BioPAX pathway converted from "Translocation of SLC2A4 (GLUT4) to the plasma membrane" in the Reactome database. Translocation of SLC2A4 (GLUT4) to the plasma membrane In adipocytes and myocytes insulin signaling causes intracellular vesicles carrying the GLUT4 (SLC2A4) glucose transporter to translocate to the plasma membrane, allowing the cells to take up glucose from the bloodstream (reviewed in Zaid et al. 2008, Leney and Tavare 2009, Bogan and Kandror 2010, Foley et al. 2011, Hoffman and Elmendorf 2011, Kandror and Pilch 2011, Jaldin-Fincati et al. 2017). In myocytes muscle contraction alone can also cause translocation of GLUT4.<br>Though the entire pathway leading to GLUT4 translocation has not been elucidated, several steps are known. Insulin activates the kinases AKT1 and AKT2. Muscle contraction activates the kinase AMPK-alpha2 and possibly also AKT. AKT2 and, to a lesser extent, AKT1 phosphorylate the RAB GTPase activators TBC1D1 and TBC1D4, causing them to bind 14-3-3 proteins and lose GTPase activation activity. As a result RAB proteins (probably RAB8A, RAB10, RAB14 and possibly RAB13) accumulate GTP. The connection between RAB:GTP and vesicle translocation is unknown but may involve recruitment and activation of myosins.<br>Myosins 1C, 2A, 2B, 5A, 5B have all been shown to play a role in translocating GLUT4 vesicles near the periphery of the cell. Following docking at the plasma membrane the vesicles fuse with the plasma membrane in a process that depends on interaction between VAMP2 on the vesicle and SNAP23 and SYNTAXIN-4 at the plasma membrane. Authored: May, B, 2011-07-07 Reviewed: Klip, Amira, 2012-08-21 Edited: May, B, 2011-07-07 LEFT-TO-RIGHT RAB4A:GTP binds KIF3 and activates KIF3 As inferred from mouse adipocytes, insulin signals via PKC-lambda to cause Rab4 to load GTP and associate with Kif3, which then has higher affinity for microtubules. Motor activity of Kif3 along microtubules is believed to transport vesicles containing Glut4 (Slc2a4) across the cytosol to the cortical actin network. Authored: May, B, 2012-05-27 Reviewed: Klip, Amira, 2012-08-21 Edited: May, B, 2012-05-27 Microtubule Reactome DB_ID: 190599 cytosol GENE ONTOLOGY GO:0005829 Microtubule protofilament Reactome DB_ID: 8982424 Reactome Database ID Release 83 8982424 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8982424 Reactome R-HSA-8982424 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-8982424.2 Reactome http://www.reactome.org ChEBI 36080 additional information MI MI:0361 13 Reactome Database ID Release 83 190599 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=190599 Reactome R-HSA-190599 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-190599.2 GGC-RAB4A:GTP Reactome DB_ID: 1458538 cytoplasmic vesicle membrane GENE ONTOLOGY GO:0030659 GTP Guanosine 5'-triphosphate Reactome DB_ID: 1996291 GTP [ChEBI:15996] GTP Guanosine 5'-triphosphate ChEBI CHEBI:15996 Reactome Database ID Release 83 1996291 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1996291 Reactome R-ALL-1996291 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-1996291.2 COMPOUND C00044 1 GGC-RAB4A Ras-related protein Rab-4A RAB4A_HUMAN Reactome DB_ID: 1458526 UniProt:P20338 RAB4A RAB4A RAB4 FUNCTION Small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state (PubMed:15907487, PubMed:16034420). Involved in protein transport (PubMed:29425100). Plays a role in vesicular traffic. Mediates VEGFR2 endosomal trafficking to enhance VEGFR2 signaling (PubMed:29425100). Acts as a regulator of platelet alpha-granule release during activation and aggregation of platelets (By similarity).SUBUNIT Interacts with SGSM1, SGSM2 and SGSM3 (By similarity). Interacts with RAB11FIP1, RABEP1, ZFYVE20 and RUFY1 (PubMed:10698684, PubMed:11786538, PubMed:11788822, PubMed:14617813, PubMed:15280022, PubMed:16034420). Interacts (membrane-bound form) with NDRG1; the interaction involves NDRG1 in vesicular recycling of E-cadherin (PubMed:17786215). Interacts (in GTP-bound form) with GRIPAP1 (via N-terminus) (PubMed:20098723). Interacts with RABEP1 and RBSN (PubMed:20098723). Does not interact with HPS4 (By similarity). Interacts with RABEP2; this interaction may mediate VEGFR2 cell surface expression (PubMed:29425100).PTM Phosphorylated by CDK1 kinase during mitosis.PTM Serotonylation of Gln-72 by TGM2 during activation and aggregation of platelets leads to constitutive activation of GTPase activity.SIMILARITY Belongs to the small GTPase superfamily. Rab family.CAUTION It is uncertain whether Met-1 or Met-6 is the initiator. Homo sapiens NCBI Taxonomy 9606 UniProt P20338 216 EQUAL S-geranylgeranyl-L-cysteine MOD MOD:00113 218 EQUAL 1 EQUAL 218 EQUAL Reactome Database ID Release 83 1458526 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458526 Reactome R-HSA-1458526 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-1458526.2 1 Reactome Database ID Release 83 1458538 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458538 Reactome R-HSA-1458538 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-1458538.2 KIF3 Reactome DB_ID: 2316334 KIFAP3 Kinesin-associated protein 3 KIFA3_HUMAN Reactome DB_ID: 984736 UniProt:Q92845 KIFAP3 KIFAP3 KIF3AP SMAP FUNCTION Involved in tethering the chromosomes to the spindle pole and in chromosome movement. Binds to the tail domain of the KIF3A/KIF3B heterodimer to form a heterotrimeric KIF3 complex and may regulate the membrane binding of this complex (By similarity).SUBUNIT Heterotrimer of KIFAP3, KIF3A and KIF3B. Interacts with RAP1GDS1/SMG GDS. Interacts with SMC3 subunit of the cohesin complex.PTM Phosphorylated on tyrosine residues by SRC in vitro; this reduces the binding affinity of the protein for RAP1GDS1. UniProt Q92845 1 EQUAL 792 EQUAL Reactome Database ID Release 83 984736 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=984736 Reactome R-HSA-984736 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-984736.1 1 KIF3B Kinesin-like protein KIF3B KIF3B_HUMAN Reactome DB_ID: 984662 UniProt:O15066 KIF3B KIF3B KIAA0359 FUNCTION Microtubule-based molecular motor that transport intracellular cargos, such as vesicles, organelles and protein complexes. Uses ATP hydrolysis to generate force to bind and move along the microtubule (By similarity). Plays a role in cilia formation (PubMed:32386558). Involved in photoreceptor integrity and opsin trafficking in rod photoreceptors (PubMed:32386558). Transports vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit GRIN2A into neuronal dendrites (By similarity).SUBUNIT Heterodimer of KIF3A and KIF3B (By similarity). KIF3A/KIF3B heterodimer interacts with KIFAP3 forming a heterotrimeric (KIF3A/KIF3B/KIFAP3) complex (By similarity). Interacts directly with IFT20 (By similarity). Interacts with the SMC3 subunit of the cohesin complex (PubMed:9506951). Interacts with FLCN (PubMed:27072130).SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. Kinesin II subfamily. UniProt O15066 1 EQUAL 747 EQUAL Reactome Database ID Release 83 984662 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=984662 Reactome R-HSA-984662 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-984662.1 1 KIF3A Kinesin-like protein KIF3A KIF3A_HUMAN Reactome DB_ID: 984767 UniProt:Q9Y496 KIF3A KIF3A KIF3 FUNCTION Microtubule-based anterograde translocator for membranous organelles. Plus end-directed microtubule sliding activity in vitro. Plays a role in primary cilia formation. Plays a role in centriole cohesion and subdistal appendage organization and function. Regulates the formation of the subdistal appendage via recruitment of DCTN1 to the centriole. Also required for ciliary basal feet formation and microtubule anchoring to mother centriole.SUBUNIT Heterodimer of KIF3A and KIF3B (By similarity). Interacts with PIFO (PubMed:20643351). Interacts with CLN3 (PubMed:22261744). Interacts with DCTN1 (By similarity). Interacts with FLCN (PubMed:27072130). Interacts with AP3B1 (PubMed:19934039).SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. Kinesin II subfamily. UniProt Q9Y496 1 EQUAL 699 EQUAL Reactome Database ID Release 83 984767 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=984767 Reactome R-HSA-984767 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-984767.1 1 Reactome Database ID Release 83 2316334 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316334 Reactome R-HSA-2316334 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316334.1 ComplexPortal CPX-3201 GGC-RAB4A:GTP:KIF3:microtubule Reactome DB_ID: 1458522 1 1 1 Reactome Database ID Release 83 1458522 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458522 Reactome R-HSA-1458522 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458522.3 Reactome Database ID Release 83 2316347 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316347 Reactome R-HSA-2316347 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-2316347.2 LEFT-TO-RIGHT 2.7.11.1 p-AKT1,p-AKT2 phosphorylates AS160 (TBC1D4) As inferred from mouse, AKT2 and, to a lesser extent, AKT1 phosphorylate AS160 (TBC1D4) in response to insulin signaling (Howlett et al. 2007, Karlsson et al 2005). AS160, a RAB GTPase activating protein, interacts with IRAP (LNPEP) and is associated with cytoplasmic vesicles containing GLUT4 (SLC2A4). Authored: May, B, 2011-07-07 Reviewed: Klip, Amira, 2012-08-21 Edited: May, B, 2011-07-07 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 6 AS160:IRAP TBC1D4:LNPEP Reactome DB_ID: 1445125 AS160 TBC1D4 TBC1 domain family member 4 TBCD4_HUMAN Reactome DB_ID: 1445122 UniProt:O60343 TBC1D4 TBC1D4 AS160 KIAA0603 FUNCTION May act as a GTPase-activating protein for RAB2A, RAB8A, RAB10 and RAB14. Isoform 2 promotes insulin-induced glucose transporter SLC2A4/GLUT4 translocation at the plasma membrane, thus increasing glucose uptake.TISSUE SPECIFICITY Widely expressed. Isoform 2 is the highest overexpressed in most tissues. Isoform 1 is highly expressed in skeletal muscle and heart, but was not detectable in the liver nor in adipose tissue. Isoform 2 is strongly expressed in adrenal and thyroid gland, and also in lung, kidney, colon, brain and adipose tissue. Isoform 2 is moderately expressed in skeletal muscle. Expressed in pancreatic Langerhans islets, including beta cells (at protein level). Expression is decreased by twofold in pancreatic islets in type 2 diabetes patients compared to control subjects. Up-regulated in T-cells from patients with atopic dermatitis.PTM Phosphorylated by AKT1; insulin-induced. Also phosphorylated by AMPK in response to insulin. Insulin-stimulated phosphorylation is required for SLC2A4/GLUT4 translocation. Has no effect on SLC2A4/GLUT4 internalization. Physiological hyperinsulinemia increases phosphorylation in skeletal muscle. Insulin-stimulated phosphorylation is reduced by 39% in type 2 diabetic patients. UniProt O60343 1 EQUAL 1298 EQUAL Reactome Database ID Release 83 1445122 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445122 Reactome R-HSA-1445122 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445122.1 1 IRAP LNPEP LNPEP Leucyl-cystinyl aminopeptidase LCAP_HUMAN Reactome DB_ID: 1445121 UniProt:Q9UIQ6 LNPEP LNPEP OTASE FUNCTION Release of an N-terminal amino acid, cleaves before cysteine, leucine as well as other amino acids. Degrades peptide hormones such as oxytocin, vasopressin and angiotensin III, and plays a role in maintaining homeostasis during pregnancy. May be involved in the inactivation of neuronal peptides in the brain. Cleaves Met-enkephalin and dynorphin. Binds angiotensin IV and may be the angiotensin IV receptor in the brain.SUBUNIT Homodimer. Binds tankyrases 1 and 2.TISSUE SPECIFICITY Highly expressed in placenta, heart, kidney and small intestine. Detected at lower levels in neuronal cells in the brain, in skeletal muscle, spleen, liver, testes and colon.PTM The pregnancy serum form is derived from the membrane-bound form by proteolytic processing.PTM N-glycosylated.SIMILARITY Belongs to the peptidase M1 family. UniProt Q9UIQ6 1 EQUAL 1025 EQUAL Reactome Database ID Release 83 1445121 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445121 Reactome R-HSA-1445121 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445121.1 1 Reactome Database ID Release 83 1445125 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445125 Reactome R-HSA-1445125 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445125.1 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 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 6 p-5S,T642-AS160:IRAP Phosphorylated TBC1D4:LNPEP Reactome DB_ID: 1445133 1 TBC1D4 p-5S,T642-TBC1D4 p-6S-TBC1D4 p-5S-T642-AS160 p-5S-T642-TBC1D4 Phosphorylated TBC1D4 TBC1 domain family member 4 TBCD4_HUMAN Reactome DB_ID: 1445101 318 EQUAL O-phospho-L-serine MOD MOD:00046 341 EQUAL 570 EQUAL 588 EQUAL 642 EQUAL O-phospho-L-threonine MOD MOD:00047 751 EQUAL 1 EQUAL 1298 EQUAL Reactome Database ID Release 83 1445101 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445101 Reactome R-HSA-1445101 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445101.1 1 Reactome Database ID Release 83 1445133 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445133 Reactome R-HSA-1445133 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445133.1 ACTIVATION Converted from EntitySet in Reactome p-AKT1,p-AKT2 Reactome DB_ID: 9023954 PKB p-T308,S473-AKT1 p-S473,T308-AKT1 p-T308, S473-AKT1 Phospho-AKT1 (T308, S473) phospho-PKB alpha (T308, S473) RAC-alpha serine/threonine kinase RAC-PK-alpha Protein kinase B C-AKT Reactome DB_ID: 199430 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:P31749 AKT1 AKT1 PKB RAC FUNCTION AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface (By similarity). Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling (By similarity). Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport (PubMed:11994271). AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity (By similarity). Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven (By similarity). AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase) (PubMed:11154276). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis (PubMed:11154276). AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating the TORC1 signaling pathway, and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1 (PubMed:12150915). Also regulates the TORC1 signaling pathway by catalyzing phosphorylation of CASTOR1 (PubMed:33594058). AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization (PubMed:10358075). In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319' (PubMed:10358075). FOXO3 and FOXO4 are phosphorylated on equivalent sites (PubMed:10358075). AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein) (PubMed:9829964). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1 (PubMed:9829964). AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis (By similarity). Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis (By similarity). Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity (By similarity). The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I) (PubMed:12176338, PubMed:12964941). AKT mediates the antiapoptotic effects of IGF-I (By similarity). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). May be involved in the regulation of the placental development (By similarity). Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3 (PubMed:17726016). Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation (PubMed:20086174, PubMed:20231902). Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation (PubMed:19592491). Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity (PubMed:10576742). Phosphorylation of BAD stimulates its pro-apoptotic activity (PubMed:10926925). Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53 (PubMed:23431171). Phosphorylates palladin (PALLD), modulating cytoskeletal organization and cell motility (PubMed:20471940). Phosphorylates prohibitin (PHB), playing an important role in cell metabolism and proliferation (PubMed:18507042). Phosphorylates CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization (PubMed:16982699). These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation (PubMed:16139227). Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation (PubMed:20682768). Phosphorylates PCK1 at 'Ser-90', reducing the binding affinity of PCK1 to oxaloacetate and changing PCK1 into an atypical protein kinase activity using GTP as donor (PubMed:32322062). Also acts as an activator of TMEM175 potassium channel activity in response to growth factors: forms the lysoK(GF) complex together with TMEM175 and acts by promoting TMEM175 channel activation, independently of its protein kinase activity (PubMed:32228865).ACTIVITY REGULATION Three specific sites, one in the kinase domain (Thr-308) and the two other ones in the C-terminal regulatory region (Ser-473 and Tyr-474), need to be phosphorylated for its full activation (PubMed:20481595, PubMed:21392984, PubMed:9512493, PubMed:9736715). Inhibited by pyrrolopyrimidine inhibitors like aniline triazole and spiroindoline (PubMed:18456494, PubMed:20810279).SUBUNIT Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts (via the C-terminus) with CCDC88A (via its C-terminus). Interacts with GRB10; the interaction leads to GRB10 phosphorylation thus promoting YWHAE-binding (By similarity). Interacts with AGAP2 (isoform 2/PIKE-A); the interaction occurs in the presence of guanine nucleotides. Interacts with AKTIP. Interacts (via PH domain) with MTCP1, TCL1A and TCL1B. Interacts with CDKN1B; the interaction phosphorylates CDKN1B promoting 14-3-3 binding and cell-cycle progression. Interacts with MAP3K5 and TRAF6. Interacts with BAD, PPP2R5B, STK3 and STK4. Interacts (via PH domain) with SIRT1. Interacts with SRPK2 in a phosphorylation-dependent manner. Interacts with RAF1. Interacts with TRIM13; the interaction ubiquitinates AKT1 leading to its proteasomal degradation. Interacts with TNK2 and CLK2. Interacts (via the C-terminus) with THEM4 (via its C-terminus). Interacts with and phosphorylated by PDPK1. Interacts with PA2G4 (By similarity). Interacts with KIF14; the interaction is detected in the plasma membrane upon INS stimulation and promotes AKT1 phosphorylation (PubMed:24784001). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (PubMed:23676467). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529). Forms a complex with WDFY2 and FOXO1 (By similarity). Interacts with FAM168A (PubMed:23251525). Interacts with SYAP1 (via phosphorylated form and BSD domain); this interaction is enhanced in a mTORC2-mediated manner in response to epidermal growth factor (EGF) stimulation and activates AKT1 (PubMed:23300339). Interacts with PKHM3 (By similarity). Interacts with FKBP5/FKBP51; promoting interaction between Akt/AKT1 and PHLPP1, thereby enhancing dephosphorylation and subsequent activation of Akt/AKT1 (PubMed:28147277). Interacts with TMEM175; leading to formation of the lysoK(GF) complex (PubMed:32228865). Acts as a negative regulator of the cGAS-STING pathway by mediating phosphorylation of CGAS during mitosis, leading to its inhibition (PubMed:26440888).TISSUE SPECIFICITY Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Expressed in all human cell types so far analyzed. The Tyr-176 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages.DOMAIN Binding of the PH domain to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3-kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane. The PH domain mediates interaction with TNK2 and Tyr-176 is also essential for this interaction.DOMAIN The AGC-kinase C-terminal mediates interaction with THEM4.PTM O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1. O-GlcNAcylation at Ser-473 also probably interferes with phosphorylation at this site.PTM Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity (PubMed:12149249, PubMed:14761976, PubMed:15047712, PubMed:16266983, PubMed:17013611, PubMed:20978158, PubMed:9736715, PubMed:23799035, PubMed:8978681, PubMed:28147277). Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA (PubMed:20333297). This phosphorylated form localizes to the cell membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation (PubMed:9512493). Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1 (PubMed:21464307, PubMed:8978681). Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1 (PubMed:15718470, PubMed:18456494, PubMed:20481595, PubMed:8978681). Ser-473 phosphorylation is enhanced by interaction with AGAP2 isoform 2 (PIKE-A) (PubMed:14761976). Ser-473 phosphorylation is enhanced in focal cortical dysplasias with Taylor-type balloon cells (PubMed:17013611). Ser-473 phosphorylation is enhanced by signaling through activated FLT3 (By similarity). Ser-473 is dephosphorylated by PHLPP (PubMed:28147277). Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase (PubMed:21329884). The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase (PubMed:21329884). Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling (PubMed:9512493).PTM Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT1 ubiquitination is critical for phosphorylation and activation (PubMed:19713527). When ubiquitinated, it translocates to the plasma membrane, where it becomes phosphorylated (PubMed:20059950). When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome (PubMed:20059950). Also ubiquitinated by TRIM13 leading to its proteasomal degradation (PubMed:21333377). Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation (PubMed:22410793). Ubiquitinated via 'Lys-48'-linked polyubiquitination by ZNRF1, leading to its degradation by the proteasome (By similarity).PTM Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B. Acetylation results in reduced phosphorylation and inhibition of activity. Deacetylated at Lys-14 and Lys-20 by SIRT1. SIRT1-mediated deacetylation relieves the inhibition.PTM Cleavage by caspase-3/CASP3 (By similarity). Cleaved at the caspase-3 consensus site Asp-462 during apoptosis, resulting in down-regulation of the AKT signaling pathway and decreased cell survival (PubMed:23152800).DISEASE Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.CAUTION PUBMED:19940129 has been retracted because the same data were used to represent different experimental conditions.CAUTION In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain. UniProt P31749 308 EQUAL 473 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 83 199430 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199430 Reactome R-HSA-199430 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199430.1 PKB beta p-T309,S474-AKT2 p-S474,T309-AKT2 Phospho-AKT2 (T309, S474) RAC-beta serine/threonine protein kinase RAC-PK-beta Protein kinase Akt-2 Protein kinase B, beta Reactome DB_ID: 202056 UniProt:P31751 AKT2 AKT2 FUNCTION AKT2 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development.FUNCTION One of the few specific substrates of AKT2 identified recently is PITX2. Phosphorylation of PITX2 impairs its association with the CCND1 mRNA-stabilizing complex thus shortening the half-life of CCND1. AKT2 seems also to be the principal isoform responsible of the regulation of glucose uptake. Phosphorylates C2CD5 on 'Ser-197' during insulin-stimulated adipocytes. AKT2 is also specifically involved in skeletal muscle differentiation, one of its substrates in this process being ANKRD2. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis. Phosphorylates CLK2 on 'Thr-343'.ACTIVITY REGULATION Two specific sites, one in the kinase domain (Thr-309) and the other in the C-terminal regulatory region (Ser-474), need to be phosphorylated for its full activation (PubMed:18800763, PubMed:19179070). Aminofurazans, such as 4-[2-(4-amino-2,5-dihydro-1,2,5-oxadiazol-3-yl)-6-{[(1S)-3-amino-1-phenylpropyl]oxy}-1-ethyl-1H-imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol (compound 32), are potent AKT2 inhibitors (PubMed:19179070).SUBUNIT Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts (via PH domain) with MTCP1, TCL1A and TCL1B. Interacts with CLK2, PBH2 and TRAF6. Interacts (when phosphorylated) with CLIP3, the interaction promotes cell membrane localization (PubMed:19139280). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529).TISSUE SPECIFICITY Expressed in all cell types so far analyzed.DOMAIN Binding of the PH domain to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3-kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane.PTM Phosphorylation on Thr-309 and Ser-474 is required for full activity.PTM Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT2 ubiquitination. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome.PTM O-GlcNAcylation at Thr-306 and Thr-313 inhibits activating phosphorylation at Thr-309 via disrupting the interaction between AKT and PDK1.DISEASE Defects in AKT2 are a cause of susceptibility to breast cancer (BC). AKT2 promotes metastasis of tumor cells without affecting the latency of tumor development. With AKT3, also plays a pivotal role in the biology of glioblastoma.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.CAUTION In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain. UniProt P31751 309 EQUAL 474 EQUAL 1 EQUAL 481 EQUAL Reactome Database ID Release 83 202056 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202056 Reactome R-HSA-202056 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202056.1 Reactome Database ID Release 83 9023954 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9023954 Reactome R-HSA-9023954 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9023954.1 GENE ONTOLOGY GO:0004674 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 83 9023956 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9023956 Reactome Database ID Release 83 1445144 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445144 Reactome R-HSA-1445144 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445144.3 17369524 Pubmed 2007 Resistance exercise and insulin regulate AS160 and interaction with 14-3-3 in human skeletal muscle Howlett, KF Sakamoto, K Garnham, A Cameron-Smith, D Hargreaves, M Diabetes 56:1608-14 15919790 Pubmed 2005 Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects Karlsson, HK Zierath, JR Kane, S Krook, A Lienhard, GE Wallberg-Henriksson, H Diabetes 54:1692-7 LEFT-TO-RIGHT 14-3-3 binds p-5S,T642-AS160 (TBC1D4) AS160 (TBC1D4) phosphorylated on serines 318, 341, 570, 588, and 751 and threonine 642 binds to all 14-3-3 proteins, although binding to 14-3-3 delta (YWHAZ) is comparatively low (Ramm et al. 2006, Howlett et al. 2007, Ngo et al. 2009, Treebak et al. 2009, Koumanov et al. 2011). As inferred from mouse, binding to 14-3-3 does not interfere with the interaction between AS160 and IRAP (LNPEP). Authored: May, B, 2011-07-07 Reviewed: Klip, Amira, 2012-08-21 Edited: May, B, 2011-07-07 Converted from EntitySet in Reactome 14-3-3 dimer Reactome DB_ID: 1445138 YWHAH dimer 14-3-3 eta dimer Reactome DB_ID: 2262715 YWHAH 14-3-3 eta 14-3-3 protein eta 1433F_HUMAN Reactome DB_ID: 1445107 UniProt:Q04917 YWHAH YWHAH YWHA1 FUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negatively regulates the kinase activity of PDPK1.SUBUNIT Homodimer (By similarity). Interacts with many nuclear hormone receptors and cofactors including AR, ESR1, ESR2, MC2R, NR3C1, NRIP1, PPARBP and THRA. Interacts with ABL1 (phosphorylated form); the interaction retains it in the cytoplasm. Interacts with ARHGEF28 and CDK16 (By similarity). Weakly interacts with CDKN1B. Interacts with GAB2. Interacts with KCNK18 in a phosphorylation-dependent manner. Interacts with SAMSN1 (By similarity). Interacts with the 'Ser-241' phosphorylated form of PDPK1. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with SLITRK1 (PubMed:19640509). Interacts with MEFV (PubMed:27030597).TISSUE SPECIFICITY Expressed mainly in the brain and present in other tissues albeit at lower levels.PTM Phosphorylated on Ser-59 by protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion.SIMILARITY Belongs to the 14-3-3 family. UniProt Q04917 2 EQUAL 246 EQUAL Reactome Database ID Release 83 1445107 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445107 Reactome R-HSA-1445107 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445107.1 2 Reactome Database ID Release 83 2262715 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2262715 Reactome R-HSA-2262715 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-2262715.2 YWHAG dimer 14-3-3 gamma dimer Reactome DB_ID: 2262713 YWHAG 14-3-3 protein gamma 14-3-3 gamma Reactome DB_ID: 380312 UniProt:P61981 YWHAG YWHAG FUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.SUBUNIT Homodimer. Interacts with SAMSN1 (By similarity). Interacts with RAF1, SSH1 and CRTC2/TORC2. Interacts with ABL1 (phosphorylated form); the interaction retains it in the cytoplasm. Interacts with GAB2. Interacts with MDM4 (phosphorylated); negatively regulates MDM4 activity toward TP53. Interacts with PKA-phosphorylated AANAT and SIRT2.Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with SLITRK1 (PubMed:19640509). Interacts with LRRK2; this interaction is dependent on LRRK2 phosphorylation (PubMed:28202711). Interacts with MARK2 and MARK3 (PubMed:16959763). Interacts with MEFV (PubMed:27030597). Interacts with ENDOG, TSC2 and PIK3C3; interaction with ENDOG weakens its interaction with TSC2 and PIK3C3 (PubMed:33473107).TISSUE SPECIFICITY Highly expressed in brain, skeletal muscle, and heart.PTM Phosphorylated by various PKC isozymes.SIMILARITY Belongs to the 14-3-3 family. UniProt P61981 1 EQUAL 247 EQUAL Reactome Database ID Release 83 380312 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380312 Reactome R-HSA-380312 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380312.1 2 Reactome Database ID Release 83 2262713 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2262713 Reactome R-HSA-2262713 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-2262713.2 SFN dimer 14-3-3 sigma dimer Reactome DB_ID: 2262716 SFN 14-3-3 sigma 14-3-3 protein sigma 1433S_HUMAN Reactome DB_ID: 1445105 UniProt:P31947 SFN SFN HME1 FUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway. May also regulate MDM2 autoubiquitination and degradation and thereby activate p53/TP53.FUNCTION p53-regulated inhibitor of G2/M progression.SUBUNIT Homodimer (PubMed:28202711). Interacts with KRT17 and SAMSN1 (By similarity). Found in a complex with XPO7, EIF4A1, ARHGAP1, VPS26A, VPS29 and VPS35. Interacts with GAB2. Interacts with SRPK2. Interacts with COPS6. Interacts with COP1; this interaction leads to proteasomal degradation. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB (PubMed:23572552). Interacts with SLITRK1 (PubMed:19640509). Interacts with LRRK2; this interaction is dependent on LRRK2 phosphorylation (PubMed:28202711).TISSUE SPECIFICITY Present mainly in tissues enriched in stratified squamous keratinizing epithelium.PTM Ubiquitinated. Ubiquitination by RFFL induces proteasomal degradation and indirectly regulates p53/TP53 activation.SIMILARITY Belongs to the 14-3-3 family. UniProt P31947 1 EQUAL 248 EQUAL Reactome Database ID Release 83 1445105 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445105 Reactome R-HSA-1445105 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445105.1 2 Reactome Database ID Release 83 2262716 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2262716 Reactome R-HSA-2262716 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2262716.3 YWHAQ dimer 14-3-3 theta dimer Reactome DB_ID: 2262714 YWHAQ 14-3-3 theta 14-3-3 protein theta 1433T_HUMAN Reactome DB_ID: 1445116 UniProt:P27348 YWHAQ YWHAQ FUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negatively regulates the kinase activity of PDPK1.SUBUNIT Homodimer. Interacts with CDK16 (By similarity). Interacts with RGS7 (phosphorylated form) (PubMed:10862767). Interacts with SSH1. Interacts with CDKN1B ('Thr-198' phosphorylated form); the interaction translocates CDKN1B to the cytoplasm. Interacts with GAB2. Interacts with the 'Ser-241' phosphorylated form of PDPK1. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with SLITRK1 (PubMed:19640509). Interacts with RIPOR2 isoform 2 (PubMed:25588844). Interacts with INAVA; the interaction increases upon PRR (pattern recognition receptor) stimulation and is required for cellular signaling pathway activation and cytokine secretion (PubMed:28436939). Interacts with MARK2, MARK3 and MARK4 (PubMed:16959763). Interacts with MEFV (PubMed:27030597).TISSUE SPECIFICITY Abundantly expressed in brain, heart and pancreas, and at lower levels in kidney and placenta. Up-regulated in the lumbar spinal cord from patients with sporadic amyotrophic lateral sclerosis (ALS) compared with controls, with highest levels of expression in individuals with predominant lower motor neuron involvement.PTM Ser-232 is probably phosphorylated by CK1.SIMILARITY Belongs to the 14-3-3 family. UniProt P27348 1 EQUAL 245 EQUAL Reactome Database ID Release 83 1445116 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445116 Reactome R-HSA-1445116 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445116.1 2 Reactome Database ID Release 83 2262714 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2262714 Reactome R-HSA-2262714 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-2262714.2 YWHAZ dimer 14-3-3 zeta dimer Reactome DB_ID: 206751 YWHAZ 14-3-3 zeta Reactome DB_ID: 206099 UniProt:P63104 YWHAZ YWHAZ FUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways (PubMed:14578935, PubMed:15071501, PubMed:15644438, PubMed:16376338, PubMed:16959763, PubMed:31024343, PubMed:9360956). Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif (PubMed:35662396). Binding generally results in the modulation of the activity of the binding partner (PubMed:35662396). Promotes cytosolic retention and inactivation of TFEB transcription factor by binding to phosphorylated TFEB (PubMed:35662396). Induces ARHGEF7 activity on RAC1 as well as lamellipodia and membrane ruffle formation (PubMed:16959763). In neurons, regulates spine maturation through the modulation of ARHGEF7 activity (By similarity).SUBUNIT Interacts with CDK16 and BSPRY (By similarity). Interacts with WEE1 (C-terminal). Interacts with SAMSN1 (By similarity). Interacts with MLF1 (phosphorylated form); the interaction retains it in the cytoplasm (By similarity). Interacts with Thr-phosphorylated ITGB2 (By similarity). Interacts with BCL2L11 (By similarity). Homodimer (PubMed:12865427, PubMed:16376338). Heterodimerizes with YWHAE (PubMed:16376338). Homo- and heterodimerization is inhibited by phosphorylation on Ser-58 (PubMed:16376338). Interacts with FOXO4, NOXA1, SSH1 and ARHGEF2. Interacts with Pseudomonas aeruginosa exoS (unphosphorylated form). Interacts with BAX; the interaction occurs in the cytoplasm. Under stress conditions, MAPK8-mediated phosphorylation releases BAX to mitochondria. Interacts with phosphorylated RAF1; the interaction is inhibited when YWHAZ is phosphorylated on Thr-232 (PubMed:31024343). Interacts with BRAF (PubMed:31024343). Interacts with TP53; the interaction enhances p53 transcriptional activity. The Ser-58 phosphorylated form inhibits this interaction and p53 transcriptional activity. Interacts with ABL1 (phosphorylated form); the interaction retains ABL1 in the cytoplasm. Interacts with PKA-phosphorylated AANAT; the interaction modulates AANAT enzymatic activity by increasing affinity for arylalkylamines and acetyl-CoA and protecting the enzyme from dephosphorylation and proteasomal degradation. It may also prevent thiol-dependent inactivation. Interacts with AKT1; the interaction phosphorylates YWHAZ and modulates dimerization. Interacts with GAB2 and TLK2. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with ZFP36L1 (via phosphorylated form); this interaction occurs in a p38 MAPK- and AKT-signaling pathways (By similarity). Interacts with SLITRK1 (PubMed:19640509). Interacts with AK5, LDB1, MADD, MARK3, PDE1A and SMARCB1 (PubMed:16959763). Interacts with MEFV (PubMed:27030597).PTM The delta, brain-specific form differs from the zeta form in being phosphorylated (Probable). Phosphorylation on Ser-184 by MAPK8; promotes dissociation of BAX and translocation of BAX to mitochondria (PubMed:15071501, PubMed:15696159). Phosphorylation on Thr-232; inhibits binding of RAF1 (PubMed:9360956). Phosphorylated on Ser-58 by PKA and protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion (PubMed:11956222, PubMed:12865427, PubMed:15883165, PubMed:16376338). Phosphorylation on Ser-58 by PKA; disrupts homodimerization and heterodimerization with YHAE and TP53 (PubMed:11956222, PubMed:12865427, PubMed:15883165, PubMed:16376338).SIMILARITY Belongs to the 14-3-3 family.CAUTION Was originally thought to have phospholipase A2 activity. UniProt P63104 1 EQUAL 245 EQUAL Reactome Database ID Release 83 206099 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=206099 Reactome R-HSA-206099 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-206099.1 2 Reactome Database ID Release 83 206751 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=206751 Reactome R-HSA-206751 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-206751.3 YWHAB dimer Reactome DB_ID: 2028645 YWHAB 14-3-3 protein beta/alpha 143B protein Protein kinase C inhibitor protein-1 KCIP-1 Protein 1054 Reactome DB_ID: 48888 UniProt:P31946 YWHAB YWHAB FUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negative regulator of osteogenesis. Blocks the nuclear translocation of the phosphorylated form (by AKT1) of SRPK2 and antagonizes its stimulatory effect on cyclin D1 expression resulting in blockage of neuronal apoptosis elicited by SRPK2. Negative regulator of signaling cascades that mediate activation of MAP kinases via AKAP13.SUBUNIT Homodimer (PubMed:17717073). Interacts with SAMSN1 and PRKCE (By similarity). Interacts with AKAP13 (PubMed:21224381). Interacts with SSH1 and TORC2/CRTC2 (PubMed:15454081, PubMed:15159416). Interacts with ABL1; the interaction results in cytoplasmic location of ABL1 and inhibition of cABL-mediated apoptosis (PubMed:15696159). Interacts with ROR2 (dimer); the interaction results in phosphorylation of YWHAB on tyrosine residues (PubMed:17717073). Interacts with GAB2 (PubMed:19172738). Interacts with YAP1 (phosphorylated form) (PubMed:17974916). Interacts with the phosphorylated (by AKT1) form of SRPK2 (PubMed:19592491). Interacts with PKA-phosphorylated AANAT (PubMed:11427721). Interacts with MYO1C (PubMed:24636949). Interacts with SIRT2 (PubMed:18249187). Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with the 'Ser-1134' and 'Ser-1161' phosphorylated form of SOS1 (PubMed:22827337). Interacts (via phosphorylated form) with YWHAB; this interaction occurs in a protein kinase AKT1-dependent manner (PubMed:15538381). Interacts with SLITRK1 (PubMed:19640509). Interacts with SYNPO2 (phosphorylated form); YWHAB competes with ACTN2 for interaction with SYNPO2 (By similarity). Interacts with RIPOR2 (via phosphorylated form) isoform 2; this interaction occurs in a chemokine-dependent manner and does not compete for binding of RIPOR2 with RHOA nor blocks inhibition of RIPOR2-mediated RHOA activity (PubMed:25588844). Interacts with MARK2 and MARK3 (PubMed:16959763). Interacts with TESK1; the interaction is dependent on the phosphorylation of TESK1 'Ser-437' and inhibits TESK1 kinase activity (PubMed:11555644). Interacts with MEFV (PubMed:27030597).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL46.SUBUNIT (Microbial infection) Probably interacts with Chlamydia trachomatis protein IncG.PTM The alpha, brain-specific form differs from the beta form in being phosphorylated. Phosphorylated on Ser-60 by protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion.SIMILARITY Belongs to the 14-3-3 family. UniProt P31946 1 EQUAL 246 EQUAL Reactome Database ID Release 83 48888 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=48888 Reactome R-HSA-48888 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-48888.1 2 Reactome Database ID Release 83 2028645 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2028645 Reactome R-HSA-2028645 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2028645.1 YWHAE dimer 14-3-3E homodimer Reactome DB_ID: 194364 YWHAE 14-3-3 protein epsilon 143E_HUMAN 14-3-3 epsilon Reactome DB_ID: 194368 UniProt:P62258 YWHAE YWHAE FUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner (By similarity). Positively regulates phosphorylated protein HSF1 nuclear export to the cytoplasm (PubMed:12917326).SUBUNIT Homodimer (PubMed:17085597). Heterodimerizes with YWHAZ (PubMed:16376338). Interacts with PKA-phosphorylated AANAT (PubMed:11427721). Interacts with ABL1 (phosphorylated form); the interaction retains it in the cytoplasm (PubMed:15696159). Interacts with ARHGEF28 (By similarity). Interacts with BEX3 (By similarity). Weakly interacts with CDKN1B (PubMed:12042314). Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with DENND1A (PubMed:26055712). Interacts with GAB2 (PubMed:19172738). Interacts with phosphorylated GRB10 (PubMed:15722337). Interacts with KSR1 (PubMed:10409742). Interacts with NDEL1 (By similarity). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with the phosphorylated (by AKT1) form of SRPK2 (PubMed:19592491). Interacts with TIAM2. Interacts with the 'Ser-1134' and 'Ser-1161' phosphorylated form of SOS1 (By similarity). Interacts with ZFP36 (via phosphorylated form) (By similarity). Interacts with SLITRK1 (PubMed:19640509). Interacts with HSF1 (via phosphorylated form); this interaction promotes HSF1 sequestration in the cytoplasm in a ERK-dependent manner (PubMed:12917326). Interacts with RIPOR2 isoform 2 (PubMed:25588844). Interacts with KLHL22; required for the nuclear localization of KLHL22 upon amino acid starvation (PubMed:29769719). Interacts with CRTC1 (PubMed:30611118). Interacts with CRTC2 (probably when phosphorylated at 'Ser-171') (PubMed:30611118). Interacts with CRTC3 (probably when phosphorylated at 'Ser-162' and/or 'Ser-273') (PubMed:30611118). Interacts with ATP2B1 and ATP2B3; this interaction inhibits calcium-transporting ATPase activity (PubMed:18029012). Interacts with MEFV (PubMed:27030597).SUBUNIT (Microbial infection) Interacts with HCV core protein.SIMILARITY Belongs to the 14-3-3 family. UniProt P62258 1 EQUAL 255 EQUAL Reactome Database ID Release 83 194368 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194368 Reactome R-HSA-194368 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194368.1 2 Reactome Database ID Release 83 194364 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194364 Reactome R-HSA-194364 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194364.1 Reactome Database ID Release 83 1445138 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445138 Reactome R-HSA-1445138 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445138.1 p-5S,T642-AS160:14-3-3:IRAP p-5S-T642-TBC1D4:14-3-3:LNPEP Phosphorylated TBC1D4:14-3-3:LNPEP Reactome DB_ID: 1445124 Phospho AS160:14-3-3 Phosphorylated TBC1D4:14-3-3 Reactome DB_ID: 1445126 1 1 Reactome Database ID Release 83 1445126 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445126 Reactome R-HSA-1445126 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-1445126.2 1 1 Reactome Database ID Release 83 1445124 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445124 Reactome R-HSA-1445124 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445124.1 Reactome Database ID Release 83 1445149 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445149 Reactome R-HSA-1445149 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-1445149.2 16880201 Pubmed 2006 A role for 14-3-3 in insulin-stimulated GLUT4 translocation through its interaction with the RabGAP AS160 Ramm, G Larance, M Guilhaus, M James, DE J Biol Chem 281:29174-80 21454690 Pubmed 2011 AS160 phosphotyrosine-binding domain constructs inhibit insulin-stimulated GLUT4 vesicle fusion with the plasma membrane Koumanov, F Richardson, JD Murrow, BA Holman, GD J Biol Chem 286:16574-82 19252894 Pubmed 2009 Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle Treebak, JT Frøsig, C Pehmøller, C Chen, S Maarbjerg, SJ Brandt, N Mackintosh, C Zierath, JR Hardie, DG Kiens, B Richter, EA Pilegaard, H Wojtaszewski, JF Diabetologia 52:891-900 19013499 Pubmed 2009 Reduced phosphorylation of AS160 contributes to glucocorticoid-mediated inhibition of glucose uptake in human and murine adipocytes Ngo, S Barry, JB Nisbet, JC Prins, JB Whitehead, JP Mol Cell Endocrinol 302:33-40 LEFT-TO-RIGHT 2.7.11.1 AMPK-alpha2 phosphorylates TBC1D1 In response to muscle contraction and insulin signaling, AMPK-alpha2 phosphorylates TBC1D1 on serine 237 and probably other residues (Frosig et al. 2010, Vichaiwong et al. 2010). As inferred from rat L6 muscle cells TBC1D1 colocalizes with perinuclear vesicles bearing GLUT4 (SLC2A4) and may be involved in an early step that mobilizes them (Chen et al. 2008). Human TBC1D1 appears cytosolic and is believed to be concentrated near vesicle membranes (Park et al. 2011). Authored: May, B, 2011-07-15 Reviewed: Klip, Amira, 2012-08-21 Edited: May, B, 2011-07-15 TBC1D1 TBC1 domain family member 1 TBCD1_HUMAN Reactome DB_ID: 1454718 UniProt:Q86TI0 TBC1D1 TBC1D1 KIAA1108 FUNCTION May act as a GTPase-activating protein for Rab family protein(s). May play a role in the cell cycle and differentiation of various tissues. Involved in the trafficking and translocation of GLUT4-containing vesicles and insulin-stimulated glucose uptake into cells (By similarity).SUBUNIT Interacts with APPL2 (via BAR domain); interaction is dependent of TBC1D1 phosphorylation at Ser-235; interaction diminishes the phosphorylation of TBC1D1 at Thr-596, resulting in inhibition of SLC2A4/GLUT4 translocation and glucose uptake.PTM Insulin-stimulated phosphorylation by AKT family kinases stimulates SLC2A4/GLUT4 translocation. UniProt Q86TI0 1 EQUAL 1168 EQUAL Reactome Database ID Release 83 1454718 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454718 Reactome R-HSA-1454718 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1454718.1 TBC1D1 p-S237-TBC1D1 TBC1D1 (pSer237) TBC1 domain family member 1 TBCD1_HUMAN Reactome DB_ID: 1454673 237 EQUAL 1 EQUAL 1168 EQUAL Reactome Database ID Release 83 1454673 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454673 Reactome R-HSA-1454673 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1454673.1 ACTIVATION activeUnit: #Protein24 AMPK-alpha2:AMPK-beta:AMPK-gamma:AMP Reactome DB_ID: 1454683 AMPK gamma:AMP Reactome DB_ID: 2316451 Converted from EntitySet in Reactome AMPK gamma Reactome DB_ID: 381851 PRKAG1 AMPK gamma1 5'-AMP-activated protein kinase subunit gamma-1 AAKG1_HUMAN Reactome DB_ID: 380946 UniProt:P54619 PRKAG1 PRKAG1 FUNCTION AMP/ATP-binding subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Gamma non-catalytic subunit mediates binding to AMP, ADP and ATP, leading to activate or inhibit AMPK: AMP-binding results in allosteric activation of alpha catalytic subunit (PRKAA1 or PRKAA2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. ADP also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. ATP promotes dephosphorylation of catalytic subunit, rendering the AMPK enzyme inactive.SUBUNIT AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2.DOMAIN The AMPK pseudosubstrate motif resembles the sequence around sites phosphorylated on target proteins of AMPK, except the presence of a non-phosphorylatable residue in place of Ser. In the absence of AMP this pseudosubstrate sequence may bind to the active site groove on the alpha subunit (PRKAA1 or PRKAA2), preventing phosphorylation by the upstream activating kinase STK11/LKB1.DOMAIN The 4 CBS domains mediate binding to nucleotides. Of the 4 potential nucleotide-binding sites, 3 are occupied, designated as sites 1, 3, and 4 based on the CBS modules that provide the acidic residue for coordination with the 2'- and 3'-hydroxyl groups of the ribose of AMP. Of these, site 4 appears to be a structural site that retains a tightly held AMP molecule (AMP 3). The 2 remaining sites, 1 and 3, can bind either AMP, ADP or ATP. Site 1 (AMP, ADP or ATP 1) is the high-affinity binding site and likely accommodates AMP or ADP. Site 3 (AMP, ADP or ATP 2) is the weakest nucleotide-binding site on the gamma subunit, yet it is exquisitely sensitive to changes in nucleotide levels and this allows AMPK to respond rapidly to changes in cellular energy status. Site 3 is likely to be responsible for protection of a conserved threonine in the activation loop of the alpha catalytic subunit through conformational changes induced by binding of AMP or ADP.PTM Phosphorylated by ULK1 and ULK2; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1, ULK2 and AMPK.SIMILARITY Belongs to the 5'-AMP-activated protein kinase gamma subunit family. UniProt P54619 1 EQUAL 331 EQUAL Reactome Database ID Release 83 380946 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380946 Reactome R-HSA-380946 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380946.1 PRKAG2 AMPK gamma2 Reactome DB_ID: 200419 UniProt:Q9UGJ0 PRKAG2 PRKAG2 FUNCTION AMP/ATP-binding subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Gamma non-catalytic subunit mediates binding to AMP, ADP and ATP, leading to activate or inhibit AMPK: AMP-binding results in allosteric activation of alpha catalytic subunit (PRKAA1 or PRKAA2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. ADP also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. ATP promotes dephosphorylation of catalytic subunit, rendering the AMPK enzyme inactive.SUBUNIT AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2.TISSUE SPECIFICITY Isoform B is ubiquitously expressed except in liver and thymus. The highest level is detected in heart with abundant expression in placenta and testis.DOMAIN The AMPK pseudosubstrate motif resembles the sequence around sites phosphorylated on target proteins of AMPK, except the presence of a non-phosphorylatable residue in place of Ser. In the absence of AMP this pseudosubstrate sequence may bind to the active site groove on the alpha subunit (PRKAA1 or PRKAA2), preventing phosphorylation by the upstream activating kinase STK11/LKB1.DOMAIN The 4 CBS domains mediate binding to nucleotides. Of the 4 potential nucleotide-binding sites, 3 are occupied, designated as sites 1, 3, and 4 based on the CBS modules that provide the acidic residue for coordination with the 2'- and 3'-hydroxyl groups of the ribose of AMP. Of these, site 4 appears to be a structural site that retains a tightly held AMP molecule (AMP 3). The 2 remaining sites, 1 and 3, can bind either AMP, ADP or ATP. Site 1 (AMP, ADP or ATP 1) is the high-affinity binding site and likely accommodates AMP or ADP. Site 3 (AMP, ADP or ATP 2) is the weakest nucleotide-binding site on the gamma subunit, yet it is exquisitely sensitive to changes in nucleotide levels and this allows AMPK to respond rapidly to changes in cellular energy status. Site 3 is likely to be responsible for protection of a conserved threonine in the activation loop of the alpha catalytic subunit through conformational changes induced by binding of AMP or ADP.PTM Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK.SIMILARITY Belongs to the 5'-AMP-activated protein kinase gamma subunit family. UniProt Q9UGJ0 1 EQUAL 569 EQUAL Reactome Database ID Release 83 200419 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200419 Reactome R-HSA-200419 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-200419.2 PRKAG3 AMPK gamma3 5'-AMP-activated protein kinase subunit gamma-3 AAKG3_HUMAN Reactome DB_ID: 381839 UniProt:Q9UGI9 PRKAG3 PRKAG3 AMPKG3 FUNCTION AMP/ATP-binding subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. AMPK also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. The AMPK gamma3 subunit is a non-catalytic subunit with a regulatory role in muscle energy metabolism (PubMed:17878938). It mediates binding to AMP, ADP and ATP, leading to AMPK activation or inhibition: AMP-binding results in allosteric activation of alpha catalytic subunit (PRKAA1 or PRKAA2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. ADP also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. ATP promotes dephosphorylation of catalytic subunit, rendering the AMPK enzyme inactive.SUBUNIT AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2 (By similarity).TISSUE SPECIFICITY Skeletal muscle, with weak expression in heart and pancreas.DOMAIN The AMPK pseudosubstrate motif resembles the sequence around sites phosphorylated on target proteins of AMPK, except the presence of a non-phosphorylatable residue in place of Ser. In the absence of AMP this pseudosubstrate sequence may bind to the active site groove on the alpha subunit (PRKAA1 or PRKAA2), preventing phosphorylation by the upstream activating kinase STK11/LKB1.DOMAIN The 4 CBS domains mediate binding to nucleotides. Of the 4 potential nucleotide-binding sites, 3 are occupied, designated as sites 1, 3, and 4 based on the CBS modules that provide the acidic residue for coordination with the 2'- and 3'-hydroxyl groups of the ribose of AMP. Of these, site 4 appears to be a structural site that retains a tightly held AMP molecule (AMP 3). The 2 remaining sites, 1 and 3, can bind either AMP, ADP or ATP. Site 1 (AMP, ADP or ATP 1) is the high-affinity binding site and likely accommodates AMP or ADP. Site 3 (AMP, ADP or ATP 2) is the weakest nucleotide-binding site on the gamma subunit, yet it is exquisitely sensitive to changes in nucleotide levels and this allows AMPK to respond rapidly to changes in cellular energy status. Site 3 is likely to be responsible for protection of a conserved threonine in the activation loop of the alpha catalytic subunit through conformational changes induced by binding of AMP or ADP.PTM Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK.POLYMORPHISM Genetic variation in PRKAG3 defines the skeletal muscle glycogen content and metabolism quantitative trait locus (SMGMQTL) [MIM:619030]. Muscle fibers from carriers of variant Trp-225 have approximately 90% more muscle glycogen content than controls and decreased levels of intramuscular triglyceride.SIMILARITY Belongs to the 5'-AMP-activated protein kinase gamma subunit family. UniProt Q9UGI9 1 EQUAL 489 EQUAL Reactome Database ID Release 83 381839 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381839 Reactome R-HSA-381839 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381839.1 Reactome Database ID Release 83 381851 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381851 Reactome R-HSA-381851 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381851.1 1 AMP adenosine 5'-monophosphate adenosine 5'-monophosphate(2-) Adenylic acid Adenylate 5'-AMP 5'-Adenylic acid 5'-Adenosine monophosphate Reactome DB_ID: 76577 adenosine 5'-monophosphate(2-) [ChEBI:456215] adenosine 5'-monophosphate(2-) AMP Adenosine-5-monophosphate(2-) AMP dianion 5'-O-phosphonatoadenosine Adenosine-5-monophosphate dianion AMP(2-) ChEBI CHEBI:456215 Reactome Database ID Release 83 76577 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76577 Reactome R-ALL-76577 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-76577.5 COMPOUND C00020 1 Reactome Database ID Release 83 2316451 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316451 Reactome R-HSA-2316451 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316451.1 1 p-T172-PRKAA2 p-T172-AMPK alpha2 Reactome DB_ID: 200417 UniProt:P54646 PRKAA2 PRKAA2 AMPK AMPK2 FUNCTION Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism (PubMed:17307971, PubMed:17712357). In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation (PubMed:17307971, PubMed:17712357). AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators (PubMed:17307971, PubMed:17712357). Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively (PubMed:7959015). Promotes lipolysis of lipid droplets by mediating phosphorylation of isoform 1 of CHKA (CHKalpha2) (PubMed:34077757). Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3 (By similarity). Involved in insulin receptor/INSR internalization (PubMed:25687571). AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160 (By similarity). Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A (PubMed:11554766, PubMed:11518699, PubMed:15866171, PubMed:17711846, PubMed:18184930). Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm (By similarity). In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription (By similarity). Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2 (PubMed:14651849, PubMed:20160076, PubMed:21205641). In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1 (PubMed:21205641). In that process also activates WDR45/WIPI4 (PubMed:28561066). Phosphorylates CASP6, thereby preventing its autoprocessing and subsequent activation (PubMed:32029622). AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it (By similarity). May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it (By similarity). Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin (PubMed:17486097). Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1 (PubMed:12519745, PubMed:20074060). Plays an important role in the differential regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and PIK3R4) complexes, in response to glucose starvation (By similarity). Can inhibit the non-autophagy complex by phosphorylating PIK3C3 and can activate the pro-autophagy complex by phosphorylating BECN1 (By similarity).ACTIVITY REGULATION Activated by phosphorylation on Thr-172 (PubMed:15980064). Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-172 (PubMed:15980064). AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-172 (PubMed:15980064). ADP also stimulates Thr-172 phosphorylation, without stimulating already phosphorylated AMPK (PubMed:15980064). ATP promotes dephosphorylation of Thr-172, rendering the enzyme inactive (PubMed:15980064). Under physiological conditions AMPK mainly exists in its inactive form in complex with ATP, which is much more abundant than AMP. AMPK is activated by antihyperglycemic drug metformin, a drug prescribed to patients with type 2 diabetes: in vivo, metformin seems to mainly inhibit liver gluconeogenesis. However, metformin can be used to activate AMPK in muscle and other cells in culture or ex vivo (PubMed:11602624). Selectively inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine. Activated by resveratrol, a natural polyphenol present in red wine, and S17834, a synthetic polyphenol. Salicylate/aspirin directly activates kinase activity, primarily by inhibiting Thr-172 dephosphorylation.SUBUNIT AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3) (PubMed:21543851). Interacts with FNIP1 and FNIP2. Associates with internalized insulin receptor/INSR complexes on Golgi/endosomal membranes; PRKAA2/AMPK2 together with ATIC and HACD3/PTPLAD1 is proposed to be part of a signaling network regulating INSR autophosphorylation and endocytosis (PubMed:25687571).DOMAIN The AIS (autoinhibitory sequence) region shows some sequence similarity with the ubiquitin-associated domains and represses kinase activity.PTM Ubiquitinated.PTM Phosphorylated at Thr-172 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Also phosphorylated at Thr-172 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio. CAMKK1 can also phosphorylate Thr-172, but at much lower level. Dephosphorylated by protein phosphatase 2A and 2C (PP2A and PP2C). Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK. Dephosphorylated by PPM1A and PPM1B at Thr-172 (mediated by STK11/LKB1).SIMILARITY Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily. UniProt P54646 172 EQUAL 1 EQUAL 552 EQUAL Reactome Database ID Release 83 200417 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200417 Reactome R-HSA-200417 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-200417.1 1 Converted from EntitySet in Reactome AMPK beta Reactome DB_ID: 381854 PRKAB1 AMPK beta1 5'-AMP-activated protein kinase subunit beta-1 AAKB1_HUMAN Reactome DB_ID: 380968 UniProt:Q9Y478 PRKAB1 PRKAB1 AMPK FUNCTION Non-catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Beta non-catalytic subunit acts as a scaffold on which the AMPK complex assembles, via its C-terminus that bridges alpha (PRKAA1 or PRKAA2) and gamma subunits (PRKAG1, PRKAG2 or PRKAG3).SUBUNIT AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2.DOMAIN The glycogen-binding domain may target AMPK to glycogen so that other factors like glycogen-bound debranching enzyme or protein phosphatases can directly affect AMPK activity.PTM Phosphorylated when associated with the catalytic subunit (PRKAA1 or PRKAA2). Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK.SIMILARITY Belongs to the 5'-AMP-activated protein kinase beta subunit family. UniProt Q9Y478 2 EQUAL 270 EQUAL Reactome Database ID Release 83 380968 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380968 Reactome R-HSA-380968 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380968.1 PRKAB2 AMPK beta 2 Reactome DB_ID: 200413 UniProt:O43741 PRKAB2 PRKAB2 FUNCTION Non-catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Beta non-catalytic subunit acts as a scaffold on which the AMPK complex assembles, via its C-terminus that bridges alpha (PRKAA1 or PRKAA2) and gamma subunits (PRKAG1, PRKAG2 or PRKAG3).SUBUNIT AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3).PTM Phosphorylated when associated with the catalytic subunit (PRKAA1 or PRKAA2). Phosphorylated by ULK1 and ULK2; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1, ULK2 and AMPK.SIMILARITY Belongs to the 5'-AMP-activated protein kinase beta subunit family. UniProt O43741 1 EQUAL 272 EQUAL Reactome Database ID Release 83 200413 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200413 Reactome R-HSA-200413 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-200413.2 Reactome Database ID Release 83 381854 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381854 Reactome R-HSA-381854 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381854.1 1 Reactome Database ID Release 83 1454683 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454683 Reactome R-HSA-1454683 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1454683.1 Reactome Database ID Release 83 1454665 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454665 Reactome Database ID Release 83 1454699 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454699 Reactome R-HSA-1454699 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1454699.1 20837646 Pubmed 2010 Exercise-induced TBC1D1 Ser237 phosphorylation and 14-3-3 protein binding capacity in human skeletal muscle Frøsig, C Pehmøller, C Birk, JB Richter, EA Wojtaszewski, JF J Physiol 588:4539-48 21454505 Pubmed 2011 Crystal structures of human TBC1D1 and TBC1D4 (AS160) RabGTPase-activating protein (RabGAP) domains reveal critical elements for GLUT4 translocation Park, Sang-Youn Jin, Wanzhu Woo, Ju Rang Shoelson, SE J. Biol. Chem. 286:18130-8 20701589 Pubmed 2010 Contraction regulates site-specific phosphorylation of TBC1D1 in skeletal muscle Vichaiwong, K Purohit, S An, D Toyoda, T Jessen, N Hirshman, MF Goodyear, LJ Biochem J 431:311-20 17995453 Pubmed 2008 Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators Chen, S Murphy, J Toth, R Campbell, DG Morrice, NA Mackintosh, C Biochem J 409:449-59 LEFT-TO-RIGHT 14-3-3 Binds p-S237-TBC1D1 TBC1D1 phosphorylated on serine-237 binds 14-3-3 proteins in assays with yeast 14-3-3 proteins BMH1 and BMH2 (Chen et al. 2008, Frosig et al. 2010). Binding with human 14-3-3 proteins is inferred. Authored: May, B, 2011-07-15 Reviewed: Klip, Amira, 2012-08-21 Edited: May, B, 2011-07-15 p-S237-TBC1D1:14-3-3 TBC1D1 (pSer237):14-3-3 Reactome DB_ID: 1454696 1 1 Reactome Database ID Release 83 1454696 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454696 Reactome R-HSA-1454696 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1454696.1 Reactome Database ID Release 83 1454689 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454689 Reactome R-HSA-1454689 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-1454689.2 LEFT-TO-RIGHT RAB8A,10,13,14 exchange GDP for GTP RAB8A/10/13/14 release GDP and bind GTP to yield the active complex. Guanine nucleotide exchange factors (GEFs) stimulate the reaction. GTPase-activating proteins (GAPs) oppose the reaction by stimulating the intrinsic GTPase activity of the RAB proteins. Authored: May, B, 2012-05-16 Reviewed: Klip, Amira, 2012-08-21 Edited: May, B, 2012-05-16 Converted from EntitySet in Reactome GGC-RAB8A,10,13,14:GDP Reactome DB_ID: 1445130 GGC-RAB10:GDP Reactome DB_ID: 9605173 GGC-RAB10 Ras-related protein Rab-10 RAB10_HUMAN Reactome DB_ID: 8876076 UniProt:P61026 RAB10 RAB10 FUNCTION The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes (PubMed:21248164). Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion (PubMed:21248164). That Rab is mainly involved in the biosynthetic transport of proteins from the Golgi to the plasma membrane (PubMed:21248164). Regulates, for instance, SLC2A4/GLUT4 glucose transporter-enriched vesicles delivery to the plasma membrane (By similarity). In parallel, it regulates the transport of TLR4, a toll-like receptor to the plasma membrane and therefore may be important for innate immune response (By similarity). Also plays a specific role in asymmetric protein transport to the plasma membrane (PubMed:16641372). In neurons, it is involved in axonogenesis through regulation of vesicular membrane trafficking toward the axonal plasma membrane (By similarity). In epithelial cells, it regulates transport from the Golgi to the basolateral membrane (PubMed:16641372). May play a role in the basolateral recycling pathway and in phagosome maturation (By similarity). May play a role in endoplasmic reticulum dynamics and morphology controlling tubulation along microtubules and tubules fusion (PubMed:23263280). Together with LRRK2, RAB8A, and RILPL1, it regulates ciliogenesis (PubMed:30398148). When phosphorylated by LRRK2 on Thr-73, binds RILPL1 and inhibits ciliogenesis (PubMed:30398148).FUNCTION (Microbial infection) Upon Legionella pneumophila infection promotes endoplasmic reticulum recruitment and bacterial replication. Plays a role in remodeling the Legionella-containing vacuole (LCV) into an endoplasmic reticulum-like vacuole.ACTIVITY REGULATION Rab activation is generally mediated by a guanine exchange factor (GEF), while inactivation through hydrolysis of bound GTP is catalyzed by a GTPase activating protein (GAP) (Probable). That Rab is activated by the DENND4C and RABIF guanine exchange factors (GEF) (PubMed:20937701, PubMed:31540829).SUBUNIT Interacts with MYO5A; mediates the transport to the plasma membrane of SLC2A4/GLUT4 storage vesicles (PubMed:22908308). Interacts with GDI1 and with GDI2; negatively regulates RAB10 association with membranes and activation (PubMed:19570034, PubMed:26824392, PubMed:29125462). Interacts (GDP-bound form) with LLGL1; the interaction is direct and promotes RAB10 association with membranes and activation through competition with the Rab inhibitor GDI1 (By similarity). Interacts with EXOC4; probably associates with the exocyst (By similarity). Interacts (GTP-bound form) with MICALCL, MICAL1, MICAL3, EHBP1 and EHBP1L1; at least in case of MICAL1 two molecules of RAB10 can bind to one molecule of MICAL1 (PubMed:27552051). Interacts with TBC1D13 (By similarity). Interacts with SEC16A (By similarity). Interacts with CHM and CHML (PubMed:29125462). Interacts with LRRK2; interaction facilitates phosphorylation of Thr-73 (PubMed:26824392). Interacts (when phosphorylated on Thr-73) with RILPL1 and RILPL2 (PubMed:30398148, PubMed:29125462). Interacts with TBC1D21 (PubMed:28067790).TISSUE SPECIFICITY Expressed in the hippocampus (PubMed:29562525). Expressed in neutrophils (at protein level) (PubMed:29127255). Expressed in the testis (at protein level) (PubMed:28067790).PTM Ubiquitinated upon Legionella pneumophila infection. Ubiquitination does not lead to proteasomal degradation.PTM Phosphorylation of Thr-73 in the switch II region by LRRK2 prevents the association of RAB regulatory proteins, including CHM, CHML and RAB GDP dissociation inhibitors GDI1 and GDI2.SIMILARITY Belongs to the small GTPase superfamily. Rab family. UniProt P61026 199 EQUAL 200 EQUAL 1 EQUAL 200 EQUAL Reactome Database ID Release 83 8876076 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8876076 Reactome R-HSA-8876076 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8876076.1 1 GDP Guanosine 5'-diphosphate Guanosine diphosphate GDP(3-) Reactome DB_ID: 29420 GDP(3-) [ChEBI:58189] GDP(3-) 5'-O-[(phosphonatooxy)phosphinato]guanosine guanosine 5'-diphosphate(3-) GDP guanosine 5'-diphosphate trianion guanosine 5'-diphosphate GDP trianion ChEBI CHEBI:58189 Reactome Database ID Release 83 29420 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29420 Reactome R-ALL-29420 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29420.3 COMPOUND C00035 1 Reactome Database ID Release 83 9605173 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605173 Reactome R-HSA-9605173 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605173.1 GGC-RAB13:GDP Reactome DB_ID: 9605170 GGC-RAB13 Ras-related protein Rab-13 RAB13_HUMAN Reactome DB_ID: 1445110 UniProt:P51153 RAB13 RAB13 GIG4 FUNCTION The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. That Rab is involved in endocytic recycling and regulates the transport to the plasma membrane of transmembrane proteins like the tight junction protein OCLN/occludin. Thereby, it regulates the assembly and the activity of tight junctions. Moreover, it may also regulate tight junction assembly by activating the PKA signaling pathway and by reorganizing the actin cytoskeleton through the activation of the downstream effectors PRKACA and MICALL2 respectively. Through its role in tight junction assembly, may play a role in the establishment of Sertoli cell barrier. Plays also a role in angiogenesis through regulation of endothelial cells chemotaxis. Also involved in neurite outgrowth. Has also been proposed to play a role in post-Golgi membrane trafficking from the TGN to the recycling endosome. Finally, it has been involved in insulin-induced transport to the plasma membrane of the glucose transporter GLUT4 and therefore may play a role in glucose homeostasis.ACTIVITY REGULATION Rab activation is generally mediated by a guanine exchange factor (GEF), while inactivation through hydrolysis of bound GTP is catalyzed by a GTPase activating protein (GAP). That Rab may be activated by DENND1C, a guanine exchange factor. Activated in response to insulin.SUBUNIT Interacts (GTP-bound form) with MICALL2; competes with RAB8A and is involved in tight junctions assembly. Interacts (GTP-bound form) with MICALL1. Interacts (GTP-bound form) with MICAL1, MICAL3, MICALCL, EHBP1 and EHBP1L1; ternary complexes of RAB8A, RAB13 and either MICAL1 or EHBP1L1 are possible. Interacts with PRKACA; downstream effector of RAB13 involved in tight junction assembly. Interacts with GRB2; may recruit RAB13 to the leading edge of migrating endothelial cells where it can activate RHOA. Interacts (isoprenylated form) with PDE6D; dissociates RAB13 from membranes. Interacts with BICDL2/BICDR2. Interacts with LEPROT and LEPROTL1.TISSUE SPECIFICITY Detected in several types of epithelia, including intestine, kidney, liver and in endothelial cells.INDUCTION Up-regulated during osteoclast differentiation.PTM (Microbial infection) Stearoylated By S.flexneri N-epsilon-fatty acyltransferase IcsB, thereby disrupting the host actin cytoskeleton.SIMILARITY Belongs to the small GTPase superfamily. Rab family. UniProt P51153 200 EQUAL 1 EQUAL 200 EQUAL Reactome Database ID Release 83 1445110 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445110 Reactome R-HSA-1445110 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-1445110.2 1 1 Reactome Database ID Release 83 9605170 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605170 Reactome R-HSA-9605170 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605170.1 GGC-RAB14:GDP Reactome DB_ID: 9605171 GGC-RAB14 Ras-related protein Rab-14 RAB14_HUMAN Reactome DB_ID: 1445086 UniProt:P61106 RAB14 RAB14 FUNCTION Involved in membrane trafficking between the Golgi complex and endosomes during early embryonic development. Regulates the Golgi to endosome transport of FGFR-containing vesicles during early development, a key process for developing basement membrane and epiblast and primitive endoderm lineages during early postimplantation development. May act by modulating the kinesin KIF16B-cargo association to endosomes (By similarity). Regulates, together with its guanine nucleotide exchange factor DENND6A, the specific endocytic transport of ADAM10, N-cadherin/CDH2 shedding and cell-cell adhesion.SUBUNIT Interacts with KIF16B (By similarity). Interacts with ZFYVE20.SIMILARITY Belongs to the small GTPase superfamily. Rab family. UniProt P61106 213 EQUAL 215 EQUAL 2 EQUAL 215 EQUAL Reactome Database ID Release 83 1445086 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445086 Reactome R-HSA-1445086 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-1445086.2 1 1 Reactome Database ID Release 83 9605171 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605171 Reactome R-HSA-9605171 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605171.1 GGC-RAB8A:GDP Reactome DB_ID: 9605160 1 GGC-RAB8A Ras-related protein Rab-8A RAB8A_HUMAN Reactome DB_ID: 1445093 UniProt:P61006 RAB8A RAB8A MEL RAB8 FUNCTION The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. That Rab is involved in polarized vesicular trafficking and neurotransmitter release. Together with RAB11A, RAB3IP, the exocyst complex, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis (PubMed:20890297). Regulates the compacted morphology of the Golgi (PubMed:26209634). Together with MYO5B and RAB11A participates in epithelial cell polarization (PubMed:21282656). Also involved in membrane trafficking to the cilium and ciliogenesis (PubMed:21844891, PubMed:30398148). Together with MICALL2, may also regulate adherens junction assembly (By similarity). May play a role in insulin-induced transport to the plasma membrane of the glucose transporter GLUT4 and therefore play a role in glucose homeostasis (By similarity). Involved in autophagy (PubMed:27103069).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 (Probable). Activated in response to insulin (By similarity).SUBUNIT Interacts (GTP-bound form) with MICALL1; regulates RAB8A association with recycling endosomes (By similarity). Interacts with MICALL2; competes with RAB13 and is involved in E-cadherin endocytic recycling (By similarity). Interacts (GTP-bound form) with MICAL1, MICALCL, MICAL3, EHBP1 and EHBP1L1; at least in case of MICAL1, MICALCL, MICAL3 and EHBP1L1 two molecules of RAB8A can bind to one molecule of the effector protein; ternary complexes of RAB8A, RAB13 and either MICAL1 or EHBP1L1 are possible (PubMed:27552051). Interacts with EHD1 (PubMed:19864458). Interacts with MAP4K2 and SYTL4 (By similarity). Interacts with SGSM1 and SGSM3 (By similarity). Interacts with RABIF, RIMS2, RPH3A and RPH3A (By similarity). Interacts with OPTN (PubMed:15837803). Interacts with RAB3IP (PubMed:12221131). Interacts with MYO5B (PubMed:21282656). Interacts with PIFO (PubMed:20643351). Interacts with BIRC6/bruce (PubMed:18329369). Interacts with OCRL (PubMed:22543976, PubMed:21378754). Interacts with AHI1 (By similarity). Interacts with DCDC1 (PubMed:22159412). Interacts with LRRK2; interaction facilitates phosphorylation of Thr-72 (PubMed:26824392). Interacts with RAB31P, GDI1, GDI2, CHM, CHML, RABGGTA, RABGGTB, TBC1D15 and INPP5B; these interactions are dependent on Thr-72 not being phosphorylated (PubMed:26824392, PubMed:29125462). Interacts with RILPL1 and RILPL2; these interactions are dependent on the phosphorylation of Thr-72 by LRRK2 (PubMed:29125462, PubMed:30398148). Interacts with DZIP1; prevents inhibition by the GDP-dissociation inhibitor GDI2 (PubMed:25860027).PTM Phosphorylation of Thr-72 in the switch II region by LRRK2 prevents the association of RAB regulatory proteins, including CHM, CHML and RAB GDP dissociation inhibitors GDI1 and GDI2.SIMILARITY Belongs to the small GTPase superfamily. Rab family. UniProt P61006 204 EQUAL 1 EQUAL 204 EQUAL Reactome Database ID Release 83 1445093 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445093 Reactome R-HSA-1445093 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-1445093.2 1 Reactome Database ID Release 83 9605160 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605160 Reactome R-HSA-9605160 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605160.1 Reactome Database ID Release 83 1445130 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445130 Reactome R-HSA-1445130 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-1445130.2 Converted from EntitySet in Reactome GGC-RAB8A,10,13,14:GTP Reactome DB_ID: 1445137 GGC-RAB10:GTP Reactome DB_ID: 8876128 1 GTP Guanosine 5'-triphosphate GTP)(4-) Reactome DB_ID: 29438 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI CHEBI:37565 Reactome Database ID Release 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 COMPOUND C00044 1 Reactome Database ID Release 83 8876128 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8876128 Reactome R-HSA-8876128 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8876128.1 GGC-RAB13:GTP Reactome DB_ID: 9604176 1 1 Reactome Database ID Release 83 9604176 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9604176 Reactome R-HSA-9604176 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9604176.1 GGC-RAB14:GTP Reactome DB_ID: 9605169 1 1 Reactome Database ID Release 83 9605169 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605169 Reactome R-HSA-9605169 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605169.1 GGC-RAB8A:GTP Reactome DB_ID: 9605155 1 1 Reactome Database ID Release 83 9605155 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605155 Reactome R-HSA-9605155 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605155.1 Reactome Database ID Release 83 1445137 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445137 Reactome R-HSA-1445137 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-1445137.2 GDP Guanosine 5'-diphosphate Guanosine diphosphate Reactome DB_ID: 1996292 GDP [ChEBI:17552] GDP Guanosine 5'-diphosphate Guanosine diphosphate ChEBI CHEBI:17552 Reactome Database ID Release 83 1996292 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1996292 Reactome R-ALL-1996292 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-1996292.2 COMPOUND C00035 Reactome Database ID Release 83 2255343 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2255343 Reactome R-HSA-2255343 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-2255343.2 20937701 Pubmed 2010 Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors Yoshimura, Shin-ichiro Gerondopoulos, Andreas Linford, Andrea Rigden, Daniel J Barr, Francis A J. Cell Biol. 191:367-81 20631154 Pubmed 2010 Interaction of retinitis pigmentosa GTPase regulator (RPGR) with RAB8A GTPase: implications for cilia dysfunction and photoreceptor degeneration Murga-Zamalloa, Carlos A Atkins, Stephen J Peranen, Johan Swaroop, Anand Khanna, Hemant Hum. Mol. Genet. 19:3591-8 LEFT-TO-RIGHT 3.6.5.4 3.6.5.3 3.6.5.2 3.6.5.1 RAB8A,10,13,14 hydrolyze GTP RAB proteins have intrinsic weak GTPase activity that is enhanced by RAB-GTPase activating proteins (RAB-GAPs, Sano et al. 2007). The GTPase activity of RAB13 is inferred from other RAB proteins. AS160 (TBC1D4) and TBC1D1 are GAPs that activate the GTPase activity of RAB8A/10/13. Insulin signaling activates AKT, which phosphorylates and inactivates AS160 and TBC1D1, allowing GTP-bound (active) RABs to accumulate. As inferred from mouse, TBC1D1 activates GTPase activity of RAB2A, 8A, 8B, 10, and 14 (Roach et al. 2007). The GAP domain of TBC1D4 (AS160) activates the GTPase activity of RAB proteins (Sano et al. 2007). The effect of TBC1D4 on RAB13 is inferred from rat muscle cells (Sun et al. 2010). Authored: May, B, 2011-07-07 Reviewed: Klip, Amira, 2012-08-21 Edited: May, B, 2011-07-07 ACTIVATION activeUnit: #Protein32 GENE ONTOLOGY GO:0003924 Reactome Database ID Release 83 1458467 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458467 Converted from EntitySet in Reactome GGC-RAB8A,10,13,14 Reactome DB_ID: 1445136 Reactome Database ID Release 83 1445136 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445136 Reactome R-HSA-1445136 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-1445136.2 Reactome Database ID Release 83 1445143 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445143 Reactome R-HSA-1445143 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-HSA-1445143.5 15971998 Pubmed 2005 AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain Mîinea, CP Sano, H Kane, S Sano, E Fukuda, M Peränen, J Lane, WS Lienhard, GE Biochem J 391:87-93 ACTIVATION Reactome Database ID Release 83 1454728 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454728 Reactome R-HSA-1454728 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1454728.1 ACTIVATION Reactome Database ID Release 83 1449643 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449643 Reactome R-HSA-1449643 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449643.1 LEFT-TO-RIGHT 2.7.11.1 p-AKT2 phosphorylates Myosin 5A As inferred from mouse, AKT2 phosphorylates Myosin 5A on serine-1652. The phosphorylation promotes association of Myosin 5A with actin and ATPase activity of Myosin 5A. Authored: May, B, 2011-07-12 Reviewed: Klip, Amira, 2012-08-21 Edited: May, B, 2011-07-12 MYO5A dimer Reactome DB_ID: 9605111 MYO5A Myosin-Va MYO5A_HUMAN Reactome DB_ID: 1428499 UniProt:Q9Y4I1 MYO5A MYO5A MYH12 FUNCTION Processive actin-based motor that can move in large steps approximating the 36-nm pseudo-repeat of the actin filament. Involved in melanosome transport. Also mediates the transport of vesicles to the plasma membrane. May also be required for some polarization process involved in dendrite formation.SUBUNIT May be a homodimer, which associates with multiple calmodulin or myosin light chains (By similarity). Interacts with RIPL2, the interaction is required for its role in dendrite formation (By similarity). Interacts with MLPH (PubMed:12062444). Interacts with SYTL4 (By similarity). Interacts with MYRIP (By similarity). Interacts with RAB10; mediates the transport to the plasma membrane of SLC2A4/GLUT4 storage vesicles (PubMed:22908308). Interacts with FMR1; this interaction occurs in association with polyribosome (By similarity).TISSUE SPECIFICITY Detected in melanocytes.SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Myosin family. UniProt Q9Y4I1 1 EQUAL 1855 EQUAL Reactome Database ID Release 83 1428499 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1428499 Reactome R-HSA-1428499 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1428499.1 2 Reactome Database ID Release 83 9605111 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605111 Reactome R-HSA-9605111 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605111.1 2 2 p-S1652-MYO5A dimer Reactome DB_ID: 9605106 MYO5A_HUMAN p-S1652-MYO5A MYO5A (pSer1652) Myosin-Va (pSer1652) Reactome DB_ID: 1449606 1652 EQUAL 1 EQUAL 1855 EQUAL Reactome Database ID Release 83 1449606 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449606 Reactome R-HSA-1449606 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449606.1 2 Reactome Database ID Release 83 9605106 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605106 Reactome R-HSA-9605106 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605106.1 ACTIVATION Reactome Database ID Release 83 1445142 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445142 Reactome Database ID Release 83 1449597 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449597 Reactome R-HSA-1449597 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449597.3 LEFT-TO-RIGHT 2.7.11.1 p-AKT2 phosphorylates RGC2 As inferred from mouse, AKT2 (PKB-beta) phosphorylates RBC2 (RALGAPA2) on serine-486, serine-696, and threonine-715 in response to insulin. The phosphorylation prevents RBC1:RBC2 from activating RALA GTPase and allows RALA:GTP to accumulate. Authored: May, B, 2011-07-17 Reviewed: Klip, Amira, 2012-08-21 Edited: May, B, 2011-07-17 RGC1:RGC2 RALGAPB:RALGAPA2 Reactome DB_ID: 1458509 RGC2 RALGAPA2 Ral GTPase-activating protein subunit alpha-2 RGPA2_HUMAN Reactome DB_ID: 1458508 UniProt:Q2PPJ7 RALGAPA2 RALGAPA2 C20orf74 KIAA1272 FUNCTION Catalytic subunit of the heterodimeric RalGAP2 complex which acts as a GTPase activator for the Ras-like small GTPases RALA and RALB.SUBUNIT Component of the heterodimeric RalGAP2 complex with RALGAPB. Heterodimerization is required for activity (By similarity). UniProt Q2PPJ7 1 EQUAL 1873 EQUAL Reactome Database ID Release 83 1458508 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458508 Reactome R-HSA-1458508 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458508.1 1 RGC1 RALGAPB Ral GTPase-activating protein subunit beta RLGPB_HUMAN Reactome DB_ID: 1458461 UniProt:Q86X10 RALGAPB RALGAPB KIAA1219 FUNCTION Non-catalytic subunit of the heterodimeric RalGAP1 and RalGAP2 complexes which act as GTPase activators for the Ras-like small GTPases RALA and RALB.SUBUNIT Component of the heterodimeric RalGAP1 complex with RALGAPA1 and of the heterodimeric RalGAP2 complex with RALGAPA2. Heterodimerization is required for activity (By similarity).TISSUE SPECIFICITY Highly expressed in brain, mostly in amygdala. UniProt Q86X10 1 EQUAL 1494 EQUAL Reactome Database ID Release 83 1458461 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458461 Reactome R-HSA-1458461 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458461.1 1 Reactome Database ID Release 83 1458509 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458509 Reactome R-HSA-1458509 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458509.1 3 3 RGC1:phospho-RGC2 RGC1:p-486,696-T715-RGC2 RALGAPB:pSer486,696,pThr715-RALGAPA2 Reactome DB_ID: 1458472 1 RGPA2_HUMAN p-S486,S696,T715-RALGAPA2 p-S486,696-T715-RALGAPA2 p-S486,696-T715-RGC2 pSer486,696,pThr715-RALGAPA2 Ral GTPase-activating protein subunit alpha-2 Reactome DB_ID: 1458477 486 EQUAL 696 EQUAL 715 EQUAL 1 EQUAL 1873 EQUAL Reactome Database ID Release 83 1458477 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458477 Reactome R-HSA-1458477 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458477.1 1 Reactome Database ID Release 83 1458472 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458472 Reactome R-HSA-1458472 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458472.1 ACTIVATION Reactome Database ID Release 83 1458463 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458463 Reactome R-HSA-1458463 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-1458463.2 LEFT-TO-RIGHT Activation of RALA RALA exchanges GDP for GTP RALA releases GDP and binds GTP, producing the active form of RALA. The reaction is accelerated by guanine nucleotide exchange factors (GEFs) and opposed by GTPase-activating proteins (GAPs) which enhance the conversion of RALA:GTP back to RALA:GDP by activating the GTPase activity of RALA. Authored: May, B, 2012-05-16 Reviewed: Klip, Amira, 2012-08-21 Edited: May, B, 2012-05-16 GGC-RALA:GDP Reactome DB_ID: 1458466 GGC-RALA Ras-related protein Ral-A RALA_HUMAN Reactome DB_ID: 1458479 UniProt:P11233 RALA RALA RAL FUNCTION Multifunctional GTPase involved in a variety of cellular processes including gene expression, cell migration, cell proliferation, oncogenic transformation and membrane trafficking. Accomplishes its multiple functions by interacting with distinct downstream effectors (PubMed:18756269, PubMed:19306925, PubMed:20005108, PubMed:21822277, PubMed:30500825). Acts as a GTP sensor for GTP-dependent exocytosis of dense core vesicles. The RALA-exocyst complex regulates integrin-dependent membrane raft exocytosis and growth signaling (PubMed:20005108). Key regulator of LPAR1 signaling and competes with GRK2 for binding to LPAR1 thus affecting the signaling properties of the receptor. Required for anchorage-independent proliferation of transformed cells (PubMed:19306925). During mitosis, supports the stabilization and elongation of the intracellular bridge between dividing cells. Cooperates with EXOC2 to recruit other components of the exocyst to the early midbody (PubMed:18756269). During mitosis, also controls mitochondrial fission by recruiting to the mitochondrion RALBP1, which mediates the phosphorylation and activation of DNM1L by the mitotic kinase cyclin B-CDK1 (PubMed:21822277).ACTIVITY REGULATION Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP).SUBUNIT Interacts (via effector domain) with RALBP1; during mitosis, recruits RALBP1 to the mitochondrion where it promotes DNM1L phosphorylation and mitochondrial fission (PubMed:7673236, PubMed:21822277). Interacts with EXOC2/Sec5 and EXOC8/Exo84; binding to EXOC2 and EXOC8 is mutually exclusive (PubMed:14525976, PubMed:18756269, PubMed:15920473). Interacts with Clostridium exoenzyme C3 (PubMed:16177825, PubMed:15809419). Interacts with RALGPS1 (PubMed:10747847). Interacts with LPAR1 and LPAR2. Interacts with GRK2 in response to LPAR1 activation. RALA and GRK2 binding to LPAR1 is mutually exclusive (PubMed:19306925). Interacts with CDC42 (By similarity).INDUCTION Activated in an LPA-dependent manner by LPAR1 and in an LPA-independent manner by LPAR2.PTM Phosphorylated. Phosphorylation at Ser-194 by AURKA/Aurora kinase A, during mitosis, induces RALA localization to the mitochondrion where it regulates mitochondrial fission.PTM Prenylation is essential for membrane localization. The geranylgeranylated form and the farnesylated mutant do not undergo alternative prenylation in response to geranylgeranyltransferase I inhibitors (GGTIs) and farnesyltransferase I inhibitors (FTIs).PTM (Microbial infection) Glucosylated at Thr-46 by P.sordellii toxin TcsL from strain 6018 (PubMed:8858106). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form (PubMed:8858106). Not glucosylated by TcsL from strain VPI 9048 (PubMed:8858106).SIMILARITY Belongs to the small GTPase superfamily. Ras family. UniProt P11233 203 EQUAL 1 EQUAL 203 EQUAL Reactome Database ID Release 83 1458479 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458479 Reactome R-HSA-1458479 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-1458479.2 1 1 Reactome Database ID Release 83 1458466 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458466 Reactome R-HSA-1458466 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-1458466.2 GGC-RALA:GTP Reactome DB_ID: 1458506 1 1 Reactome Database ID Release 83 1458506 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458506 Reactome R-HSA-1458506 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-1458506.2 Reactome Database ID Release 83 2255342 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2255342 Reactome R-HSA-2255342 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-2255342.2 8094051 Pubmed 1993 Characterization of a guanine nucleotide dissociation stimulator for a ras-related GTPase Albright, C F Giddings, B W Liu, J Vito, M Weinberg, R A EMBO J. 12:339-47 2550440 Pubmed 1989 Identification of the ral and rac1 gene products, low molecular mass GTP-binding proteins from human platelets Polakis, P G Weber, R F Nevins, B Didsbury, J R Evans, T Snyderman, R J. Biol. Chem. 264:16383-9 LEFT-TO-RIGHT RALA:GTP binds MYO1C:CALM1 and activates MYO1C As inferred from mouse, insulin causes phosphorylation and inactivation of the Ral GTPase activating complex RGC, causing RALA:GTP to accumulate and associate with the unconventional myosin MYO1C. MYO1C, with calmodulin as a light chain, motors across cortical actin and interacts with the exocyst complex to tether vesicles at the plasma membrane (Chen et al. 2007). Authored: May, B, 2012-05-27 Reviewed: Klip, Amira, 2012-08-21 Edited: May, B, 2012-05-27 f-actin (ADP) Reactome DB_ID: 202998 Reactome Database ID Release 83 202998 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202998 Reactome R-HSA-202998 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-202998.2 ChEBI 36080 MYO1C:CALM1 Reactome DB_ID: 2316345 CALM1 Calmodulin CALM_HUMAN Reactome DB_ID: 9016707 UniProt:P0DP23 CALM1 CALM1 CALM CAM CAM1 FUNCTION Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding (PubMed:16760425, PubMed:23893133, PubMed:26969752, PubMed:27165696, PubMed:28890335, PubMed:31454269, PubMed:35568036). Calcium-binding is required for the activation of calmodulin (PubMed:16760425, PubMed:23893133, PubMed:26969752, PubMed:27165696, PubMed:28890335, PubMed:31454269, PubMed:35568036). Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases, such as myosin light-chain kinases and calmodulin-dependent protein kinase type II (CaMK2), and phosphatases (PubMed:16760425, PubMed:23893133, PubMed:26969752, PubMed:27165696, PubMed:28890335, PubMed:31454269, PubMed:35568036). Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Is a regulator of voltage-dependent L-type calcium channels (PubMed:31454269). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696). Forms a potassium channel complex with KCNQ1 and regulates electrophysiological activity of the channel via calcium-binding (PubMed:25441029). Acts as a sensor to modulate the endoplasmic reticulum contacts with other organelles mediated by VMP1:ATP2A2 (PubMed:28890335).FUNCTION (Microbial infection) Required for Legionella pneumophila SidJ glutamylase activity.FUNCTION (Microbial infection) Required for C.violaceum CopC arginine ADP-riboxanase activity.ACTIVITY REGULATION (Microbial infection) Inactivated by S.flexneri OspC1 and OspC3 proteins, which specifically bind the apo-form of calmodulin, thereby preventing calcium-binding and activity.SUBUNIT Interacts with MYO1C, MYO5A and RRAD. Interacts with MYO10 (By similarity). Interacts with CEP97, CCP110, TTN/titin and SRY (PubMed:9804419, PubMed:12871148, PubMed:15746192, PubMed:16760425, PubMed:17719545). Interacts with USP6; the interaction is calcium dependent (PubMed:16127172). Interacts with CDK5RAP2 (PubMed:20466722). Interacts with SCN5A (PubMed:21167176). Interacts with RYR1 (PubMed:18650434). Interacts with FCHO1 (PubMed:22484487). Interacts with MIP in a 1:2 stoichiometry; the interaction with the cytoplasmic domains from two MIP subunits promotes MIP water channel closure (PubMed:23893133). Interacts with ORAI1; this may play a role in the regulation of ORAI1-mediated calcium transport (By similarity). Interacts with IQCF1 (By similarity). Interacts with SYT7 (By similarity). Interacts with CEACAM1 (via cytoplasmic domain); this interaction is in a calcium dependent manner and reduces homophilic cell adhesion through dissociation of dimer (By similarity). Interacts with RYR2; regulates RYR2 calcium-release channel activity (PubMed:27516456, PubMed:18650434, PubMed:26164367). Interacts with PCP4; regulates calmodulin calcium-binding (PubMed:27876793). Interacts with the heterotetrameric KCNQ2 and KCNQ3 channel; the interaction is calcium-independent, constitutive and participates in the proper assembly of a functional heterotetrameric M channel (PubMed:27564677). Interacts with alpha-synuclein/SNCA (PubMed:23607618). Interacts with SLC9A1 in a calcium-dependent manner (PubMed:30287853). In the absence of Ca(+2), interacts with GIMAP4 (via IQ domain) (By similarity). Interacts with SCN8A; the interaction modulates the inactivation rate of SCN8A (By similarity). Interaction with KIF1A; the interaction is increased in presence of calcium and increases neuronal dense core vesicles motility (PubMed:30021165). Interacts with KCNN3 (PubMed:31155282). Interacts with KCNQ1 (via C-terminus); forms a heterooctameric structure (with 4:4 KCNQ1:CALM stoichiometry) in a calcium-independent manner (PubMed:18165683,PubMed:25441029). Interacts with PIK3C3; the interaction modulates PIK3C3 kinase activity (PubMed:28890335). Interacts with HINT1; interaction increases in the presence of calcium ions (By similarity). Interacts with HINT3 (By similarity). Interacts with GARIN2; in mature sperm flagella (By similarity).SUBUNIT (Microbial infection) Interacts with Rubella virus protease/methyltransferase p150.SUBUNIT (Microbial infection) Interacts with Legionella pneumophila glutamylase SidJ.SUBUNIT (Microbial infection) Interacts with C.violaceum CopC (PubMed:35446120, PubMed:35338844). C.violaceum CopC interacts specifically with the apo form of calmodulin (PubMed:35446120).SUBUNIT (Microbial infection) Interacts with S.flexneri OspC1 and OspC3 (PubMed:35568036). S.flexneri OspC1 and OspC3 interact specifically with the apo form of calmodulin and prevents calcium-binding (PubMed:35568036).DOMAIN The N-terminal and C-terminal lobes of CALM bind to the C-terminus of KCNQ1 in a clamp-like conformation. Binding of CALM C-terminus to KCNQ1 is calcium-independent but is essential for assembly of the structure. Binding of CALM N-terminus to KCNQ1 is calcium-dependent and regulates electrophysiological activity of the channel.PTM Ubiquitination results in a strongly decreased activity.PTM Phosphorylation results in a decreased activity.MISCELLANEOUS This protein has four functional calcium-binding sites.SIMILARITY Belongs to the calmodulin family. UniProt P0DP23 2 EQUAL 149 EQUAL Reactome Database ID Release 83 9016707 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9016707 Reactome R-HSA-9016707 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9016707.1 1 MYO1C Myosin-Ic MYO1C_HUMAN Reactome DB_ID: 1449619 UniProt:O00159 MYO1C MYO1C FUNCTION Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. Their highly divergent tails are presumed to bind to membranous compartments, which would be moved relative to actin filaments. Involved in glucose transporter recycling in response to insulin by regulating movement of intracellular GLUT4-containing vesicles to the plasma membrane. Component of the hair cell's (the sensory cells of the inner ear) adaptation-motor complex. Acts as a mediator of adaptation of mechanoelectrical transduction in stereocilia of vestibular hair cells. Binds phosphoinositides and links the actin cytoskeleton to cellular membranes.SUBUNIT Interacts (via its IQ motifs) with CABP1 and CIB1; the interaction with CABP1 and CIB1 is calcium-dependent (By similarity). Interacts (via tail domain) with PLEKHB1 (via PH domain); the interaction is not affected by the presence or absence of calcium and CALM (By similarity). Interacts with POLR1A (By similarity). Interacts with POLR2A (By similarity). Component of the B-WICH complex, at least composed of SMARCA5/SNF2H, BAZ1B/WSTF, SF3B1, DEK, MYO1C, ERCC6, MYBBP1A and DDX21 (PubMed:16603771). Interacts (via its IQ motifs) with CALM; this precludes interaction with YWHAB (PubMed:24636949). Interacts with YWHAB; this precludes interaction with CALM (PubMed:24636949). Interacts with RPS6 (PubMed:16877530). Interacts with actin (PubMed:16877530). Interacts with LLPH (By similarity). Interacts with GLUT4 (By similarity). Interacts (via its IQ motifs) with SH3BGRL3; the interaction is dependent on calcium and takes place at membrane ruffles (PubMed:34380438).DOMAIN Binds directly to large unilamellar vesicles (LUVs) containing phosphatidylinositol 4,5-bisphosphate (PIP2) or inositol 1,4,5-trisphosphate (InsP3). The PIP2-binding site corresponds to the myosin tail domain (PH-like) present in its tail domain (By similarity).PTM Isoform 2 contains a N-acetylmethionine at position 1.SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Myosin family.CAUTION Represents an unconventional myosin. This protein should not be confused with the conventional myosin-1 (MYH1). UniProt O00159 1 EQUAL 1063 EQUAL Reactome Database ID Release 83 1449619 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449619 Reactome R-HSA-1449619 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449619.1 1 Reactome Database ID Release 83 2316345 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316345 Reactome R-HSA-2316345 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-2316345.2 GGC-RALA:GTP:MYO1C:Calmodulin:F-actin Reactome DB_ID: 2316344 1 1 1 Reactome Database ID Release 83 2316344 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316344 Reactome R-HSA-2316344 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316344.3 Reactome Database ID Release 83 2316349 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316349 Reactome R-HSA-2316349 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316349.1 LEFT-TO-RIGHT 3.6.5.4 3.6.5.3 3.6.5.2 3.6.5.1 RALA hydrolyzes GTP RALA is a guanine nucleotide binding protein that hydrolyzes bound GTP to yield GDP and phosphate. RGC1 and RGC2 are GAPs (GTPase-activating proteins) that activate the GTPase activity of RALA. Insulin activates AKT, which phosphorylates RGC2, inactivating the GAP activity of RGC1:RGC2 and allowing RALA:GTP to accumulate. As inferred from mouse, RGC1:RGC2 (RALGAPB:RALGAPA2) activate the GTPase activity of RALA (Chen et al. 2011). Authored: May, B, 2011-07-17 Reviewed: Klip, Amira, 2012-08-21 Edited: May, B, 2011-07-17 Pi Orthophosphate hydrogenphosphate Phosphate Inorganic Phosphate Reactome DB_ID: 2255331 hydrogenphosphate [ChEBI:43474] hydrogenphosphate hydrogen phosphate phosphate [PO3(OH)](2-) INORGANIC PHOSPHATE GROUP HYDROGENPHOSPHATE ION HPO4(2-) [P(OH)O3](2-) ChEBI CHEBI:43474 Reactome Database ID Release 83 2255331 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2255331 Reactome R-ALL-2255331 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-2255331.4 COMPOUND C00009 ACTIVATION activeUnit: #Protein38 Reactome Database ID Release 83 1458493 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458493 Reactome Database ID Release 83 1458485 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458485 Reactome R-HSA-1458485 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-HSA-1458485.4 8664345 Pubmed 1996 Characterization of human platelet GTPase activating protein for the Ral GTP-binding protein Bhullar, RP Seneviratne, HD Biochim Biophys Acta 1311:181-8 ACTIVATION Reactome Database ID Release 83 1458520 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458520 Reactome R-HSA-1458520 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458520.1 LEFT-TO-RIGHT 2.7.11.1 p-AKT2 phosphorylates C2CD5 The protein kinase B beta (AKT) pathway mediates insulin-stimulated glucose transport by increasing glucose transporter GLUT4 translocation from intracellular stores to the plasma membrane. C2 domain-containing protein 5 (C2CD5 aka C2 domain-containing phosphoprotein 138kDa) has been shown to be required for optimal insulin-stimulated GLUT4 translocation and fusion of GLUT4 vesicles with the plasma membrane in adipocytes. It is also able to bind Ca2+ and lipid membranes in its C2 domain. C2CD5 is a substrate for RAC-beta serine/threonine-protein kinase (AKT2), which phosphorylates C2CD5 at serine 197. Phosphorylated C2CD5 optimises GLUT4 translocation to the plasma membrane. The role of human C2CD5 is inferred from the role of the orthologous mouse protein (Xie et al. 2011). Authored: Jassal, Bijay, 2014-02-07 Reviewed: D'Eustachio, Peter, 2015-02-11 Edited: Jassal, Bijay, 2014-02-07 C2CD5:2xCa2+ Reactome DB_ID: 5260209 Ca2+ Calcium calcium(2+) Reactome DB_ID: 74016 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI CHEBI:29108 Reactome Database ID Release 83 74016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74016 Reactome R-ALL-74016 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-74016.3 COMPOUND C00076 2 C2CD5 C2 domain-containing protein 5 C2CD5_HUMAN Reactome DB_ID: 5216175 UniProt:Q86YS7 C2CD5 C2CD5 CDP138 KIAA0528 FUNCTION Required for insulin-stimulated glucose transport and glucose transporter SLC2A4/GLUT4 translocation from intracellular glucose storage vesicle (GSV) to the plasma membrane (PM) in adipocytes. Binds phospholipid membranes in a calcium-dependent manner and is necessary for the optimal membrane fusion between SLC2A4/GLUT4 GSV and the PM.DOMAIN The C2 domain binds to calcium and membrane lipids.PTM Phosphorylated on Ser-197 by active myristoylated kinase AKT2; insulin-stimulated phosphorylation by AKT2 regulates SLC2A4/GLUT4 translocation into the plasma membrane. UniProt Q86YS7 1 EQUAL 1000 EQUAL Reactome Database ID Release 83 5216175 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5216175 Reactome R-HSA-5216175 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5216175.1 1 Reactome Database ID Release 83 5260209 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5260209 Reactome R-HSA-5260209 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5260209.1 p-S197-C2CD5:2xCa2+ Reactome DB_ID: 5260210 2 C2CD5_HUMAN p-S197-C2CD5 C2 domain-containing protein 5 Reactome DB_ID: 5260194 197 EQUAL 1 EQUAL 1000 EQUAL Reactome Database ID Release 83 5260194 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5260194 Reactome R-HSA-5260194 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5260194.1 1 Reactome Database ID Release 83 5260210 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5260210 Reactome R-HSA-5260210 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5260210.1 ACTIVATION Reactome Database ID Release 83 5260201 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5260201 Reactome R-HSA-5260201 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5260201.1 21907143 Pubmed 2011 C2 domain-containing phosphoprotein CDP138 regulates GLUT4 insertion into the plasma membrane Xie, Xiangyang Gong, Zhenwei Mansuy-Aubert, Virginie Zhou, Qiong L Tatulian, Suren A Sehrt, Daniel Gnad, Florian Brill, Laurence M Motamedchaboki, Khatereh Chen, Yu Czech, Michael P Mann, Matthias Krüger, Marcus Jiang, Zhen Y Cell Metab. 14:378-89 LEFT-TO-RIGHT 5.6.1.8 SLC2A4 (GLUT4) vesicle translocates and docks at the plasma membrane As inferred from mouse, GLUT4 (SLC2A4) initially translocates from endosomes to insulin-responsive vesicles (IRVs, GSVs). RAB11 appears to play a role in this process. IRVs bearing GLUT4 are then translocated across the cortical actin network to the plasma membrane. Unconventional myosin 5A (MYO5A) interacts with RAB10 or RAB8A on the vesicle and participates in transport of the IRV. Myosin 1C appears to act close to the plasma membrane and may facilitate fusion of the vesicle with the plasma membrane. RAB:GTP complexes coupled to the vesicles may interact with myosins to regulate their activity. Non-muscle myosin IIA (MYH9) appears to interact with the SNAP23 complex to dock the IRV at the inner membrane face. As inferred from mouse (Sano et al. 2007) and rat (Ishikura et al. 2007, Ishikura and Klip 2008, Sun et al. 2010), RAB:GTP activates translocation of GLUT4 (SLC2A4) to the plasma membrane, possibly by interacting with myosins. RAB8A, RAB10, and RAB14 predominate in 3T3-L1 adipocytes; RAB13 predominates in L6 muscle cells. As inferred from mouse (Zeigerer et al. 2002) and rat (Uhlig et al. 2005), RAB11A enhances translocation of GLUT4 to the plasma membrane by mobilizing GLUT4 (SLC2A4) from endosomes to insulin responsive vesicles. As inferred from mouse (Ueda et al. 2008, Ueda et al. 2010) and rat (Chiu et al. 2010), RAC1:GTP enhances translocation of GLUT4 (SLC2A4) to the plasma membrane by causing actin remodeling that requires ARP2/3. The exact mechanism of RAC1 action is unknown. As inferred from mouse, TC10 participates in the translocation and docking of GLUT4 (SLC2A4) vesicles at the plasma membrane (Chang et al. 2007). Authored: May, B, 2012-05-27 Reviewed: Klip, Amira, 2012-08-21 Edited: May, B, 2012-05-27 Exocyst Complex Reactome DB_ID: 264974 EXOC7 Reactome DB_ID: 2872288 UniProt:Q9UPT5 EXOC7 EXOC7 EXO70 KIAA1067 FUNCTION Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane. In adipocytes, plays a crucial role in targeting SLC2A4 vesicle to the plasma membrane in response to insulin, perhaps directing the vesicle to the precise site of fusion (By similarity). It is required for neuron survival and plays an essential role in cortical development (By similarity).SUBUNIT The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8. Interacts with ARHQ in a GTP-dependent manner. Interacts with RAB11FIP3 (By similarity).TISSUE SPECIFICITY Abundant in the ventricular zone, the outer subventricular zone and the cortical plate of the fetal cortex.DOMAIN The N-terminus is involved in SEC8 and ARHQ binding.DOMAIN The C-terminus is required for translocation to the plasma membrane.SIMILARITY Belongs to the EXO70 family. UniProt Q9UPT5 1 EQUAL 735 EQUAL Reactome Database ID Release 83 2872288 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2872288 Reactome R-HSA-2872288 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2872288.1 1 EXOC6 Reactome DB_ID: 265041 UniProt:Q8TAG9 EXOC6 EXOC6 SEC15A SEC15L SEC15L1 FUNCTION Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane. Together with RAB11A, RAB3IP, RAB8A, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis (By similarity).SUBUNIT The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (By similarity). Interacts with CNTRL. Interacts with RAB11A in a GTP-dependent manner (By similarity).SIMILARITY Belongs to the SEC15 family. UniProt Q8TAG9 1 EQUAL 804 EQUAL Reactome Database ID Release 83 265041 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265041 Reactome R-HSA-265041 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-265041.1 1 EXOC2 Reactome DB_ID: 264887 UniProt:Q96KP1 EXOC2 EXOC2 SEC5 SEC5L1 FUNCTION Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.SUBUNIT The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (By similarity). Interacts with EXOC3L1 (By similarity). Interacts with GNEFR/DELGEF; this interaction occurs only in the presence of magnesium or manganese and is stimulated by dCTP or GTP (PubMed:12459492). Interacts with RALA and RALB (PubMed:18756269, PubMed:19166349, PubMed:12459492) (By similarity). Interacts with ARL13B; regulates ARL13B localization to the cilium membrane.TISSUE SPECIFICITY Widely expressed with highest levels in brain and placenta.DOMAIN Interacts with RALA through the TIG domain.SIMILARITY Belongs to the SEC5 family. UniProt Q96KP1 1 EQUAL 924 EQUAL Reactome Database ID Release 83 264887 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=264887 Reactome R-HSA-264887 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-264887.1 1 EXOC8 Reactome DB_ID: 264948 UniProt:Q8IYI6 EXOC8 EXOC8 FUNCTION Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.SUBUNIT The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (By similarity). Interacts (via PH domain) with GTP-bound RALA and RALB (PubMed:14525976, PubMed:18756269). Interacts with SH3BP1; required for the localization of both SH3BP1 and the exocyst to the leading edge of migrating cells (PubMed:21658605).SIMILARITY Belongs to the EXO84 family. UniProt Q8IYI6 1 EQUAL 725 EQUAL Reactome Database ID Release 83 264948 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=264948 Reactome R-HSA-264948 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-264948.1 1 EXOC5 Reactome DB_ID: 265045 UniProt:O00471 EXOC5 EXOC5 SEC10 SEC10L1 FUNCTION Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.SUBUNIT The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (By similarity). Interacts with EXOC3L1 (By similarity).TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the SEC10 family. UniProt O00471 1 EQUAL 708 EQUAL Reactome Database ID Release 83 265045 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265045 Reactome R-HSA-265045 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-265045.1 1 EXOC4 Reactome DB_ID: 264989 UniProt:Q96A65 EXOC4 EXOC4 KIAA1699 SEC8 SEC8L1 FUNCTION Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.SUBUNIT The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (By similarity). Interacts with BIRC6/bruce (PubMed:18329369). Interacts with MYRIP (By similarity). Interacts with SH3BP1; required for the localization of both SH3BP1 and the exocyst to the leading edge of migrating cells (PubMed:21658605). Interacts with SLC6A9 (By similarity).SIMILARITY Belongs to the SEC8 family. UniProt Q96A65 2 EQUAL 974 EQUAL Reactome Database ID Release 83 264989 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=264989 Reactome R-HSA-264989 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-264989.1 1 EXOC1 Reactome DB_ID: 2872284 UniProt:Q9NV70 EXOC1 EXOC1 SEC3 SEC3L1 BM-012 FUNCTION Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.FUNCTION (Microbial infection) Has an antiviral effect against flaviviruses by affecting viral RNA transcription and translation through the sequestration of elongation factor 1-alpha (EEF1A1). This results in decreased viral RNA synthesis and decreased viral protein translation.SUBUNIT The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8. Interacts with EEF1A1 (PubMed:19889084). Interacts with SLC6A9; interaction increases the transporter capacity of SLC6A9 probably by promoting its insertion into the cell membrane (PubMed:16181645).SUBUNIT (Microbial infection) Interacts with West Nile virus and Dengue virus capsid protein C; this interaction results in EXOC1 degradation through the proteasome degradation pathway.SIMILARITY Belongs to the SEC3 family. UniProt Q9NV70 2 EQUAL 894 EQUAL Reactome Database ID Release 83 2872284 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2872284 Reactome R-HSA-2872284 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2872284.1 1 EXOC3 Reactome DB_ID: 2872286 secretory granule membrane GENE ONTOLOGY GO:0030667 UniProt:O60645 EXOC3 EXOC3 SEC6 SEC6L1 FUNCTION Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.SUBUNIT The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (By similarity). Interacts with EXOC3L1 (By similarity). Interacts with BIRC6/bruce. Interacts with MYRIP (By similarity). Interacts with SLC6A9 (By similarity).TISSUE SPECIFICITY Expressed in epididymis (at protein level).SIMILARITY Belongs to the SEC6 family. UniProt O60645 1 EQUAL 756 EQUAL Reactome Database ID Release 83 2872286 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2872286 Reactome R-HSA-2872286 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2872286.1 1 Reactome Database ID Release 83 264974 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=264974 Reactome R-HSA-264974 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-264974.2 ComplexPortal CPX-4943 ComplexPortal CPX-4944 GGC-RALA:GTP:MYO1C:Exocyst Reactome DB_ID: 2316343 1 1 Reactome Database ID Release 83 2316343 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316343 Reactome R-HSA-2316343 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316343.3 ACTIVATION activeUnit: #Protein40 GENE ONTOLOGY GO:0000146 Reactome Database ID Release 83 1449634 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449634 Reactome Database ID Release 83 2316352 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316352 Reactome R-HSA-2316352 7 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316352.7 ACTIVATION Reactome Database ID Release 83 2316462 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316462 Reactome R-HSA-2316462 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-2316462.2 RHOQ:GTP TC10:GTP Reactome DB_ID: 2316453 RHOQ TC10 RhoQ Reactome DB_ID: 194879 UniProt:P17081 RHOQ RHOQ ARHQ RASL7A TC10 FUNCTION Plasma membrane-associated small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. In active state binds to a variety of effector proteins to regulate cellular responses. Involved in epithelial cell polarization processes. May play a role in CFTR trafficking to the plasma membrane. Causes the formation of thin, actin-rich surface projections called filopodia.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.SUBUNIT Interacts with CDC42EP4 in a GTP-dependent manner. Interacts with ARHGAP33/TCGAP (By similarity). Interacts with CDC42EP1, CDC42EP2, CDC42EP3, PARD6A, PARD6G (and probably PARD6B) 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). Interacts with EXO70 in a GTP-dependent manner. Interacts with GOPC.PTM May be post-translationally modified by both palmitoylation and polyisoprenylation.SIMILARITY Belongs to the small GTPase superfamily. Rho family. UniProt P17081 1 EQUAL 202 EQUAL Reactome Database ID Release 83 194879 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194879 Reactome R-HSA-194879 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194879.1 1 1 Reactome Database ID Release 83 2316453 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316453 Reactome R-HSA-2316453 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316453.1 ACTIVATION Reactome Database ID Release 83 1458572 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458572 Reactome R-HSA-1458572 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-1458572.2 ACTIVATION Reactome Database ID Release 83 9676112 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9676112 ACTIVATION Reactome Database ID Release 83 9036998 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9036998 Reactome R-HSA-9036998 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9036998.1 MYH9 Myosin-9 MYH9_HUMAN Reactome DB_ID: 419173 UniProt:P35579 MYH9 MYH9 FUNCTION Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping. Required for cortical actin clearance prior to oocyte exocytosis (By similarity). Promotes cell motility in conjunction with S100A4 (PubMed:16707441). During cell spreading, plays an important role in cytoskeleton reorganization, focal contact formation (in the margins but not the central part of spreading cells), and lamellipodial retraction; this function is mechanically antagonized by MYH10 (PubMed:20052411).SUBUNIT Myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2). Interacts with RASIP1 (By similarity). Interacts with DDR1 (By similarity). Interacts with PDLIM2 (By similarity). Interacts with SVIL (PubMed:12917436, PubMed:17925381). Interacts with HTRA3 (PubMed:22229724). Interacts with Myo7a (By similarity). Interacts with CFAP95 (PubMed:28345668). Interacts with LIMCH1; independently of the integration of MYH9 into the myosin complex (PubMed:28228547). Interacts with RAB3A (PubMed:27325790). Interacts with ZBED4 (PubMed:22693546). Interacts with S100A4; this interaction increases cell motility (PubMed:16707441).TISSUE SPECIFICITY In the kidney, expressed in the glomeruli. Also expressed in leukocytes.DOMAIN The rodlike tail sequence is highly repetitive, showing cycles of a 28-residue repeat pattern composed of 4 heptapeptides, characteristic for alpha-helical coiled coils.PTM ISGylated.PTM Ubiquitination.DISEASE Subjects with mutations in the motor domain of MYH9 present with severe thrombocytopenia and develop nephritis and deafness before the age of 40 years, while those with mutations in the tail domain have a much lower risk of noncongenital complications and significantly higher platelet counts. The clinical course of patients with mutations in the four most frequently affected residues of MYH9 (responsible for 70% of MYH9-related cases) were evaluated. Mutations at residue 1933 do not induce kidney damage or cataracts and cause deafness only in the elderly, those in position 702 result in severe thrombocytopenia and produce nephritis and deafness at a juvenile age, while alterations at residue 1424 or 1841 result in intermediate clinical pictures.DISEASE Genetic variations in MYH9 are associated with non-diabetic end stage renal disease (ESRD).SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Myosin family. UniProt P35579 2 EQUAL 1960 EQUAL Reactome Database ID Release 83 419173 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419173 Reactome R-HSA-419173 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419173.1 ACTIVATION Reactome Database ID Release 83 1458528 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458528 Reactome R-HSA-1458528 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-1458528.2 GGC-RAB11A:GTP Reactome DB_ID: 1458542 1 GGC-RAB11A Ras-related protein Rab-11A RB11A_HUMAN Reactome DB_ID: 1458519 UniProt:P62491 RAB11A RAB11A RAB11 FUNCTION The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. The small Rab GTPase RAB11A regulates endocytic recycling. Acts as a major regulator of membrane delivery during cytokinesis. Together with MYO5B and RAB8A participates in epithelial cell polarization. Together with RAB3IP, RAB8A, the exocyst complex, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis. Together with MYO5B participates in CFTR trafficking to the plasma membrane and TF (Transferrin) recycling in nonpolarized cells. Required in a complex with MYO5B and RAB11FIP2 for the transport of NPC1L1 to the plasma membrane. Participates in the sorting and basolateral transport of CDH1 from the Golgi apparatus to the plasma membrane. Regulates the recycling of FCGRT (receptor of Fc region of monomeric Ig G) to basolateral membranes. May also play a role in melanosome transport and release from melanocytes.SUBUNIT Interacts with RAB11FIP5 and STXBP6. Interacts with SGSM1, SGSM2 and SGSM3 (By similarity). Interacts with EXOC6 in a GTP-dependent manner (By similarity). Interacts with RAB11FIP1, RAB11FIP2, RAB11FIP3 (via its C-terminus) and RAB11FIP4. Interacts with EVI5; EVI5 and RAB11FIP3 may be mutually exclusive and compete for binding RAB11A. Interacts with RAB11FIP5 (By similarity). Interacts with STXBP6 (By similarity). Interacts with VIPAS39. Interacts with MYO5B. Found in a complex with MYO5B and CFTR. Interacts with NPC1L1. Interacts (GDP-bound form) with ZFYVE27 (PubMed:21976701, PubMed:17082457). Interacts with BIRC6/bruce. May interact with TBC1D14. Interacts with UNC119; in a cell cycle-dependent manner. GDP-bound and nucleotide-free forms interact with SH3BP5 (PubMed:26506309, PubMed:30217979). Interacts (GDP-bound form) with KIF5A in a ZFYVE27-dependent manner (PubMed:21976701). Interacts (GDP-bound form) with RELCH (By similarity). Found in a complex composed of RELCH, OSBP1 and RAB11A (By similarity). Interacts with TBC1D12 (PubMed:28384198). Interacts with DEF6 (PubMed:31308374).PTM (Microbial infection) Glycosylated on arginine residues by S.typhimurium protein Ssek3.SIMILARITY Belongs to the small GTPase superfamily. Rab family. UniProt P62491 212 EQUAL 213 EQUAL 2 EQUAL 213 EQUAL Reactome Database ID Release 83 1458519 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458519 Reactome R-HSA-1458519 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-1458519.2 1 Reactome Database ID Release 83 1458542 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458542 Reactome R-HSA-1458542 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-1458542.2 ACTIVATION Reactome Database ID Release 83 1458541 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458541 Reactome R-HSA-1458541 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458541.3 RAC1:GTP Reactome DB_ID: 217289 RAC1 GGC-PalmC-RAC1 Ras-related C3 botulinum toxin substrate 1 RAC1_HUMAN Reactome DB_ID: 2316446 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. UniProt P63000 178 EQUAL S-palmitoyl-L-cysteine MOD MOD:00115 189 EQUAL 1 EQUAL 189 EQUAL Reactome Database ID Release 83 2316446 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316446 Reactome R-HSA-2316446 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316446.1 1 1 Reactome Database ID Release 83 217289 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=217289 Reactome R-HSA-217289 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-217289.3 ACTIVATION Reactome Database ID Release 83 5358685 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5358685 Reactome R-HSA-5358685 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-5358685.2 LEFT-TO-RIGHT SLC2A4 (GLUT4) vesicle fuses with the plasma membrane After docking at the membrane VAMP2 on the vesicle interacts with SYNTAXIN-4 and SNAP23 on the plasma membrane to catalyze fusion of the vesicle with the plasma membrane. STXBP3 (MUNC18C) bound to STX4 prevents fusion until STXBP3 is phosphorylated. Authored: May, B, 2011-07-12 Reviewed: Klip, Amira, 2012-08-21 Edited: May, B, 2011-07-12 SNAP23 Synaptosomal-associated protein 23 SNP23_HUMAN Reactome DB_ID: 376345 UniProt:O00161 SNAP23 SNAP23 FUNCTION Essential component of the high affinity receptor for the general membrane fusion machinery and an important regulator of transport vesicle docking and fusion.SUBUNIT Homotetramer (via coiled-coil domain), also forms heterotetramers with STX4 and VAMP3 (PubMed:12556468). Found in a complex with VAMP8 and STX1A (PubMed:12130530). Found in a complex with VAMP8 and STX4 in pancreas (By similarity). Interacts simultaneously with SNAPIN and SYN4 (By similarity). Interacts with STX1A (By similarity). Interacts with STX12 (By similarity). Interacts tightly to multiple syntaxins and synaptobrevins/VAMPs (By similarity). Interacts with ZDHHC13 (via ANK repeats) (By similarity). Interacts with ZDHHC17 (via ANK repeats) (PubMed:28882895).TISSUE SPECIFICITY Ubiquitous. Highest levels where found in placenta.SIMILARITY Belongs to the SNAP-25 family. UniProt O00161 1 EQUAL 211 EQUAL Reactome Database ID Release 83 376345 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376345 Reactome R-HSA-376345 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376345.1 GLUT4:TUG SLC2A4:ASPSCR1 Reactome DB_ID: 1449566 TUG ASPSCR1 TUG (ASPSCR1) Tether containing UBX domain for GLUT4 ASPC1_HUMAN ASPSCR1 Reactome DB_ID: 1449582 UniProt:Q9BZE9 ASPSCR1 ASPSCR1 ASPL RCC17 TUG UBXD9 UBXN9 FUNCTION Tethering protein that sequesters GLUT4-containing vesicles in the cytoplasm in the absence of insulin. Modulates the amount of GLUT4 that is available at the cell surface (By similarity). Enhances VCP methylation catalyzed by VCPKMT.SUBUNIT Interacts with GLUT4 (By similarity). Interacts with VCPKMT. Interacts with VCP.TISSUE SPECIFICITY Ubiquitous. Highly expressed in testis, heart, skeletal muscle and pancreas.DISEASE A chromosomal aberration involving ASPSCR1 is found in patients with alveolar soft part sarcoma. Translocation t(X;17)(p11;q25) with TFE3 forms a ASPSCR1-TFE3 fusion protein.DISEASE A chromosomal aberration involving ASPSCR1 has been found in two patients with of papillary renal cell carcinoma. Translocation t(X;17)(p11.2;q25). UniProt Q9BZE9 1 EQUAL 553 EQUAL Reactome Database ID Release 83 1449582 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449582 Reactome R-HSA-1449582 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449582.1 1 GLUT4 SLC2A4 Solute carrier family 2, facilitated glucose transporter member 4 GTR4_HUMAN Reactome DB_ID: 1449565 UniProt:P14672 SLC2A4 SLC2A4 GLUT4 FUNCTION Insulin-regulated facilitative glucose transporter, which plays a key role in removal of glucose from circulation. Response to insulin is regulated by its intracellular localization: in the absence of insulin, it is efficiently retained intracellularly within storage compartments in muscle and fat cells. Upon insulin stimulation, translocates from these compartments to the cell surface where it transports glucose from the extracellular milieu into the cell.SUBUNIT Interacts with NDUFA9 (By similarity). Binds to DAXX (PubMed:11842083). Interacts via its N-terminus with SRFBP1 (PubMed:16647043). Interacts with TRARG1; the interaction is required for proper SLC2A4 recycling after insulin stimulation (By similarity).TISSUE SPECIFICITY Skeletal and cardiac muscles; brown and white fat.DOMAIN The dileucine internalization motif is critical for intracellular sequestration.PTM Sumoylated.PTM Palmitoylated (PubMed:28057756). Palmitoylation by ZDHHC7 controls the insulin-dependent translocation of GLUT4 to the plasma membrane (PubMed:28057756).MISCELLANEOUS Insulin-stimulated phosphorylation of TBC1D4 is required for GLUT4 translocation.SIMILARITY Belongs to the major facilitator superfamily. Sugar transporter (TC 2.A.1.1) family. Glucose transporter subfamily. UniProt P14672 1 EQUAL 509 EQUAL Reactome Database ID Release 83 1449565 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449565 Reactome R-HSA-1449565 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449565.1 1 Reactome Database ID Release 83 1449566 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449566 Reactome R-HSA-1449566 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-1449566.2 STX4:STXBP3 (MUNC18C) Reactome DB_ID: 2263479 STXBP3 STXBP3 (MUNC18C) Syntaxin-binding protein 3 STXB3_HUMAN Reactome DB_ID: 2263473 UniProt:O00186 STXBP3 STXBP3 FUNCTION Together with STX4 and VAMP2, may play a role in insulin-dependent movement of GLUT4 and in docking/fusion of intracellular GLUT4-containing vesicles with the cell surface in adipocytes.SUBUNIT Interacts with DOC2B; the interaction is direct, occurs at the cell membrane, excludes interaction with STX4 and regulates glucose-stimulated insulin secretion (By similarity). Interacts with STX4.TISSUE SPECIFICITY Megakaryocytes and platelets.PTM Phosphorylated by PKC in platelets in response to thrombin stimulation; phosphorylation inhibits binding to STX4.SIMILARITY Belongs to the STXBP/unc-18/SEC1 family. UniProt O00186 1 EQUAL 592 EQUAL Reactome Database ID Release 83 2263473 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2263473 Reactome R-HSA-2263473 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2263473.1 1 STX4 Syntaxin 4 Reactome DB_ID: 181519 UniProt:Q12846 STX4 STX4 STX4A FUNCTION Plasma membrane t-SNARE that mediates docking of transport vesicles (By similarity). Necessary for the translocation of SLC2A4 from intracellular vesicles to the plasma membrane (By similarity). In neurons, recruited at neurite tips to membrane domains rich in the phospholipid 1-oleoyl-2-palmitoyl-PC (OPPC) which promotes neurite tip surface expression of the dopamine transporter SLC6A3/DAT by facilitating fusion of SLC6A3-containing transport vesicles with the plasma membrane (By similarity). Together with STXB3 and VAMP2, may also play a role in docking/fusion of intracellular GLUT4-containing vesicles with the cell surface in adipocytes and in docking of synaptic vesicles at presynaptic active zones (By similarity).SUBUNIT Component of the SNARE complex composed of STX4, SNAP23 and VAMP7 that interacts with SYT7 during lysosomal exocytosis. Found in a complex with VAMP8 and SNAP23. Detected in a complex with SNAP23 and STXBP4. Interacts with VAMP2. Interacts with SNAP23 and SNAPIN. Interacts with LLGL1. Interacts (via C-terminus) with CENPF. Interacts with DOC2B. Interacts with STXBP6. Interacts with STXBP3; excludes interaction with DOC2B and SNAP25. Interacts with STXBP4; excludes interaction with VAMP2 (By similarity). Interacts with STXBP5L (By similarity).TISSUE SPECIFICITY Expressed in neutrophils and neutrophil-differentiated HL-60 cells. Expression in neutrophils increases with differentiation.SIMILARITY Belongs to the syntaxin family. UniProt Q12846 1 EQUAL 297 EQUAL Reactome Database ID Release 83 181519 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181519 Reactome R-HSA-181519 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181519.1 1 Reactome Database ID Release 83 2263479 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2263479 Reactome R-HSA-2263479 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2263479.1 VAMP2 Vesicle-associated membrane protein 2 VAMP2_HUMAN Reactome DB_ID: 1449630 UniProt:P63027 VAMP2 VAMP2 SYB2 FUNCTION Involved in the targeting and/or fusion of transport vesicles to their target membrane (By similarity). Major SNARE protein of synaptic vesicles which mediates fusion of synaptic vesicles to release neurotransmitters. Essential for fast vesicular exocytosis and activity-dependent neurotransmitter release as well as fast endocytosis that mediates rapid reuse of synaptic vesicles (By similarity) (PubMed:30929742). Modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1.SUBUNIT Part of the SNARE core complex containing SNAP25, VAMP2 and STX1A. This complex binds to CPLX1. Interacts with BVES and STX4 (By similarity). Interacts with VAPA and VAPB. Interacts with WDFY2, PRKCZ and PRKCI (PubMed:17313651). Forms a complex with WDFY2 and PRKCZ (PubMed:17313651). Interacts (via N-terminus) with KCNB1 (via N-terminus and C-terminus); stimulates the channel inactivation rate of KCNB1 (By similarity). Interacts with SEPT8; the interaction inhibits interaction of VAMP2 with SYP. Interacts with SYP; the interaction is inhibited by interaction with SEPT8 (By similarity). Interacts with PICALM (PubMed:22118466, PubMed:21808019). Interacts with alpha-synuclein/SNCA (PubMed:20798282). Interacts with STX3 (By similarity).TISSUE SPECIFICITY Nervous system and skeletal muscle.PTM Phosphorylated by PRKCZ in vitro and this phosphorylation is increased in the presence of WDFY2.PTM (Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type B (BoNT/B, botB) which hydrolyzes the 76-Gln-|-Phe-77 bond and probably inhibits neurotransmitter release (PubMed:7803399).PTM (Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type D (BoNT/D, botD) which probably hydrolyzes the 59-Lys-|-Leu-60 bond and inhibits neurotransmitter release (PubMed:22289120). Note that humans are not known to be infected by C.botulinum type D.PTM (Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type F (BoNT/F, botF) which hydrolyzes the 58-Gln-|-Lys-59 bond and probably inhibits neurotransmitter release (PubMed:19543288).PTM (Microbial infection) Targeted and hydrolyzed by C.tetani tetanus toxin (tetX) which hydrolyzes the 76-Gln-|-Phe-77 bond and probably inhibits neurotransmitter release (PubMed:7803399).SIMILARITY Belongs to the synaptobrevin family.CAUTION A structure of a fragment of this protein in complex with the catalytic domain of C.botulinum neurotoxin type B (BoNT/B, botB) was reported; because of the lack of clear and continuous electron density for the VAMP2 peptide in the complex structure, the paper was retracted (PubMed:10932255, PubMed:19578378). However this protein is a substrate for BoNT/B (PubMed:7803399, PubMed:22289120). UniProt P63027 2 EQUAL 116 EQUAL Reactome Database ID Release 83 1449630 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449630 Reactome R-HSA-1449630 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449630.1 STXBP3 p-Y521-STXBP3 p-Y521-STXBP3 (MUNC18C) Syntaxin-binding protein 3 STXB3_HUMAN Reactome DB_ID: 2263472 521 EQUAL O4'-phospho-L-tyrosine MOD MOD:00048 1 EQUAL 592 EQUAL Reactome Database ID Release 83 2263472 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2263472 Reactome R-HSA-2263472 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2263472.1 VAMP2:STX4:SNAP23 Reactome DB_ID: 1449628 1 1 1 Reactome Database ID Release 83 1449628 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449628 Reactome R-HSA-1449628 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-1449628.2 GLUT4 SLC2A4 Solute carrier family 2, facilitated glucose transporter, member 4 Glucose transporter type 4, insulin-responsive Reactome DB_ID: 70383 1 EQUAL 509 EQUAL Reactome Database ID Release 83 70383 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70383 Reactome R-HSA-70383 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-70383.1 Reactome Database ID Release 83 1449574 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449574 Reactome R-HSA-1449574 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-1449574.2 Reactome Database ID Release 83 1445148 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445148 Reactome R-HSA-1445148 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-1445148.2 20417083 Pubmed 2010 Biogenesis and regulation of insulin-responsive vesicles containing GLUT4 Bogan, JS Kandror, KV Curr Opin Cell Biol 22:506-12 21216617 Pubmed 2011 Signaling, cytoskeletal and membrane mechanisms regulating GLUT4 exocytosis Hoffman, NJ Elmendorf, JS Trends Endocrinol Metab 22:110-6 19389739 Pubmed 2009 The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targets Leney, SE Tavaré, JM J Endocrinol 203:1-18 21306486 Pubmed 2011 The sugar is sIRVed: sorting Glut4 and its fellow travelers Kandror, KV Pilch, PF Traffic 12:665-71 21405107 Pubmed 2011 Endocytosis, recycling, and regulated exocytosis of glucose transporter 4 Foley, K Boguslavsky, S Klip, A Biochemistry 50:3048-61 28602209 Pubmed 2017 Update on GLUT4 Vesicle Traffic: A Cornerstone of Insulin Action Jaldin-Fincati, Javier R Pavarotti, Martin Frendo-Cumbo, Scott Bilan, Philip J Klip, Amira Trends Endocrinol. Metab. 28:597-611 18570632 Pubmed 2008 Insulin action on glucose transporters through molecular switches, tracks and tethers Zaid, H Antonescu, Costin Randhawa, VK Klip, A Biochem J 413:201-15