BioPAX pathway converted from "Sema3A PAK dependent Axon repulsion" in the Reactome database. 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 Sema3A:Nrp-1:pPlexinA:Fyn:Fes:Rac-1-GTP Reactome DB_ID: 399872 plasma membrane GENE ONTOLOGY GO:0005886 RAC1:GTP Reactome DB_ID: 442641 GTP Guanosine 5'-triphosphate GTP)(4-) Reactome DB_ID: 29438 cytosol GENE ONTOLOGY GO:0005829 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI CHEBI:37565 Reactome Database ID Release 83 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 Reactome http://www.reactome.org COMPOUND C00044 additional information MI MI:0361 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).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 1 EQUAL 189 EQUAL Reactome Database ID Release 83 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 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 1 Sema3A:NRP-1:pPlexin-A:Fyn:Fes Reactome DB_ID: 399859 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 83 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 1 Sema3A:NRP-1:pPlexin-A:fyn Reactome DB_ID: 419622 NRP1:p-Plexin-A1-4:FYN Reactome DB_ID: 419625 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). 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 Database ID Release 83 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 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 83 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 1 Converted from EntitySet in Reactome p-Plexin-A1-4 Reactome DB_ID: 419620 p-Y-PLXNA1 phosphorylated Plexin-A1 Reactome DB_ID: 419614 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 O4'-phospho-L-tyrosine MOD MOD:00048 27 EQUAL 1896 EQUAL Reactome Database ID Release 83 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 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 83 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 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 83 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 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 83 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 83 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 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 1 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 83 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 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 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 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 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 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 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 (PubMed:10995762, PubMed:11804587, PubMed:15893667, PubMed:9032240). Phosphorylation of Thr-84 by OXSR1 inhibits activation (By similarity).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). 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 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.CAUTION The interaction between DSCAM, PAK1 and RAC1 has beend described. This article has been withdrawn by the authors.CAUTION There are data describing interaction and regulation by the product of CRIPAK, a putative single exon gene (PubMed:16278681). However, considering all available data there is no sufficient supporting evidence for the existence of such protein. UniProt Q13153 1 EQUAL 545 EQUAL Reactome Database ID Release 83 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 83 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 (PubMed:7744004, PubMed:19273597, PubMed:19923322, PubMed:9171063, PubMed:12853446, PubMed:16617111). Acts as downstream effector of the small GTPases CDC42 and RAC1 (PubMed:7744004). 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 (PubMed:7744004). Full-length PAK2 stimulates cell survival and cell growth (PubMed:7744004). Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration (PubMed:21317288). Phosphorylates JUN and plays an important role in EGF-induced cell proliferation (PubMed:21177766). Phosphorylates many other substrates including histone H4 to promote assembly of H3.3 and H4 into nucleosomes, BAD, ribosomal protein S6, or MBP (PubMed:21724829). Phosphorylates CASP7, thereby preventing its activity (PubMed:21555521, PubMed:27889207). Additionally, associates with ARHGEF7 and GIT1 to perform kinase-independent functions such as spindle orientation control during mitosis (PubMed:19273597, PubMed:19923322). 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 (PubMed:9171063, PubMed:12853446, PubMed:16617111). Caspase-activated PAK2 phosphorylates MKNK1 and reduces cellular translation (PubMed:15234964).ACTIVITY REGULATION Activated by binding small G proteins (By similarity). 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 (PubMed:9786869).SUBUNIT Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1 (PubMed:20696164). Interacts with SH3MD4 (PubMed:16374509). Interacts with SCRIB (PubMed:18716323). Interacts with ARHGEF7 and GIT1 (PubMed:19273597). PAK-2p34 interacts with ARHGAP10 (PubMed:15471851).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.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 83 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 83 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 83 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 83 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 83 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 83 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 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 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 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 83 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 COMPOUND C00002 2 Sema3A:Nrp-1:PlexinA:Rac1-GTP:pPAK Reactome DB_ID: 399874 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 O-phospho-L-serine MOD MOD:00046 423 EQUAL O-phospho-L-threonine MOD MOD:00047 1 EQUAL 545 EQUAL Reactome Database ID Release 83 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 83 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 83 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 83 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 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 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5'-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 83 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 2 ACTIVATION activeUnit: #Protein14 GENE ONTOLOGY GO:0004674 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity 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 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 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 83 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 p-T508-LIMK1 Reactome DB_ID: 399816 508 EQUAL 1 EQUAL 647 EQUAL Reactome Database ID Release 83 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 ACTIVATION activeUnit: #Protein15 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 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 2 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 mitochondrial outer membrane which promotes host antiviral response (PubMed:20628368, PubMed:25609812).FUNCTION (Microbial infection) Seems to interfere with N.meningitidis NadA-mediated invasion of human cells. Decreasing HSP90 levels increases adhesion and entry of E.coli expressing NadA into human Chang cells; increasing its levels leads to decreased adhesion and invasion.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). Forms a complex with ASL, ASS1 and NOS2; the complex regulates cell-autonomous L-arginine synthesis and citrulline recycling while channeling extracellular L-arginine to nitric oxide synthesis pathway.SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein US11; this interaction inhibits TBK1-induced interferon production.SUBUNIT (Microbial infection) Interacts with N.meningitidis serogroup B adhesin A (nadA). Interaction is stabilized by ADP and 17-AAG (17-N-allylamino-17-demethoxygeldanamycin) and inhibited by ATP. Decreasing HSP90 levels increases adhesion and entry of bacterial into human Chang cells; increasing its levels leads to decreased adhseion and invasion.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 83 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).FUNCTION (Microbial infection) Binding to N.meningitidis NadA stimulates monocytes (PubMed:21949862). Seems to interfere with N.meningitidis NadA-mediated invasion of human cells (Probable).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).SUBUNIT (Microbial infection) Protein on the cell surface interacts with N.meningitidis serogroup B adhesin A (nadA).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 83 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 83 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 pLIMK dimer:HSP-90 Reactome DB_ID: 419632 2 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 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 83 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 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 ACTIVATION activeUnit: #Protein20 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 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). 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 Database ID Release 83 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 83 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 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 ACTIVATION 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