BioPAX pathway converted from "Translocation of SLC2A4 (GLUT4) to the plasma membrane" in the Reactome database.Translocation of SLC2A4 (GLUT4) to the plasma membraneIn 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, 2011-07-07Reviewed: Klip, Amira, 2012-08-21Edited: May, B, 2011-07-07LEFT-TO-RIGHTRAB4A:GTP binds KIF3 and activates KIF3As 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, 2012-05-27Reviewed: Klip, Amira, 2012-08-21Edited: May, B, 2012-05-27GGC-RAB4A:GTPReactome DB_ID: 1458538cytoplasmic vesicle membraneGENE ONTOLOGYGO:0030659GGC-RAB4ARas-related protein Rab-4ARAB4A_HUMANReactome DB_ID: 1458526UniProt:P20338 RAB4ARAB4ARAB4FUNCTION Protein transport. Plays a role in vesicular traffic. Mediates VEGFR2 endosomal trafficking to enhance VEGFR2 signaling.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.SIMILARITY Belongs to the small GTPase superfamily. Rab family.CAUTION It is uncertain whether Met-1 or Met-6 is the initiator.Homo sapiensNCBI Taxonomy9606UniProtP20338216EQUALS-geranylgeranyl-L-cysteineMODMOD:00113218EQUAL1EQUAL218EQUALReactome Database ID Release 711458526Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458526ReactomeR-HSA-14585262Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458526.2Reactomehttp://www.reactome.org1GTPGuanosine 5'-triphosphateReactome DB_ID: 1996291GTP [ChEBI:15996]GTPGuanosine 5'-triphosphateChEBICHEBI:15996Reactome Database ID Release 711996291Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1996291ReactomeR-ALL-19962912Reactome stable identifier. Use this 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-1996291.21Reactome Database ID Release 711458538Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458538ReactomeR-HSA-14585382Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458538.2KIF3Reactome DB_ID: 2316334cytosolGENE ONTOLOGYGO:0005829KIF3BKinesin-like protein KIF3BKIF3B_HUMANReactome DB_ID: 984662UniProt:O15066 KIF3BKIF3BKIAA0359FUNCTION Involved in tethering the chromosomes to the spindle pole and in chromosome movement. Microtubule-based anterograde translocator for membranous organelles. Plus end-directed microtubule sliding activity in vitro (By similarity).SUBUNIT Heterodimer of KIF3A and KIF3B. Interacts directly with IFT20 (By similarity). Interacts with the SMC3 subunit of the cohesin complex.SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. Kinesin II subfamily.UniProtO150661EQUAL747EQUALReactome Database ID Release 71984662Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=984662ReactomeR-HSA-9846621Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-984662.11KIFAP3Kinesin-associated protein 3KIFA3_HUMANReactome DB_ID: 984736UniProt:Q92845 KIFAP3KIFAP3KIF3APSMAPFUNCTION 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.UniProtQ928451EQUAL792EQUALReactome Database ID Release 71984736Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=984736ReactomeR-HSA-9847361Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-984736.11KIF3AKinesin-like protein KIF3AKIF3A_HUMANReactome DB_ID: 984767UniProt:Q9Y496 KIF3AKIF3AKIF3FUNCTION 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).SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. Kinesin II subfamily.UniProtQ9Y4961EQUAL699EQUALReactome Database ID Release 71984767Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=984767ReactomeR-HSA-9847671Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-984767.11Reactome Database ID Release 712316334Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316334ReactomeR-HSA-23163341Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316334.1MicrotubuleReactome DB_ID: 190599Microtubule protofilamentReactome DB_ID: 8982424Reactome Database ID Release 718982424Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8982424ReactomeR-HSA-89824241Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8982424.113Reactome Database ID Release 71190599Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=190599ReactomeR-HSA-1905992Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-190599.2GGC-RAB4A:GTP:KIF3:microtubuleReactome DB_ID: 1458522111Reactome Database ID Release 711458522Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458522ReactomeR-HSA-14585223Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458522.3Reactome Database ID Release 712316347Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316347ReactomeR-HSA-23163472Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316347.2LEFT-TO-RIGHT2.7.11p-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, 2011-07-07Reviewed: Klip, Amira, 2012-08-21Edited: May, B, 2011-07-07AS160:IRAPTBC1D4:LNPEPReactome DB_ID: 1445125IRAPLNPEPLNPEPLeucyl-cystinyl aminopeptidaseLCAP_HUMANReactome DB_ID: 1445121UniProt:Q9UIQ6 LNPEPLNPEPOTASEFUNCTION 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.UniProtQ9UIQ61EQUAL1025EQUALReactome Database ID Release 711445121Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445121ReactomeR-HSA-14451211Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445121.11AS160TBC1D4TBC1 domain family member 4TBCD4_HUMANReactome DB_ID: 1445122UniProt:O60343 TBC1D4TBC1D4AS160KIAA0603FUNCTION 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.UniProtO603431EQUAL1298EQUALReactome Database ID Release 711445122Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445122ReactomeR-HSA-14451221Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445122.11Reactome Database ID Release 711445125Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445125ReactomeR-HSA-14451251Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445125.1ATPAdenosine 5'-triphosphateATP(4-)Reactome DB_ID: 113592ATP(4-) [ChEBI:30616]ATP(4-)ATPatpAdenosine 5'-triphosphateChEBICHEBI:30616Reactome Database ID Release 71113592Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592ReactomeR-ALL-1135924Reactome stable identifier. Use this 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-113592.46ADPAdenosine 5'-diphosphateADP(3-)Reactome DB_ID: 29370ADP(3-) [ChEBI:456216]ADP(3-)ADP5&apos;-O-[(phosphonatooxy)phosphinato]adenosineADP trianionChEBICHEBI:456216Reactome Database ID Release 7129370Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370ReactomeR-ALL-293704Reactome stable identifier. Use this 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-29370.46p-5S,T642-AS160:IRAPPhosphorylated TBC1D4:LNPEPReactome DB_ID: 1445133TBC1D4p-5S,T642-TBC1D4p-6S-TBC1D4p-5S-T642-AS160p-5S-T642-TBC1D4Phosphorylated TBC1D4TBC1 domain family member 4TBCD4_HUMANReactome DB_ID: 1445101318EQUALO-phospho-L-serineMODMOD:00046341EQUAL570EQUAL588EQUAL642EQUALO-phospho-L-threonineMODMOD:00047751EQUAL1EQUAL1298EQUALReactome Database ID Release 711445101Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445101ReactomeR-HSA-14451011Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445101.111Reactome Database ID Release 711445133Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445133ReactomeR-HSA-14451331Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445133.1ACTIVATIONConverted from EntitySet in Reactomep-AKT1,p-AKT2Reactome DB_ID: 9023954PKBp-T308,S473-AKT1p-S473,T308-AKT1p-T308, S473-AKT1Phospho-AKT1 (T308, S473)phospho-PKB alpha (T308, S473)RAC-alpha serine/threonine kinase RAC-PK-alphaProtein kinase BC-AKTReactome DB_ID: 199430plasma membraneGENE ONTOLOGYGO:0005886UniProt:P31749 AKT1AKT1PKBRACFUNCTION 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. 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. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. 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. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity. Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53.FUNCTION AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation.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. Inhibited by pyrrolopyrimidine inhibitors like aniline triazole and spiroindoline.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).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. Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA. 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. Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1. Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1. Ser-473 phosphorylation is enhanced by interaction with AGAP2 isoform 2 (PIKE-A). Ser-473 phosphorylation is enhanced in focal cortical dysplasias with Taylor-type balloon cells. Ser-473 phosphorylation is enhanced by signaling through activated FLT3. Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase. The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase. Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling.PTM Ubiquitinated via 'Lys-48'-linked polyubiquitination by ZNRF1, leading to its degradation by the proteasome (By similarity). Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT1 ubiquitination is critical for phosphorylation and activation. When ubiquitinated, it translocates to the plasma membrane, where it becomes phosphorylated. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome. Also ubiquitinated by TRIM13 leading to its proteasomal degradation. Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation.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.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 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.UniProtP31749308EQUAL473EQUAL1EQUAL480EQUALReactome Database ID Release 71199430Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199430ReactomeR-HSA-1994301Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199430.1PKB betap-T309,S474-AKT2p-S474,T309-AKT2Phospho-AKT2 (T309, S474)RAC-beta serine/threonine protein kinase RAC-PK-betaProtein kinase Akt-2Protein kinase B, betaReactome DB_ID: 202056UniProt:P31751 AKT2AKT2FUNCTION 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. Aminofurazans are potent AKT2 inhibitors.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, plays also 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.UniProtP31751309EQUAL474EQUAL1EQUAL481EQUALReactome Database ID Release 71202056Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202056ReactomeR-HSA-2020561Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202056.1Reactome Database ID Release 719023954Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9023954ReactomeR-HSA-90239541Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9023954.1GENE ONTOLOGYGO:0004674gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 719023956Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9023956Reactome Database ID Release 711445144Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445144ReactomeR-HSA-14451443Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445144.317369524Pubmed2007Resistance exercise and insulin regulate AS160 and interaction with 14-3-3 in human skeletal muscleHowlett, KFSakamoto, KGarnham, ACameron-Smith, DHargreaves, MDiabetes 56:1608-1415919790Pubmed2005Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjectsKarlsson, HKZierath, JRKane, SKrook, ALienhard, GEWallberg-Henriksson, HDiabetes 54:1692-7LEFT-TO-RIGHT14-3-3 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, 2011-07-07Reviewed: Klip, Amira, 2012-08-21Edited: May, B, 2011-07-07Converted from EntitySet in Reactome14-3-3 dimerReactome DB_ID: 144513814-3-3 eta dimerReactome DB_ID: 2262715YWHAH14-3-3 eta14-3-3 protein eta1433F_HUMANReactome DB_ID: 1445107UniProt:Q04917 YWHAHYWHAHYWHA1FUNCTION 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).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.UniProtQ049172EQUAL246EQUALReactome Database ID Release 711445107Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445107ReactomeR-HSA-14451071Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445107.12Reactome Database ID Release 712262715Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2262715ReactomeR-HSA-22627151Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2262715.1YWHAG dimer14-3-3 gamma dimerReactome DB_ID: 2262713YWHAG14-3-3 protein gamma14-3-3 gammaReactome DB_ID: 380312UniProt:P61981 YWHAGYWHAGFUNCTION 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).TISSUE SPECIFICITY Highly expressed in brain, skeletal muscle, and heart.PTM Phosphorylated by various PKC isozymes.SIMILARITY Belongs to the 14-3-3 family.UniProtP619811EQUAL247EQUALReactome Database ID Release 71380312Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380312ReactomeR-HSA-3803121Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380312.12Reactome Database ID Release 712262713Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2262713ReactomeR-HSA-22627132Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2262713.2SFN dimer14-3-3 sigma dimerReactome DB_ID: 2262716SFN14-3-3 sigma14-3-3 protein sigma1433S_HUMANReactome DB_ID: 1445105UniProt:P31947 SFNSFNHME1FUNCTION 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.UniProtP319471EQUAL248EQUALReactome Database ID Release 711445105Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445105ReactomeR-HSA-14451051Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445105.12Reactome Database ID Release 712262716Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2262716ReactomeR-HSA-22627163Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2262716.3YWHAQ dimer14-3-3 theta dimerReactome DB_ID: 2262714YWHAQ14-3-3 theta14-3-3 protein theta1433T_HUMANReactome DB_ID: 1445116UniProt:P27348 YWHAQYWHAQFUNCTION 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).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.UniProtP273481EQUAL245EQUALReactome Database ID Release 711445116Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445116ReactomeR-HSA-14451161Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445116.12Reactome Database ID Release 712262714Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2262714ReactomeR-HSA-22627142Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2262714.2YWHAZ dimer14-3-3 zeta dimerReactome DB_ID: 206751YWHAZ14-3-3 zetaReactome DB_ID: 206099UniProt:P63104 YWHAZYWHAZFUNCTION 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. 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. Heterodimerizes with YWHAE. Homo- and heterodimerization is inhibited by phosphorylation on Ser-58. 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. 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 YWHAZ (By similarity).PTM The delta, brain-specific form differs from the zeta form in being phosphorylated (By similarity). Phosphorylation on Ser-184 by MAPK8; promotes dissociation of BAX and translocation of BAX to mitochondria. Phosphorylation on Thr-232; inhibits binding of RAF1. Phosphorylated on Ser-58 by PKA and protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion. Phosphorylation on Ser-58 by PKA; disrupts homodimerization and heterodimerization with YHAE and TP53.SIMILARITY Belongs to the 14-3-3 family.CAUTION Was originally thought to have phospholipase A2 activity.UniProtP631041EQUAL245EQUALReactome Database ID Release 71206099Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=206099ReactomeR-HSA-2060991Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-206099.12Reactome Database ID Release 71206751Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=206751ReactomeR-HSA-2067513Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-206751.3YWHAB dimerReactome DB_ID: 2028645YWHAB14-3-3 protein beta/alpha143B proteinProtein kinase C inhibitor protein-1KCIP-1Protein 1054Reactome DB_ID: 48888UniProt:P31946 YWHABYWHABFUNCTION 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).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.UniProtP319461EQUAL246EQUALReactome Database ID Release 7148888Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=48888ReactomeR-HSA-488881Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-48888.12Reactome Database ID Release 712028645Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2028645ReactomeR-HSA-20286451Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2028645.1YWHAE dimer14-3-3E homodimerReactome DB_ID: 194364YWHAE14-3-3 protein epsilon143E_HUMAN14-3-3 epsilonReactome DB_ID: 194368UniProt:P62258 YWHAEYWHAEFUNCTION 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; this interaction inhibits calcium-transporting ATPase activity (PubMed:18029012).SUBUNIT (Microbial infection) Interacts with HCV core protein.SIMILARITY Belongs to the 14-3-3 family.UniProtP622581EQUAL255EQUALReactome Database ID Release 71194368Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194368ReactomeR-HSA-1943681Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194368.12Reactome Database ID Release 71194364Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194364ReactomeR-HSA-1943641Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194364.1Reactome Database ID Release 711445138Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445138ReactomeR-HSA-14451381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445138.1p-5S,T642-AS160:14-3-3:IRAPp-5S-T642-TBC1D4:14-3-3:LNPEPPhosphorylated TBC1D4:14-3-3:LNPEPReactome DB_ID: 14451241Phospho AS160:14-3-3Phosphorylated TBC1D4:14-3-3Reactome DB_ID: 144512611Reactome Database ID Release 711445126Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445126ReactomeR-HSA-14451262Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445126.21Reactome Database ID Release 711445124Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445124ReactomeR-HSA-14451241Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445124.1Reactome Database ID Release 711445149Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445149ReactomeR-HSA-14451492Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445149.221454690Pubmed2011AS160 phosphotyrosine-binding domain constructs inhibit insulin-stimulated GLUT4 vesicle fusion with the plasma membraneKoumanov, FRichardson, JDMurrow, BAHolman, GDJ Biol Chem 286:16574-8219252894Pubmed2009Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscleTreebak, JTFrøsig, CPehmøller, CChen, SMaarbjerg, SJBrandt, NMackintosh, CZierath, JRHardie, DGKiens, BRichter, EAPilegaard, HWojtaszewski, JFDiabetologia 52:891-90016880201Pubmed2006A role for 14-3-3 in insulin-stimulated GLUT4 translocation through its interaction with the RabGAP AS160Ramm, GLarance, MGuilhaus, MJames, DEJ Biol Chem 281:29174-8019013499Pubmed2009Reduced phosphorylation of AS160 contributes to glucocorticoid-mediated inhibition of glucose uptake in human and murine adipocytesNgo, SBarry, JBNisbet, JCPrins, JBWhitehead, JPMol Cell Endocrinol 302:33-40LEFT-TO-RIGHT2.7.11AMPK-alpha2 phosphorylates TBC1D1In 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, 2011-07-15Reviewed: Klip, Amira, 2012-08-21Edited: May, B, 2011-07-15TBC1D1TBC1 domain family member 1TBCD1_HUMANReactome DB_ID: 1454718UniProt:Q86TI0 TBC1D1TBC1D1KIAA1108FUNCTION 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.UniProtQ86TI01EQUAL1168EQUALReactome Database ID Release 711454718Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454718ReactomeR-HSA-14547181Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1454718.1TBC1D1p-S237-TBC1D1TBC1D1 (pSer237)TBC1 domain family member 1TBCD1_HUMANReactome DB_ID: 1454673237EQUAL1EQUAL1168EQUALReactome Database ID Release 711454673Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454673ReactomeR-HSA-14546731Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1454673.1ACTIVATIONactiveUnit: #Protein24AMPK-alpha2:AMPK-beta:AMPK-gamma:AMPReactome DB_ID: 1454683AMPK gamma:AMPReactome DB_ID: 2316451AMPadenosine 5'-monophosphateAdenylic acidAdenylate5'-AMP5'-Adenylic acid5'-Adenosine monophosphateAdenosine 5'-phosphateReactome DB_ID: 76577adenosine 5'-monophosphate [ChEBI:16027]adenosine 5'-monophosphateChEBICHEBI:16027Reactome Database ID Release 7176577Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76577ReactomeR-ALL-765774Reactome stable identifier. Use this 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-76577.41Converted from EntitySet in ReactomeAMPK gammaReactome DB_ID: 381851PRKAG1AMPK gamma15'-AMP-activated protein kinase subunit gamma-1AAKG1_HUMANReactome DB_ID: 380946UniProt:P54619 PRKAG1PRKAG1FUNCTION 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.UniProtP546191EQUAL331EQUALReactome Database ID Release 71380946Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380946ReactomeR-HSA-3809461Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380946.1PRKAG2AMPK gamma2 (inactive)Reactome DB_ID: 200419UniProt:Q9UGJ0 PRKAG2PRKAG2FUNCTION 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.UniProtQ9UGJ01EQUAL569EQUALReactome Database ID Release 71200419Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200419ReactomeR-HSA-2004191Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-200419.1PRKAG3AMPK gamma35'-AMP-activated protein kinase subunit gamma-3AAKG3_HUMANReactome DB_ID: 381839UniProt:Q9UGI9 PRKAG3PRKAG3AMPKG3FUNCTION 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 (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 PRKAG3 genetic variants can be associated with increased glycogen content in skeletal muscle [MIM:604976]. 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.UniProtQ9UGI91EQUAL489EQUALReactome Database ID Release 71381839Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381839ReactomeR-HSA-3818391Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381839.1Reactome Database ID Release 71381851Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381851ReactomeR-HSA-3818511Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381851.11Reactome Database ID Release 712316451Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316451ReactomeR-HSA-23164511Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316451.11p-T172-PRKAA2p-T172-AMPK alpha2Reactome DB_ID: 200417UniProt:P54646 PRKAA2PRKAA2AMPKAMPK2FUNCTION 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. 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. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. 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. 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. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. 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. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. In that process also activates WDR45 (PubMed:28561066). AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. 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. 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. Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-172. AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-172. ADP also stimulates Thr-172 phosphorylation, without stimulating already phosphorylated AMPK. ATP promotes dephosphorylation of Thr-172, rendering the enzyme inactive. 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). 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.UniProtP54646172EQUAL1EQUAL552EQUALReactome Database ID Release 71200417Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200417ReactomeR-HSA-2004171Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-200417.11Converted from EntitySet in ReactomeAMPK betaReactome DB_ID: 381854PRKAB1AMPK beta15'-AMP-activated protein kinase subunit beta-1AAKB1_HUMANReactome DB_ID: 380968UniProt:Q9Y478 PRKAB1PRKAB1AMPKFUNCTION 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.UniProtQ9Y4782EQUAL270EQUALReactome Database ID Release 71380968Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380968ReactomeR-HSA-3809681Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380968.1PRKAB2AMPK beta 2 (inactive)Reactome DB_ID: 200413UniProt:O43741 PRKAB2PRKAB2FUNCTION 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.UniProtO437411EQUAL272EQUALReactome Database ID Release 71200413Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200413ReactomeR-HSA-2004131Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-200413.1Reactome Database ID Release 71381854Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381854ReactomeR-HSA-3818541Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381854.11Reactome Database ID Release 711454683Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454683ReactomeR-HSA-14546831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1454683.1Reactome Database ID Release 711454665Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454665Reactome Database ID Release 711454699Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454699ReactomeR-HSA-14546991Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1454699.117995453Pubmed2008Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activatorsChen, SMurphy, JToth, RCampbell, DGMorrice, NAMackintosh, CBiochem J 409:449-5921454505Pubmed2011Crystal structures of human TBC1D1 and TBC1D4 (AS160) RabGTPase-activating protein (RabGAP) domains reveal critical elements for GLUT4 translocationPark, Sang-YounJin, WanzhuWoo, Ju RangShoelson, SEJ. Biol. Chem. 286:18130-820837646Pubmed2010Exercise-induced TBC1D1 Ser237 phosphorylation and 14-3-3 protein binding capacity in human skeletal muscleFrøsig, CPehmøller, CBirk, JBRichter, EAWojtaszewski, JFJ Physiol 588:4539-4820701589Pubmed2010Contraction regulates site-specific phosphorylation of TBC1D1 in skeletal muscleVichaiwong, KPurohit, SAn, DToyoda, TJessen, NHirshman, MFGoodyear, LJBiochem J 431:311-20LEFT-TO-RIGHT14-3-3 Binds p-S237-TBC1D1TBC1D1 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, 2011-07-15Reviewed: Klip, Amira, 2012-08-21Edited: May, B, 2011-07-15p-S237-TBC1D1:14-3-3TBC1D1 (pSer237):14-3-3Reactome DB_ID: 145469611Reactome Database ID Release 711454696Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454696ReactomeR-HSA-14546961Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1454696.1Reactome Database ID Release 711454689Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454689ReactomeR-HSA-14546892Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1454689.2LEFT-TO-RIGHTRAB8A,10,13,14 exchange GDP for GTPRAB8A/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, 2012-05-16Reviewed: Klip, Amira, 2012-08-21Edited: May, B, 2012-05-16Converted from EntitySet in ReactomeGGC-RAB8A,10,13,14:GDPReactome DB_ID: 1445130GGC-RAB10:GDPReactome DB_ID: 9605173GGC-RAB10Ras-related protein Rab-10RAB10_HUMANReactome DB_ID: 8876076UniProt:P61026 RAB10RAB10FUNCTION 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). Plays also 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).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) (By similarity). That Rab is activated by the DENND4C guanine exchange factor (GEF).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).TISSUE SPECIFICITY Expressed in the hippocampus (PubMed:29562525). Expressed in neutrophils (at protein level) (PubMed:29127255).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.UniProtP61026199EQUAL200EQUAL1EQUAL200EQUALReactome Database ID Release 718876076Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8876076ReactomeR-HSA-88760761Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8876076.11GDPGuanosine 5'-diphosphateGuanosine diphosphateReactome DB_ID: 29420GDP [ChEBI:17552]GDPGuanosine 5'-diphosphateGuanosine diphosphateChEBICHEBI:17552Reactome Database ID Release 7129420Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29420ReactomeR-ALL-294202Reactome stable identifier. Use this 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-29420.21Reactome Database ID Release 719605173Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605173ReactomeR-HSA-96051731Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605173.1GGC-RAB13:GDPReactome DB_ID: 9605170GGC-RAB13Ras-related protein Rab-13RAB13_HUMANReactome DB_ID: 1445110UniProt:P51153 RAB13RAB13GIG4FUNCTION 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.SIMILARITY Belongs to the small GTPase superfamily. Rab family.UniProtP51153200EQUAL1EQUAL200EQUALReactome Database ID Release 711445110Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445110ReactomeR-HSA-14451102Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445110.211Reactome Database ID Release 719605170Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605170ReactomeR-HSA-96051701Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605170.1GGC-RAB14:GDPReactome DB_ID: 9605171GGC-RAB14Ras-related protein Rab-14RAB14_HUMANReactome DB_ID: 1445086UniProt:P61106 RAB14RAB14FUNCTION 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.UniProtP61106213EQUAL215EQUAL2EQUAL215EQUALReactome Database ID Release 711445086Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445086ReactomeR-HSA-14450862Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445086.211Reactome Database ID Release 719605171Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605171ReactomeR-HSA-96051711Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605171.1GGC-RAB8A:GDPReactome DB_ID: 96051601GGC-RAB8ARas-related protein Rab-8ARAB8A_HUMANReactome DB_ID: 1445093UniProt:P61006 RAB8ARAB8AMELRAB8FUNCTION 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). Together with MYO5B and RAB11A participates in epithelial cell polarization (PubMed:21282656). May be involved in 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 Activated in response to insulin.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).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.UniProtP61006204EQUAL1EQUAL204EQUALReactome Database ID Release 711445093Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445093ReactomeR-HSA-14450932Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445093.21Reactome Database ID Release 719605160Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605160ReactomeR-HSA-96051601Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605160.1Reactome Database ID Release 711445130Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445130ReactomeR-HSA-14451302Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445130.2Converted from EntitySet in ReactomeGGC-RAB8A,10,13,14:GTPReactome DB_ID: 1445137GGC-RAB10:GTPReactome DB_ID: 8876128GTPGuanosine 5'-triphosphateReactome DB_ID: 29438Reactome Database ID Release 7129438Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29438ReactomeR-ALL-294383Reactome stable identifier. Use this 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-29438.311Reactome Database ID Release 718876128Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8876128ReactomeR-HSA-88761281Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8876128.1GGC-RAB13:GTPReactome DB_ID: 960417611Reactome Database ID Release 719604176Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9604176ReactomeR-HSA-96041761Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9604176.1GGC-RAB14:GTPReactome DB_ID: 960516911Reactome Database ID Release 719605169Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605169ReactomeR-HSA-96051691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605169.1GGC-RAB8A:GTPReactome DB_ID: 960515511Reactome Database ID Release 719605155Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605155ReactomeR-HSA-96051551Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605155.1Reactome Database ID Release 711445137Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445137ReactomeR-HSA-14451372Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445137.2GDPGuanosine 5'-diphosphateGuanosine diphosphateReactome DB_ID: 1996292Reactome Database ID Release 711996292Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1996292ReactomeR-ALL-19962922Reactome stable identifier. Use this 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-1996292.2Reactome Database ID Release 712255343Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2255343ReactomeR-HSA-22553432Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2255343.220631154Pubmed2010Interaction of retinitis pigmentosa GTPase regulator (RPGR) with RAB8A GTPase: implications for cilia dysfunction and photoreceptor degenerationMurga-Zamalloa, Carlos AAtkins, Stephen JPeranen, JohanSwaroop, AnandKhanna, HemantHum. Mol. Genet. 19:3591-820937701Pubmed2010Family-wide characterization of the DENN domain Rab GDP-GTP exchange factorsYoshimura, Shin-ichiroGerondopoulos, AndreasLinford, AndreaRigden, Daniel JBarr, Francis AJ. Cell Biol. 191:367-81LEFT-TO-RIGHT3.6.5.43.6.5.33.6.5.23.6.5.1RAB8A,10,13,14 hydrolyze GTPRAB 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.Authored: May, B, 2011-07-07Reviewed: Klip, Amira, 2012-08-21Edited: May, B, 2011-07-07ACTIVATIONactiveUnit: #Protein32GENE ONTOLOGYGO:0003924Reactome Database ID Release 711458467Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458467Converted from EntitySet in ReactomeGGC-RAB8A,10,13,14Reactome DB_ID: 1445136Reactome Database ID Release 711445136Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445136ReactomeR-HSA-14451362Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445136.2Reactome Database ID Release 711445143Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445143ReactomeR-HSA-14451434Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445143.415971998Pubmed2005AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domainMîinea, CPSano, HKane, SSano, EFukuda, MPeränen, JLane, WSLienhard, GEBiochem J 391:87-93ACTIVATIONThe 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).Reactome Database ID Release 711449643Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449643ReactomeR-HSA-14496431Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449643.121041651Pubmed2010Rab8A and Rab13 are activated by insulin and regulate GLUT4 translocation in muscle cellsSun, YBilan, PJLiu, ZKlip, AProc Natl Acad Sci U S A 107:19909-14ACTIVATIONAs inferred from mouse, TBC1D1 activates GTPase activity of RAB2A, 8A, 8B, 10, and 14 (Roach et al. 2007).Reactome Database ID Release 711454728Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454728ReactomeR-HSA-14547281Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1454728.117274760Pubmed2007Substrate specificity and effect on GLUT4 translocation of the Rab GTPase-activating protein Tbc1d1Roach, WGChavez, JAMîinea, CPLienhard, GEBiochem J 403:353-8LEFT-TO-RIGHT2.7.11p-AKT2 phosphorylates Myosin 5AAs 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, 2011-07-12Reviewed: Klip, Amira, 2012-08-21Edited: May, B, 2011-07-122MYO5A dimerReactome DB_ID: 9605111MYO5AMyosin-VaMYO5A_HUMANReactome DB_ID: 1428499UniProt:Q9Y4I1 MYO5AMYO5AMYH12FUNCTION 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.UniProtQ9Y4I11EQUAL1855EQUALReactome Database ID Release 711428499Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1428499ReactomeR-HSA-14284991Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1428499.12Reactome Database ID Release 719605111Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605111ReactomeR-HSA-96051111Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605111.12p-S1652-MYO5A dimerReactome DB_ID: 9605106MYO5A_HUMANp-S1652-MYO5AMYO5A (pSer1652)Myosin-Va (pSer1652)Reactome DB_ID: 14496061652EQUAL1EQUAL1855EQUALReactome Database ID Release 711449606Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449606ReactomeR-HSA-14496061Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449606.12Reactome Database ID Release 719605106Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605106ReactomeR-HSA-96051061Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605106.1ACTIVATIONReactome Database ID Release 711445142Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445142Reactome Database ID Release 711449597Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449597ReactomeR-HSA-14495973Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449597.3LEFT-TO-RIGHT2.7.11p-AKT2 phosphorylates RGC2As 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, 2011-07-17Reviewed: Klip, Amira, 2012-08-21Edited: May, B, 2011-07-173RGC1:RGC2RALGAPB:RALGAPA2Reactome DB_ID: 1458509RGC1RALGAPBRal GTPase-activating protein subunit betaRLGPB_HUMANReactome DB_ID: 1458461UniProt:Q86X10 RALGAPBRALGAPBKIAA1219FUNCTION 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.UniProtQ86X101EQUAL1494EQUALReactome Database ID Release 711458461Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458461ReactomeR-HSA-14584611Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458461.11RGC2RALGAPA2Ral GTPase-activating protein subunit alpha-2RGPA2_HUMANReactome DB_ID: 1458508UniProt:Q2PPJ7 RALGAPA2RALGAPA2C20orf74KIAA1272FUNCTION 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).UniProtQ2PPJ71EQUAL1873EQUALReactome Database ID Release 711458508Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458508ReactomeR-HSA-14585081Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458508.11Reactome Database ID Release 711458509Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458509ReactomeR-HSA-14585091Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458509.13RGC1:phospho-RGC2RGC1:p-486,696-T715-RGC2RALGAPB:pSer486,696,pThr715-RALGAPA2Reactome DB_ID: 1458472RGPA2_HUMANp-S486,S696,T715-RALGAPA2p-S486,696-T715-RALGAPA2p-S486,696-T715-RGC2pSer486,696,pThr715-RALGAPA2Ral GTPase-activating protein subunit alpha-2Reactome DB_ID: 1458477486EQUAL696EQUAL715EQUAL1EQUAL1873EQUALReactome Database ID Release 711458477Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458477ReactomeR-HSA-14584771Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458477.111Reactome Database ID Release 711458472Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458472ReactomeR-HSA-14584721Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458472.1ACTIVATIONReactome Database ID Release 711458463Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458463ReactomeR-HSA-14584632Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458463.2LEFT-TO-RIGHTActivation of RALARALA exchanges GDP for GTPRALA 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, 2012-05-16Reviewed: Klip, Amira, 2012-08-21Edited: May, B, 2012-05-16GGC-RALA:GDPReactome DB_ID: 14584661GGC-RALARas-related protein Ral-ARALA_HUMANReactome DB_ID: 1458479UniProt:P11233 RALARALARALFUNCTION 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. 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).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 (PubMed:7673236). 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 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).SIMILARITY Belongs to the small GTPase superfamily. Ras family.UniProtP11233203EQUAL1EQUAL203EQUALReactome Database ID Release 711458479Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458479ReactomeR-HSA-14584792Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458479.21Reactome Database ID Release 711458466Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458466ReactomeR-HSA-14584662Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458466.2GGC-RALA:GTPReactome DB_ID: 145850611Reactome Database ID Release 711458506Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458506ReactomeR-HSA-14585062Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458506.2Reactome Database ID Release 712255342Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2255342ReactomeR-HSA-22553422Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2255342.28094051Pubmed1993Characterization of a guanine nucleotide dissociation stimulator for a ras-related GTPaseAlbright, C FGiddings, B WLiu, JVito, MWeinberg, R AEMBO J. 12:339-472550440Pubmed1989Identification of the ral and rac1 gene products, low molecular mass GTP-binding proteins from human plateletsPolakis, P GWeber, R FNevins, BDidsbury, J REvans, TSnyderman, RJ. Biol. Chem. 264:16383-9LEFT-TO-RIGHTRALA:GTP binds MYO1C:CALM1 and activates MYO1CAs 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, 2012-05-27Reviewed: Klip, Amira, 2012-08-21Edited: May, B, 2012-05-27MYO1C:CALM1Reactome DB_ID: 2316345MYO1CMyosin-IcMYO1C_HUMANReactome DB_ID: 1449619UniProt:O00159 MYO1CMYO1CFUNCTION 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.FUNCTION Isoform 3 is involved in regulation of transcription. Associated with transcriptional active ribosomal genes. Appears to cooperate with the WICH chromatin-remodeling complex to facilitate transcription. Necessary for the formation of the first phosphodiester bond during transcription initiation (By similarity).SUBUNIT Interacts with GLUT4 (By similarity). Interacts (via its IQ motifs) with CABP1 and CIB1; the interaction with CABP1 and CIB1 is calcium-dependent. Interacts (via tail domain) with PLEKHB1 (via PH domain); the interaction is not affected by the presence or absence of calcium and CALM. Interacts with POLR1A and POLR2A. Component of the B-WICH complex, at least composed of SMARCA5/SNF2H, BAZ1B/WSTF, SF3B1, DEK, MYO1C, ERCC6, MYBBP1A and DDX21. Interacts (via its IQ motifs) with CALM; this precludes interaction with YWHAB. Interacts with YWHAB; this precludes interaction with CALM. Interacts with RPS6 and actin. Interacts with LLPH (By similarity).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).UniProtO001591EQUAL1063EQUALReactome Database ID Release 711449619Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449619ReactomeR-HSA-14496191Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449619.11CALM1CalmodulinCALM_HUMANReactome DB_ID: 9016707UniProt:P0DP23 CALM1CALM1CALMCAMCAM1FUNCTION Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696).FUNCTION (Microbial infection) Required for Legionella pneumophila SidJ glutamylase 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 to 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).SUBUNIT (Microbial infection) Interacts with Rubella virus protease/methyltransferase p150.SUBUNIT (Microbial infection) Interacts with Legionella pneumophila glutamylase SidJ.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.UniProtP0DP232EQUAL149EQUALReactome Database ID Release 719016707Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9016707ReactomeR-HSA-90167071Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9016707.11Reactome Database ID Release 712316345Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316345ReactomeR-HSA-23163452Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316345.2f-actin (ADP)Reactome DB_ID: 202998Reactome Database ID Release 71202998Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202998ReactomeR-HSA-2029981Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202998.1GGC-RALA:GTP:MYO1C:Calmodulin:F-actinReactome DB_ID: 2316344111Reactome Database ID Release 712316344Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316344ReactomeR-HSA-23163443Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316344.3Reactome Database ID Release 712316349Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316349ReactomeR-HSA-23163491Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316349.1LEFT-TO-RIGHT3.6.5.43.6.5.33.6.5.23.6.5.1RALA hydrolyzes GTPRALA 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.Authored: May, B, 2011-07-17Reviewed: Klip, Amira, 2012-08-21Edited: May, B, 2011-07-17PiOrthophosphatephosphate(3-)PhosphateInorganic PhosphateReactome DB_ID: 2255331phosphate(3-) [ChEBI:18367]phosphate(3-)ChEBICHEBI:18367Reactome Database ID Release 712255331Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2255331ReactomeR-ALL-22553313Reactome stable identifier. Use this 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-2255331.3ACTIVATIONactiveUnit: #Protein38Reactome Database ID Release 711458493Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458493Reactome Database ID Release 711458485Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458485ReactomeR-HSA-14584853Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458485.38664345Pubmed1996Characterization of human platelet GTPase activating protein for the Ral GTP-binding proteinBhullar, RPSeneviratne, HDBiochim Biophys Acta 1311:181-8ACTIVATIONAs inferred from mouse, RGC1:RGC2 (RALGAPB:RALGAPA2) activate the GTPase activity of RALA (Chen et al. 2011).Reactome Database ID Release 711458520Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458520ReactomeR-HSA-14585201Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458520.121148297Pubmed2011A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin actionChen, XWLeto, DXiong, TYu, GCheng, ADecker, SSaltiel, ARMol Biol Cell 22:141-52LEFT-TO-RIGHT2.7.11p-AKT2 phosphorylates C2CD5The 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, 2014-02-07Reviewed: D'Eustachio, Peter, 2015-02-11Edited: Jassal, Bijay, 2014-02-07C2CD5:2xCa2+Reactome DB_ID: 5260209Ca2+Calciumcalcium(2+)Reactome DB_ID: 74016calcium(2+) [ChEBI:29108]calcium(2+)ChEBICHEBI:29108Reactome Database ID Release 7174016Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74016ReactomeR-ALL-740163Reactome stable identifier. Use this 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-74016.32C2CD5C2 domain-containing protein 5C2CD5_HUMANReactome DB_ID: 5216175UniProt:Q86YS7 C2CD5C2CD5CDP138KIAA0528FUNCTION 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.UniProtQ86YS71EQUAL1000EQUALReactome Database ID Release 715216175Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5216175ReactomeR-HSA-52161751Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5216175.11Reactome Database ID Release 715260209Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5260209ReactomeR-HSA-52602091Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5260209.1p-S197-C2CD5:2xCa2+Reactome DB_ID: 5260210C2CD5_HUMANp-S197-C2CD5C2 domain-containing protein 5Reactome DB_ID: 5260194197EQUAL1EQUAL1000EQUALReactome Database ID Release 715260194Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5260194ReactomeR-HSA-52601941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5260194.112Reactome Database ID Release 715260210Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5260210ReactomeR-HSA-52602101Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5260210.1ACTIVATIONReactome Database ID Release 715260201Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5260201ReactomeR-HSA-52602011Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5260201.121907143Pubmed2011C2 domain-containing phosphoprotein CDP138 regulates GLUT4 insertion into the plasma membraneXie, XiangyangGong, ZhenweiMansuy-Aubert, VirginieZhou, Qiong LTatulian, Suren ASehrt, DanielGnad, FlorianBrill, Laurence MMotamedchaboki, KhaterehChen, YuCzech, Michael PMann, MatthiasKrüger, MarcusJiang, Zhen YCell Metab. 14:378-89LEFT-TO-RIGHTSLC2A4 (GLUT4) vesicle translocates and docks at the plasma membraneAs 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.Authored: May, B, 2012-05-27Reviewed: Klip, Amira, 2012-08-21Edited: May, B, 2012-05-27Exocyst ComplexReactome DB_ID: 264974EXOC8Reactome DB_ID: 264948UniProt:Q8IYI6 EXOC8EXOC8FUNCTION 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.UniProtQ8IYI61EQUAL725EQUALReactome Database ID Release 71264948Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=264948ReactomeR-HSA-2649481Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-264948.11EXOC1Reactome DB_ID: 2872284UniProt:Q9NV70 EXOC1EXOC1SEC3SEC3L1BM-012FUNCTION 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).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.UniProtQ9NV702EQUAL894EQUALReactome Database ID Release 712872284Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2872284ReactomeR-HSA-28722841Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2872284.11EXOC4Reactome DB_ID: 264989UniProt:Q96A65 EXOC4EXOC4KIAA1699SEC8SEC8L1FUNCTION 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. 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).SIMILARITY Belongs to the SEC8 family.UniProtQ96A652EQUAL974EQUALReactome Database ID Release 71264989Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=264989ReactomeR-HSA-2649891Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-264989.11EXOC5Reactome DB_ID: 265045UniProt:O00471 EXOC5EXOC5SEC10SEC10L1FUNCTION 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.UniProtO004711EQUAL708EQUALReactome Database ID Release 71265045Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265045ReactomeR-HSA-2650451Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-265045.11EXOC7Reactome DB_ID: 2872288UniProt:Q9UPT5 EXOC7EXOC7EXO70KIAA1067FUNCTION 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).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).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.UniProtQ9UPT51EQUAL735EQUALReactome Database ID Release 712872288Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2872288ReactomeR-HSA-28722881Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2872288.11EXOC2Reactome DB_ID: 264887UniProt:Q96KP1 EXOC2EXOC2SEC5SEC5L1FUNCTION 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).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.UniProtQ96KP11EQUAL924EQUALReactome Database ID Release 71264887Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=264887ReactomeR-HSA-2648871Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-264887.11EXOC3Reactome DB_ID: 2872286secretory granule membraneGENE ONTOLOGYGO:0030667UniProt:O60645 EXOC3EXOC3SEC6SEC6L1FUNCTION 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).TISSUE SPECIFICITY Expressed in epididymis (at protein level).SIMILARITY Belongs to the SEC6 family.UniProtO606451EQUAL756EQUALReactome Database ID Release 712872286Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2872286ReactomeR-HSA-28722861Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2872286.11EXOC6Reactome DB_ID: 265041UniProt:Q8TAG9 EXOC6EXOC6SEC15ASEC15LSEC15L1FUNCTION 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.UniProtQ8TAG91EQUAL804EQUALReactome Database ID Release 71265041Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265041ReactomeR-HSA-2650411Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-265041.11Reactome Database ID Release 71264974Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=264974ReactomeR-HSA-2649742Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-264974.2GGC-RALA:GTP:MYO1C:ExocystReactome DB_ID: 231634311Reactome Database ID Release 712316343Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316343ReactomeR-HSA-23163433Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316343.3ACTIVATIONactiveUnit: #Protein34GENE ONTOLOGYGO:0000146Reactome Database ID Release 711449577Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449577ACTIVATIONactiveUnit: #Protein39Reactome Database ID Release 711449634Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449634Reactome Database ID Release 712316352Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316352ReactomeR-HSA-23163525Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316352.5ACTIVATIONAs 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.Reactome Database ID Release 711458528Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458528ReactomeR-HSA-14585282Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458528.212134080Pubmed2002GLUT4 retention in adipocytes requires two intracellular insulin-regulated transport stepsZeigerer, ALampson, MAKarylowski, OSabatini, DDAdesnik, MRen, MMcGraw, TEMol Biol Cell 13:2421-3515866422Pubmed2005Functional role of Rab11 in GLUT4 trafficking in cardiomyocytesUhlig, MPasslack, WEckel, JMol Cell Endocrinol 235:1-9GGC-RAB11A:GTPReactome DB_ID: 1458542GGC-RAB11ARas-related protein Rab-11ARB11A_HUMANReactome DB_ID: 1458519UniProt:P62491 RAB11ARAB11ARAB11FUNCTION 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 RIP11 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 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).SIMILARITY Belongs to the small GTPase superfamily. Rab family.UniProtP62491212EQUAL213EQUAL2EQUAL213EQUALReactome Database ID Release 711458519Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458519ReactomeR-HSA-14585192Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458519.211Reactome Database ID Release 711458542Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458542ReactomeR-HSA-14585422Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458542.2ACTIVATIONAs inferred from mouse, TC10 participates in the translocation and docking of GLUT4 (SLC2A4) vesicles at the plasma membrane (Chang et al. 2007).Reactome Database ID Release 712316462Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316462ReactomeR-HSA-23164622Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316462.217008399Pubmed2007TC10alpha is required for insulin-stimulated glucose uptake in adipocytesChang, LouiseChiang, Shian-HueySaltiel, AREndocrinology 148:27-33RHOQ:GTPTC10:GTPReactome DB_ID: 2316453RHOQTC10RhoQReactome DB_ID: 194879UniProt:P17081 RHOQRHOQARHQRASL7ATC10FUNCTION 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.UniProtP170811EQUAL202EQUALReactome Database ID Release 71194879Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194879ReactomeR-HSA-1948791Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194879.111Reactome Database ID Release 712316453Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316453ReactomeR-HSA-23164531Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316453.1ACTIVATIONReactome Database ID Release 719036998Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9036998ReactomeR-HSA-90369981Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9036998.128011197Pubmed2017Septin 7 reduces nonmuscle myosin IIA activity in the SNAP23 complex and hinders GLUT4 storage vesicle docking and fusionWasik, Anita ADumont, VincentTienari, JukkaNyman, Tuula AFogarty, Christopher LForsblom, CarolLehto, MarkkuLehtonen, EeroGroop, Per-HenrikLehtonen, SannaExp. Cell Res. 350:336-348MYH9Myosin-9MYH9_HUMANReactome DB_ID: 419173UniProt:P35579 MYH9MYH9FUNCTION Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping. During cell spreading, plays an important role in cytoskeleton reorganization, focal contacts formation (in the margins but not the central part of spreading cells), and lamellipodial retraction; this function is mechanically antagonized by MYH10.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 SLC6A4 (By similarity). Interacts with PDLIM2 (By similarity). Interacts with SVIL (PubMed:12917436, PubMed:17925381). Interacts with HTRA3 (PubMed:22229724). Interacts with Myo7a (By similarity). Interacts with C9orf135 (PubMed:28345668). Interacts with LIMCH1; independently of the integration of MYH9 into the myosin complex (PubMed:28228547). Interacts with RAB3A (PubMed:27325790).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.UniProtP355792EQUAL1960EQUALReactome Database ID Release 71419173Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419173ReactomeR-HSA-4191731Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419173.1ACTIVATIONAs 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.Reactome Database ID Release 711458572Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458572ReactomeR-HSA-14585722Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458572.218701652Pubmed2008Muscle cells engage Rab8A and myosin Vb in insulin-dependent GLUT4 translocationIshikura, SKlip, AAm J Physiol Cell Physiol 295:C1016-2517403373Pubmed2007Rab10, a target of the AS160 Rab GAP, is required for insulin-stimulated translocation of GLUT4 to the adipocyte plasma membraneSano, HEguez, LTeruel, MNFukuda, MChuang, TDChavez, JALienhard, GEMcGraw, TECell Metab 5:293-30317208202Pubmed2007Rabs 8A and 14 are targets of the insulin-regulated Rab-GAP AS160 regulating GLUT4 traffic in muscle cellsIshikura, SBilan, PJKlip, ABiochem Biophys Res Commun 353:1074-9ACTIVATIONReactome Database ID Release 715358685Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5358685ReactomeR-HSA-53586852Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5358685.2ACTIVATIONAs 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.Reactome Database ID Release 711458541Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1458541ReactomeR-HSA-14585413Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1458541.318482007Pubmed2008Activation of the small GTPase Rac1 by a specific guanine-nucleotide-exchange factor suffices to induce glucose uptake into skeletal-muscle cellsUeda, ShujiKataoka, TohruSatoh, TakayaBiol. Cell 100:645-5720203090Pubmed2010Crucial role of the small GTPase Rac1 in insulin-stimulated translocation of glucose transporter 4 to the mouse skeletal muscle sarcolemmaUeda, SKitazawa, SIshida, KNishikawa, YMatsui, MMatsumoto, HAoki, TNozaki, STakeda, TTamori, YAiba, AKahn, CRKataoka, TSatoh, TFASEB J 24:2254-6120739464Pubmed2010Arp2/3- and cofilin-coordinated actin dynamics is required for insulin-mediated GLUT4 translocation to the surface of muscle cellsChiu, Tim TingPatel, NishShaw, Alisa EBamburg, James RKlip, AmiraMol. Biol. Cell 21:3529-39RAC1:GTPReactome DB_ID: 2172891RAC1GGC-PalmC-RAC1Ras-related C3 botulinum toxin substrate 1RAC1_HUMANReactome DB_ID: 2316446UniProt:P63000 RAC1RAC1TC25MIG5FUNCTION 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 synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3.FUNCTION Isoform B has an accelerated GEF-independent GDP/GTP exchange and an impaired GTP hydrolysis, which is restored partially by GTPase-activating proteins. It is able to bind to the GTPase-binding domain of PAK but not full-length PAK in a GTP-dependent manner, suggesting that the insertion does not completely abolish effector interaction.ACTIVITY REGULATION Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. GTP hydrolysis is stimulated by ARHGAP30.SUBUNIT Interacts with NISCH. Interacts with PIP5K1A. Interacts with the GTP-bound form of RAB7A. Interacts with SRGAP2. Interacts with CYFIP1/SRA-1. Interacts with PLXNB3. Interacts with ARHGDIA; the interaction is induced by SEMA5A, mediated through PLXNB3 and inactivates and stabilizes RAC1. Interacts (GTP-bound form preferentially) with PKN2 (via the REM repeats); the interaction stimulates autophosphorylation and phosphorylation of PKN2. Interacts with the GEF proteins PREX1, RASGRF2, FARP1, FARP2, DOCK1, DOCK2 and DOCK7, which promote the exchange between GDP and GTP, and therefore activate it. Interacts with PARD6A, PARD6B and PARD6G in a GTP-dependent manner. Part of a quaternary complex containing PARD3, some PARD6 protein (PARD6A, PARD6B or PARD6G) and some atypical PKC protein (PRKCI or PRKCZ), which plays a central role in epithelial cell polarization. Found in a trimeric complex composed of DOCK1 and ELMO1, which plays a central role in phagocytosis of apoptotic cells. Interacts with RALBP1 via its effector domain. Interacts with PLXNB1. Probably found in a ternary complex composed of DSCAM, PAK1 and RAC1. Interacts with DSCAM; the interaction requires PAK1. Part of a complex with MAP2K3, MAP3K3, CCM2 and DEF6. Interacts with BAIAP2, BAIAP2L1 and DEF6. Interacts with Y.pseudotuberculosis YPKA and PLCB2. Interacts with NOXA1. Interacts with ARHGEF2. Interacts with TBC1D2. Interacts with UNKL. Interacts with USP6. Interacts with SPATA13. Interacts with ARHGEF16; mediates activation of RAC1 by EPHA2. Interacts with ITGB4. Interacts with S100A8 and calprotectin (S100A8/9). Interacts with PACSIN2. Interacts with ITGB1BP1. Interacts (when active) with PPP5C (via TPR repeats); activates PPP5C phosphatase activity and translocates PPP5C to the cell membrane. Interacts with RAPH1 (via Ras associating and PH domains) (PubMed:18499456). Interacts with MTSS2 (via IMD domain); this interaction may be important to potentiate PDGF-induced RAC1 activation (PubMed:20875796). Interacts with PAK2 (PubMed:20696164). Interacts (GTP-bound form) with SH3RF1 and SH3RF3 (PubMed:20696164). Found in a complex with SH3RF1, MAPK8IP1/JIP1, MAP3K11/MLK3, MAP2K7/MKK7 and MAPK8/JNK1. Interacts (both active GTP- or inactive GDP-bound forms) with SH3RF2 (By similarity).TISSUE SPECIFICITY Isoform B is predominantly identified in skin and epithelial tissues from the intestinal tract. Its expression is elevated in colorectal tumors at various stages of neoplastic progression, as compared to their respective adjacent tissues.DOMAIN The effector region mediates interaction with DEF6.PTM (Microbial infection) AMPylation at Tyr-32 and Thr-35 are mediated by bacterial enzymes in case of infection by H.somnus and V.parahaemolyticus, respectively. AMPylation occurs in the effector region and leads to inactivation of the GTPase activity by preventing the interaction with downstream effectors, thereby inhibiting actin assembly in infected cells. It is unclear whether some human enzyme mediates AMPylation; FICD has such ability in vitro but additional experiments remain to be done to confirm results in vivo.PTM GTP-bound active form is ubiquitinated by HACE1, leading to its degradation by the proteasome.PTM (Microbial infection) Glycosylated at Tyr-32 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rac and leads to actin disassembly.SIMILARITY Belongs to the small GTPase superfamily. Rho family.UniProtP63000178EQUALS-palmitoyl-L-cysteineMODMOD:00115189EQUAL1EQUAL189EQUALReactome Database ID Release 712316446Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316446ReactomeR-HSA-23164461Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316446.11Reactome Database ID Release 71217289Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=217289ReactomeR-HSA-2172893Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-217289.3LEFT-TO-RIGHTSLC2A4 (GLUT4) vesicle fuses with the plasma membraneAfter 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, 2011-07-12Reviewed: Klip, Amira, 2012-08-21Edited: May, B, 2011-07-12STX4:STXBP3 (MUNC18C)Reactome DB_ID: 2263479STX4Syntaxin 4Reactome DB_ID: 181519UniProt:Q12846 STX4STX4STX4AFUNCTION Plasma membrane t-SNARE that mediates docking of transport vesicles. Necessary for the translocation of SLC2A4 from intracellular vesicles to the plasma membrane. Together with STXB3 and VAMP2, may also play a role in docking/fusion of intracellular GLUT4-containing vesicles with the cell surface in adipocytes (By similarity). May also play a role in docking of synaptic vesicles at presynaptic active zones.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.UniProtQ128461EQUAL297EQUALReactome Database ID Release 71181519Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181519ReactomeR-HSA-1815191Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181519.11STXBP3STXBP3 (MUNC18C)Syntaxin-binding protein 3STXB3_HUMANReactome DB_ID: 2263473UniProt:O00186 STXBP3STXBP3FUNCTION 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.UniProtO001861EQUAL592EQUALReactome Database ID Release 712263473Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2263473ReactomeR-HSA-22634731Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2263473.11Reactome Database ID Release 712263479Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2263479ReactomeR-HSA-22634791Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2263479.1GLUT4:TUGSLC2A4:ASPSCR1Reactome DB_ID: 1449566GLUT4SLC2A4Solute carrier family 2, facilitated glucose transporter member 4GTR4_HUMANReactome DB_ID: 1449565UniProt:P14672 SLC2A4SLC2A4GLUT4FUNCTION 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.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.UniProtP146721EQUAL509EQUALReactome Database ID Release 711449565Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449565ReactomeR-HSA-14495651Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449565.11TUGASPSCR1TUG (ASPSCR1)Tether containing UBX domain for GLUT4ASPC1_HUMANASPSCR1Reactome DB_ID: 1449582UniProt:Q9BZE9 ASPSCR1ASPSCR1ASPLRCC17TUGUBXD9UBXN9FUNCTION 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).UniProtQ9BZE91EQUAL553EQUALReactome Database ID Release 711449582Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449582ReactomeR-HSA-14495821Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449582.11Reactome Database ID Release 711449566Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449566ReactomeR-HSA-14495662Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449566.2VAMP2Vesicle-associated membrane protein 2VAMP2_HUMANReactome DB_ID: 1449630UniProt:P63027 VAMP2VAMP2SYB2FUNCTION Involved in the targeting and/or fusion of transport vesicles to their target membrane. Modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1.SUBUNIT Interacts (via N-terminus) with KCNB1 (via N-terminus and C-terminus); stimulates the channel inactivation rate of KCNB1 (By similarity). 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 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). 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).UniProtP630272EQUAL116EQUALReactome Database ID Release 711449630Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449630ReactomeR-HSA-14496301Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449630.1SNAP23Synaptosomal-associated protein 23SNP23_HUMANReactome DB_ID: 376345UniProt:O00161 SNAP23SNAP23FUNCTION 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.UniProtO001611EQUAL211EQUALReactome Database ID Release 71376345Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376345ReactomeR-HSA-3763451Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376345.1GLUT4SLC2A4Solute carrier family 2, facilitated glucose transporter, member 4Glucose transporter type 4, insulin-responsiveReactome DB_ID: 703831EQUAL509EQUALReactome Database ID Release 7170383Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70383ReactomeR-HSA-703831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-70383.1VAMP2:STX4:SNAP23Reactome DB_ID: 1449628111Reactome Database ID Release 711449628Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449628ReactomeR-HSA-14496282Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449628.2STXBP3p-Y521-STXBP3p-Y521-STXBP3 (MUNC18C)Syntaxin-binding protein 3STXB3_HUMANReactome DB_ID: 2263472521EQUALO4'-phospho-L-tyrosineMODMOD:000481EQUAL592EQUALReactome Database ID Release 712263472Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2263472ReactomeR-HSA-22634721Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2263472.1Reactome Database ID Release 711449574Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1449574ReactomeR-HSA-14495742Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1449574.2Reactome Database ID Release 711445148Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445148ReactomeR-HSA-14451482Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445148.221216617Pubmed2011Signaling, cytoskeletal and membrane mechanisms regulating GLUT4 exocytosisHoffman, NJElmendorf, JSTrends Endocrinol Metab 22:110-628602209Pubmed2017Update on GLUT4 Vesicle Traffic: A Cornerstone of Insulin ActionJaldin-Fincati, Javier RPavarotti, MartinFrendo-Cumbo, ScottBilan, Philip JKlip, AmiraTrends Endocrinol. Metab. 28:597-61118570632Pubmed2008Insulin action on glucose transporters through molecular switches, tracks and tethersZaid, HAntonescu, CostinRandhawa, VKKlip, ABiochem J 413:201-1521306486Pubmed2011The sugar is sIRVed: sorting Glut4 and its fellow travelersKandror, KVPilch, PFTraffic 12:665-7121405107Pubmed2011Endocytosis, recycling, and regulated exocytosis of glucose transporter 4Foley, KBoguslavsky, SKlip, ABiochemistry 50:3048-6120417083Pubmed2010Biogenesis and regulation of insulin-responsive vesicles containing GLUT4Bogan, JSKandror, KVCurr Opin Cell Biol 22:506-1219389739Pubmed2009The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targetsLeney, SETavaré, JMJ Endocrinol 203:1-18