 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 2.7.11.1 Transphosphorylation of pLIMK1 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 Reactome DB_ID: 419632 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 419630 1 Active LIMK1 [cytosol] Active LIMK1 Reactome DB_ID: 419610 2 O-phospho-L-threonine at 508 508 EQUAL O-phospho-L-serine at unknown position O-phospho-L-serine [MOD:00046] 1 EQUAL 647 EQUAL Reactome Database ID Release 83 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 Converted from EntitySet in Reactome Reactome DB_ID: 419619 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 419632 Reactome Database ID Release 83 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 83 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 2.7.11.1 Phosphorylation of cofilin by LIMK-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 Reactome DB_ID: 419630 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 350751 1 UniProt:P23528 CFL1 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). Interacts with C9orf72 (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 DB_ID: 29370 1 Reactome DB_ID: 399878 1 pCofilin: Active LIMK-1 [cytosol] pCofilin: Active LIMK-1 Reactome DB_ID: 399813 1 O-phospho-L-serine at 3 3 EQUAL 2 EQUAL 166 EQUAL Reactome DB_ID: 419630 1 Reactome Database ID Release 83 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 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 419630 Reactome Database ID Release 83 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 83 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 83 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 18374575 Pubmed 2008 Semaphorin signaling: progress made and promises ahead Zhou, Y Gunput, RA Pasterkamp, RJ Trends Biochem Sci 33:161-70