Translocation of SLC2A4 (GLUT4) to the plasma membrane (Homo sapiens)

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1, 13, 14, 16, 19...2922, 285, 63, 152, 4, 12, 211012, 219, 18, 22, 23, 2514-3-3 theta dimer[cytoplasmic vesiclemembrane]14-3-3 gamma dimer[cytosol]YWHAB dimer[cytoplasmic vesiclemembrane]14-3-3 sigma dimer[cytosol]RAB8A/10/13/14:GDP[cytoplasmic vesiclemembrane]RAB8A,10,13,14[cytoplasmic vesiclemembrane]14-3-3 gamma dimer[cytoplasmic vesiclemembrane]RALA:GTP[cytoplasmic vesiclemembrane]MYO1C:CALM1[cytosol]MYO1C:CALM1[cytosol]AS160:IRAP[cytoplasmic vesiclemembrane]RGC1:RGC2 [cytosol]TC10:GTP [plasmamembrane]Exocyst Complex[plasma membrane,cytosol, secretorygranule membrane]14-3-3zeta dimer[cytosol]RGC1:p-486,696-T715-RGC2[cytosol]RAB4A:GTP[cytoplasmic vesiclemembrane]RAB4A:GTP[cytoplasmic vesiclemembrane]Exocyst Complex[plasma membrane,cytosol, secretorygranule membrane]cytoplasmic membrane-bounded vesicle lumenp-S237-TBC1D1:14-3-3[cytosol]RAB11A:GTP[cytoplasmic vesiclemembrane]RALA:GDP[cytoplasmic vesiclemembrane]14-3-3zeta dimer[cytoplasmic vesiclemembrane]RALA:GTP:MYO1C:Calmodulin:F-actin[cytoplasmic vesiclemembrane, cytosol]AMPK gamma [cytosol]RALA:GTP:MYO1C:Exocyst[cytoplasmic vesiclemembrane, plasmamembrane]GLUT4:TUG[cytoplasmic vesiclemembrane]KIF3 [cytosol]14-3-3 eta dimer[cytoplasmic vesiclemembrane]14-3-3 sigma dimer[cytoplasmic vesiclemembrane]STX4:STXBP3(MUNC18C) [plasmamembrane]YWHAE dimer[cytosol]Phospho AS160:IRAP[cytoplasmic vesiclemembrane]YWHAB dimer[cytosol]RALA:GTP[cytoplasmic vesiclemembrane]PhosphoAS160:14-3-3:IRAP[cytoplasmic vesiclemembrane]14-3-3 dimer[cytosol]14-3-3 dimer[cytoplasmic vesiclemembrane]RAB8A/10/13/14:GTP[cytoplasmic vesiclemembrane]RAB4A:GTP:KIF3:microtubule[cytoplasmic vesiclemembrane, cytosol]AMPK gamma:AMP[cytosol]cytosolRAB8A,10,13,14[cytoplasmic vesiclemembrane]AMPK-alpha2:AMPK-beta:AMPK-gamma:AMP[cytosol]KIF3 [cytosol]MYO1C:CALM1[cytosol]AMPK beta [cytosol]Phospho AS160:14-3-3[cytoplasmic vesiclemembrane]14-3-3 theta dimer[cytosol]p-S1652-MYO5A:F-actin[cytosol]RAC1:GTP [plasmamembrane]VAMP2:STX4:SNAP23[plasma membrane,cytoplasmic vesiclemembrane]YWHAE dimer[cytoplasmic vesiclemembrane]RALA:GTP:MYO1C:Calmodulin:F-actin[cytoplasmic vesiclemembrane, cytosol]14-3-3 eta dimer[cytosol]RALA:GTP[cytoplasmic vesiclemembrane]ASPSCR1(2-553)[cytoplasmic vesiclemembrane]RALA:GTP:MYO1C:Calmodulin:F-actinSTXBP3 [plasmamembrane]GTP [cytoplasmicvesicle membrane]YWHAG(1-247)[cytosol]LNPEP(1-1025)[cytoplasmic vesiclemembrane]p-Y521-STXBP3KIF3A [cytosol]EXOC7 [plasmamembrane]ASPSCR1(2-553)LNPEP(1-1025)[cytoplasmic vesiclemembrane]RGC1:RGC2Exocyst ComplexRAB8A [cytoplasmicvesicle membrane]RALA [cytoplasmicvesicle membrane]SLC2A4RGC1:p-486,696-T715-RGC214-3-3 dimerYWHAZ [cytoplasmicvesicle membrane]AS160:IRAPSTX4 [plasmamembrane]PRKAB2 [cytosol]RAC1:GTPPRKAG1 [cytosol]GTPSTX4 [plasmamembrane]RALGAPB [cytosol]MYH4VAMP2:STX4:SNAP23YWHAB(1-246)[cytoplasmic vesiclemembrane]YWHAQ [cytoplasmicvesicle membrane]GTP [cytoplasmicvesicle membrane]GDP [cytoplasmicvesicle membrane]EXOC4 [plasmamembrane]PiYWHAG(1-247)[cytoplasmic vesiclemembrane]RALA:GDPSNAP23GTP [plasmamembrane]p-5S,T642-TBC1D4[cytoplasmic vesiclemembrane]KIFAP3 [cytosol]RAB8A/10/13/14:GTPGDPRALA [cytoplasmicvesicle membrane]p-5S,T642-TBC1D4[cytoplasmic vesiclemembrane]RALA:GTP:MYO1C:ExocystKIFAP3 [cytosol]14-3-3 dimerCALM1 [cytosol]RAB13 [cytoplasmicvesicle membrane]RAB11A:GTPADPMYO5AVAMP2p-T172-PRKAA2[cytosol]TBC1D4GTPYWHAE [cytoplasmicvesicle membrane]ATPMYO1C [cytosol]p-S237-TBC1D1ADPRAB11A [cytoplasmicvesicle membrane]STX4:STXBP3(MUNC18C)MYO1C [cytosol]RAB4A(1-213)[cytoplasmic vesiclemembrane]CALM1 [cytosol]CALM1 [cytosol]LNPEP(1-1025)[cytoplasmic vesiclemembrane]RAB14 [cytoplasmicvesicle membrane]microtubuleRAB10 [cytoplasmicvesicle membrane]TC10:GTPGDPKIF3B [cytosol]RALA [cytoplasmicvesicle membrane]EXOC6 [plasmamembrane]EXOC6 [plasmamembrane]SFN [cytoplasmicvesicle membrane]RALA:GTPYWHAQ [cytosol]VAMP2 [cytoplasmicvesicle membrane]GTP [plasmamembrane]RHOQ [plasmamembrane]PhosphoAS160:14-3-3:IRAPRALGAPB [cytosol]ATPp-S1652-MYO5A:F-actinRALGAPA2 [cytosol]GLUT4:TUGTBC1D1MYH2p-S237-TBC1D1[cytosol]GTP [cytoplasmicvesicle membrane]RAB10 [cytoplasmicvesicle membrane]RAB4A:GTPYWHAB(1-246)[cytosol]GTP [cytoplasmicvesicle membrane]SNAP23 [plasmamembrane]MYO1C [cytosol]ADPKIF3SFN [cytosol]EXOC3 [secretorygranule membrane]PRKAG3 [cytosol]TBC1D4 [cytoplasmicvesicle membrane]p-T309,S474-AKT2KIF3B [cytosol]YWHAH [cytosol]YWHAE [cytosol]KIF3A [cytosol]f-actin (ADP)ADPEXOC3 [secretorygranule membrane]EXOC5 [cytosol]EXOC2 [plasmamembrane]RAB13 [cytoplasmicvesicle membrane]RAB8A/10/13/14:GDPYWHAZ [cytosol]YWHAH [cytoplasmicvesicle membrane]GTP [cytoplasmicvesicle membrane]RAB4A(1-213)[cytoplasmic vesiclemembrane]EXOC1 [plasmamembrane]SLC2A4 [cytoplasmicvesicle membrane]EXOC8 [plasmamembrane]EXOC7 [plasmamembrane]Phospho AS160:IRAPRAB14 [cytoplasmicvesicle membrane]p-S486,S696,T715-RALGAPA2[cytosol]RALA [cytoplasmicvesicle membrane]PRKAB1(2-270)[cytosol]RAB8A [cytoplasmicvesicle membrane]EXOC4 [plasmamembrane]AMP [cytosol]EXOC2 [plasmamembrane]p-S237-TBC1D1:14-3-3GDP [cytoplasmicvesicle membrane]MYO1C:CALM1EXOC8 [plasmamembrane]ATPEXOC5 [cytosol]RAB4A:GTP:KIF3:microtubuleAMPK-alpha2:AMPK-beta:AMPK-gamma:AMPEXOC1 [plasmamembrane]GTP [cytoplasmicvesicle membrane]p-T308,S473-AKT1GGC-PalmC-RAC1[plasma membrane]ATPADPGTP [cytoplasmicvesicle membrane]PRKAG2 [cytosol]ATPp-S1652-MYO5A[cytosol]4, 21232, 2120, 274, 2178, 11, 242717


Description

In adipocytes and myocytes insulin signaling causes intracellular vesicles carrying the GLUT4 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). In myocytes muscle contraction alone can also cause translocation of GLUT4.
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.
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.Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1445148

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Bibliography

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  1. Bogan JS, Kandror KV.; ''Biogenesis and regulation of insulin-responsive vesicles containing GLUT4.''; PubMed Europe PMC Scholia
  2. Ramm G, Larance M, Guilhaus M, James DE.; ''A role for 14-3-3 in insulin-stimulated GLUT4 translocation through its interaction with the RabGAP AS160.''; PubMed Europe PMC Scholia
  3. Mîinea CP, Sano H, Kane S, Sano E, Fukuda M, Peränen J, Lane WS, Lienhard GE.; ''AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain.''; PubMed Europe PMC Scholia
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  5. Koumanov F, Richardson JD, Murrow BA, Holman GD.; ''AS160 phosphotyrosine-binding domain constructs inhibit insulin-stimulated GLUT4 vesicle fusion with the plasma membrane.''; PubMed Europe PMC Scholia
  6. Karlsson HK, Zierath JR, Kane S, Krook A, Lienhard GE, Wallberg-Henriksson H.; ''Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects.''; PubMed Europe PMC Scholia
  7. Leney SE, Tavaré JM.; ''The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targets.''; PubMed Europe PMC Scholia
  8. Polakis PG, Weber RF, Nevins B, Didsbury JR, Evans T, Snyderman R.; ''Identification of the ral and rac1 gene products, low molecular mass GTP-binding proteins from human platelets.''; PubMed Europe PMC Scholia
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  11. Xie X, Gong Z, Mansuy-Aubert V, Zhou QL, Tatulian SA, Sehrt D, Gnad F, Brill LM, Motamedchaboki K, Chen Y, Czech MP, Mann M, Krüger M, Jiang ZY.; ''C2 domain-containing phosphoprotein CDP138 regulates GLUT4 insertion into the plasma membrane.''; PubMed Europe PMC Scholia
  12. Ngo S, Barry JB, Nisbet JC, Prins JB, Whitehead JP.; ''Reduced phosphorylation of AS160 contributes to glucocorticoid-mediated inhibition of glucose uptake in human and murine adipocytes.''; PubMed Europe PMC Scholia
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  15. Foley K, Boguslavsky S, Klip A.; ''Endocytosis, recycling, and regulated exocytosis of glucose transporter 4.''; PubMed Europe PMC Scholia
  16. Kandror KV, Pilch PF.; ''The sugar is sIRVed: sorting Glut4 and its fellow travelers.''; PubMed Europe PMC Scholia
  17. Jaldin-Fincati JR, Pavarotti M, Frendo-Cumbo S, Bilan PJ, Klip A.; ''Update on GLUT4 Vesicle Traffic: A Cornerstone of Insulin Action.''; PubMed Europe PMC Scholia
  18. Syed NA, Horner KN, Misra V, Khandelwal RL.; ''Different cellular localization, translocation, and insulin-induced phosphorylation of PKBalpha in HepG2 cells and hepatocytes.''; PubMed Europe PMC Scholia
  19. Zaid H, Antonescu CN, Randhawa VK, Klip A.; ''Insulin action on glucose transporters through molecular switches, tracks and tethers.''; PubMed Europe PMC Scholia
  20. Hoffman NJ, Elmendorf JS.; ''Signaling, cytoskeletal and membrane mechanisms regulating GLUT4 exocytosis.''; PubMed Europe PMC Scholia
  21. Howlett KF, Sakamoto K, Garnham A, Cameron-Smith D, Hargreaves M.; ''Resistance exercise and insulin regulate AS160 and interaction with 14-3-3 in human skeletal muscle.''; PubMed Europe PMC Scholia
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  24. Meier R, Alessi DR, Cron P, Andjelković M, Hemmings BA.; ''Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta.''; PubMed Europe PMC Scholia
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  26. Andjelković M, Alessi DR, Meier R, Fernandez A, Lamb NJ, Frech M, Cron P, Cohen P, Lucocq JM, Hemmings BA.; ''Role of translocation in the activation and function of protein kinase B.''; PubMed Europe PMC Scholia
  27. Treebak JT, Frøsig C, Pehmøller C, Chen S, Maarbjerg SJ, Brandt N, MacKintosh C, Zierath JR, Hardie DG, Kiens B, Richter EA, Pilegaard H, Wojtaszewski JF.; ''Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle.''; PubMed Europe PMC Scholia
  28. Bhullar RP, Seneviratne HD.; ''Characterization of human platelet GTPase activating protein for the Ral GTP-binding protein.''; PubMed Europe PMC Scholia
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  30. Park SY, Jin W, Woo JR, Shoelson SE.; ''Crystal structures of human TBC1D1 and TBC1D4 (AS160) RabGTPase-activating protein (RabGAP) domains reveal critical elements for GLUT4 translocation.''; PubMed Europe PMC Scholia
  31. Andjelković M, Maira SM, Cron P, Parker PJ, Hemmings BA.; ''Domain swapping used to investigate the mechanism of protein kinase B regulation by 3-phosphoinositide-dependent protein kinase 1 and Ser473 kinase.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
115083view17:03, 25 January 2021ReactomeTeamReactome version 75
113525view12:00, 2 November 2020ReactomeTeamReactome version 74
112724view16:12, 9 October 2020ReactomeTeamReactome version 73
101640view11:50, 1 November 2018ReactomeTeamreactome version 66
101176view21:37, 31 October 2018ReactomeTeamreactome version 65
100702view20:10, 31 October 2018ReactomeTeamreactome version 64
100252view16:55, 31 October 2018ReactomeTeamreactome version 63
99804view15:19, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99352view12:48, 31 October 2018ReactomeTeamreactome version 62
94027view13:52, 16 August 2017ReactomeTeamreactome version 61
93648view11:29, 9 August 2017ReactomeTeamreactome version 61
88359view16:37, 1 August 2016FehrhartOntology Term : 'pathway pertinent to protein folding, sorting, modification, translocation and degradation' added !
86764view09:25, 11 July 2016ReactomeTeamreactome version 56
83070view09:51, 18 November 2015ReactomeTeamVersion54
81775view10:34, 26 August 2015ReactomeTeamVersion53
77058view08:35, 17 July 2014ReactomeTeamFixed remaining interactions
76763view12:12, 16 July 2014ReactomeTeamFixed remaining interactions
76087view10:15, 11 June 2014ReactomeTeamRe-fixing comment source
75798view11:33, 10 June 2014ReactomeTeamReactome 48 Update
75149view14:09, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74796view08:53, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
14-3-3 dimerProteinREACT_147925 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AMP [cytosol]MetaboliteCHEBI:16027 (ChEBI)
AMPK-alpha2:AMPK-beta:AMPK-gamma:AMPComplexREACT_148254 (Reactome)
AS160:IRAPComplexREACT_148263 (Reactome)
ASPSCR1(2-553)

[cytoplasmic vesicle

membrane]		ProteinQ9BZE9 (Uniprot-TrEMBL)
ASPSCR1(2-553)ProteinQ9BZE9 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
CALM1 [cytosol]ProteinP62158 (Uniprot-TrEMBL)
EXOC1 [plasma membrane]ProteinQ9NV70 (Uniprot-TrEMBL)
EXOC2 [plasma membrane]ProteinQ96KP1 (Uniprot-TrEMBL)
EXOC3 [secretory granule membrane]ProteinO60645 (Uniprot-TrEMBL)
EXOC4 [plasma membrane]ProteinQ96A65 (Uniprot-TrEMBL)
EXOC5 [cytosol]ProteinO00471 (Uniprot-TrEMBL)
EXOC6 [plasma membrane]ProteinQ8TAG9 (Uniprot-TrEMBL)
EXOC7 [plasma membrane]ProteinQ9UPT5 (Uniprot-TrEMBL)
EXOC8 [plasma membrane]ProteinQ8IYI6 (Uniprot-TrEMBL)
Exocyst ComplexComplexREACT_15928 (Reactome)
GDP [cytoplasmic vesicle membrane]MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GGC-PalmC-RAC1 [plasma membrane]ProteinP63000 (Uniprot-TrEMBL)
GLUT4:TUGComplexREACT_148426 (Reactome)
GTP [cytoplasmic vesicle membrane]MetaboliteCHEBI:15996 (ChEBI)
GTP [plasma membrane]MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
KIF3A [cytosol]ProteinQ9Y496 (Uniprot-TrEMBL)
KIF3B [cytosol]ProteinO15066 (Uniprot-TrEMBL)
KIF3ComplexREACT_148146 (Reactome)
KIFAP3 [cytosol]ProteinQ92845 (Uniprot-TrEMBL)
LNPEP(1-1025)

[cytoplasmic vesicle

membrane]		ProteinQ9UIQ6 (Uniprot-TrEMBL)
MYH2ProteinQ9UKX2 (Uniprot-TrEMBL)
MYH4ProteinQ9Y623 (Uniprot-TrEMBL)
MYO1C [cytosol]ProteinO00159 (Uniprot-TrEMBL)
MYO1C:CALM1ComplexREACT_148117 (Reactome)
MYO5AProteinQ9Y4I1 (Uniprot-TrEMBL)
PRKAB1(2-270) [cytosol]ProteinQ9Y478 (Uniprot-TrEMBL)
PRKAB2 [cytosol]ProteinO43741 (Uniprot-TrEMBL)
PRKAG1 [cytosol]ProteinP54619 (Uniprot-TrEMBL)
PRKAG2 [cytosol]ProteinQ9UGJ0 (Uniprot-TrEMBL)
PRKAG3 [cytosol]ProteinQ9UGI9 (Uniprot-TrEMBL)
Phospho AS160:14-3-3:IRAPComplexREACT_148392 (Reactome)
Phospho AS160:IRAPComplexREACT_147981 (Reactome) 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 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).
PiMetaboliteCHEBI:18367 (ChEBI)
RAB10 [cytoplasmic vesicle membrane]ProteinP61026 (Uniprot-TrEMBL)
RAB11A [cytoplasmic vesicle membrane]ProteinP62491 (Uniprot-TrEMBL)
RAB11A:GTPComplexREACT_120028 (Reactome)
RAB13 [cytoplasmic vesicle membrane]ProteinP51153 (Uniprot-TrEMBL)
RAB14 [cytoplasmic vesicle membrane]ProteinP61106 (Uniprot-TrEMBL)
RAB4A(1-213)

[cytoplasmic vesicle

membrane]		ProteinP20338 (Uniprot-TrEMBL)
RAB4A:GTP:KIF3:microtubuleComplexREACT_148401 (Reactome)
RAB4A:GTPComplexREACT_148449 (Reactome)
RAB8A [cytoplasmic vesicle membrane]ProteinP61006 (Uniprot-TrEMBL)
RAB8A/10/13/14:GDPComplexREACT_148262 (Reactome)
RAB8A/10/13/14:GTPComplexREACT_148450 (Reactome)
RAC1:GTPComplexREACT_148456 (Reactome)
RALA [cytoplasmic vesicle membrane]ProteinP11233 (Uniprot-TrEMBL)
RALA:GDPComplexREACT_147970 (Reactome)
RALA:GTP:MYO1C:Calmodulin:F-actinComplexREACT_148239 (Reactome)
RALA:GTP:MYO1C:ExocystComplexREACT_148060 (Reactome)
RALA:GTPComplexREACT_148153 (Reactome)
RALGAPA2 [cytosol]ProteinQ2PPJ7 (Uniprot-TrEMBL)
RALGAPB [cytosol]ProteinQ86X10 (Uniprot-TrEMBL)
RGC1:RGC2ComplexREACT_148495 (Reactome)
RGC1:p-486,696-T715-RGC2ComplexREACT_148586 (Reactome)
RHOQ [plasma membrane]ProteinP17081 (Uniprot-TrEMBL)
SFN [cytoplasmic vesicle membrane]ProteinP31947 (Uniprot-TrEMBL)
SFN [cytosol]ProteinP31947 (Uniprot-TrEMBL)
SLC2A4 [cytoplasmic vesicle membrane]ProteinP14672 (Uniprot-TrEMBL)
SLC2A4ProteinP14672 (Uniprot-TrEMBL)
SNAP23 [plasma membrane]ProteinO00161 (Uniprot-TrEMBL)
SNAP23ProteinO00161 (Uniprot-TrEMBL)
STX4 [plasma membrane]ProteinQ12846 (Uniprot-TrEMBL)
STX4:STXBP3 (MUNC18C)ComplexREACT_147908 (Reactome)
STXBP3 [plasma membrane]ProteinO00186 (Uniprot-TrEMBL)
TBC1D1ProteinQ86TI0 (Uniprot-TrEMBL) As inferred from rat L6 muscle cells, TBC1D1 is located in the perinuclear cytosol (Chen et al. 2008). TBC1D1 is observed throughout the cytosol and, based on its homology to TBC1D4 and its interaction with membrane-bound RAB proteins, TBC1D1 is expected to be concentrated near vesicle membranes.
TBC1D4 [cytoplasmic vesicle membrane]ProteinO60343 (Uniprot-TrEMBL)
TBC1D4ProteinO60343 (Uniprot-TrEMBL)
TC10:GTPComplexREACT_148007 (Reactome)
VAMP2 [cytoplasmic vesicle membrane]ProteinP63027 (Uniprot-TrEMBL)
VAMP2:STX4:SNAP23ComplexREACT_147982 (Reactome)
VAMP2ProteinP63027 (Uniprot-TrEMBL)
YWHAB(1-246)

[cytoplasmic vesicle

membrane]		ProteinP31946 (Uniprot-TrEMBL)
YWHAB(1-246) [cytosol]ProteinP31946 (Uniprot-TrEMBL)
YWHAE [cytoplasmic vesicle membrane]ProteinP62258 (Uniprot-TrEMBL)
YWHAE [cytosol]ProteinP62258 (Uniprot-TrEMBL)
YWHAG(1-247)

[cytoplasmic vesicle

membrane]		ProteinP61981 (Uniprot-TrEMBL)
YWHAG(1-247) [cytosol]ProteinP61981 (Uniprot-TrEMBL)
YWHAH [cytoplasmic vesicle membrane]ProteinQ04917 (Uniprot-TrEMBL)
YWHAH [cytosol]ProteinQ04917 (Uniprot-TrEMBL)
YWHAQ [cytoplasmic vesicle membrane]ProteinP27348 (Uniprot-TrEMBL)
YWHAQ [cytosol]ProteinP27348 (Uniprot-TrEMBL)
YWHAZ [cytoplasmic vesicle membrane]ProteinP63104 (Uniprot-TrEMBL)
YWHAZ [cytosol]ProteinP63104 (Uniprot-TrEMBL)
f-actin (ADP)REACT_148010 (Reactome)
microtubuleREACT_10446 (Reactome)
p-5S,T642-TBC1D4

[cytoplasmic vesicle

membrane]		ProteinO60343 (Uniprot-TrEMBL)
p-S1652-MYO5A [cytosol]ProteinQ9Y4I1 (Uniprot-TrEMBL)
p-S1652-MYO5A:F-actinComplexREACT_148237 (Reactome)
p-S237-TBC1D1 [cytosol]ProteinQ86TI0 (Uniprot-TrEMBL) As inferred from rat L6 muscle cells, TBC1D1 is located in the perinuclear cytosol (Chen et al. 2008). TBC1D1 is observed throughout the cytosol and, based on its homology to TBC1D4 and its interaction with membrane-bound RAB proteins, TBC1D1 is expected to be concentrated near vesicle membranes.
p-S237-TBC1D1:14-3-3ComplexREACT_148394 (Reactome)
p-S237-TBC1D1ProteinQ86TI0 (Uniprot-TrEMBL) As inferred from rat L6 muscle cells, TBC1D1 is located in the perinuclear cytosol (Chen et al. 2008). TBC1D1 is observed throughout the cytosol and, based on its homology to TBC1D4 and its interaction with membrane-bound RAB proteins, TBC1D1 is expected to be concentrated near vesicle membranes.
p-S486,S696,T715-RALGAPA2 [cytosol]ProteinQ2PPJ7 (Uniprot-TrEMBL)
p-T172-PRKAA2 [cytosol]ProteinP54646 (Uniprot-TrEMBL)
p-T308,S473-AKT1ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2ProteinP31751 (Uniprot-TrEMBL)
p-Y521-STXBP3ProteinO00186 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
14-3-3 dimerREACT_147698 (Reactome)
14-3-3 dimerREACT_147700 (Reactome)
ADPArrowREACT_147770 (Reactome)
ADPArrowREACT_147780 (Reactome)
ADPArrowREACT_147852 (Reactome)
ADPArrowREACT_147871 (Reactome)
ADPArrowREACT_147884 (Reactome)
AMPK-alpha2:AMPK-beta:AMPK-gamma:AMPmim-catalysisREACT_147871 (Reactome)
AS160:IRAPREACT_147770 (Reactome)
ASPSCR1(2-553)ArrowREACT_147780 (Reactome)
ATPREACT_147770 (Reactome)
ATPREACT_147780 (Reactome)
ATPREACT_147852 (Reactome)
ATPREACT_147871 (Reactome)
ATPREACT_147884 (Reactome)
ArrowREACT_147776 (Reactome)
Exocyst ComplexREACT_147776 (Reactome)
GDPArrowREACT_147712 (Reactome)
GDPArrowREACT_147746 (Reactome)
GLUT4:TUGREACT_147780 (Reactome)
GTPREACT_147712 (Reactome)
GTPREACT_147746 (Reactome)
KIF3REACT_147824 (Reactome)
MYH2mim-catalysisREACT_147776 (Reactome)
MYH4mim-catalysisREACT_147776 (Reactome)
MYO1C:CALM1REACT_147829 (Reactome)
MYO5AREACT_147884 (Reactome)
Phospho AS160:14-3-3:IRAPArrowREACT_147698 (Reactome)
Phospho AS160:IRAPArrowREACT_147770 (Reactome)
Phospho AS160:IRAPREACT_147698 (Reactome)
PiArrowREACT_147722 (Reactome)
RAB11A:GTPArrowREACT_147776 (Reactome)
RAB4A:GTP:KIF3:microtubuleArrowREACT_147824 (Reactome)
RAB4A:GTPREACT_147824 (Reactome)
RAB8A/10/13/14:GDPArrowREACT_147836 (Reactome)
RAB8A/10/13/14:GDPREACT_147746 (Reactome)
RAB8A/10/13/14:GTPArrowREACT_147746 (Reactome)
RAB8A/10/13/14:GTPArrowREACT_147776 (Reactome)
RAB8A/10/13/14:GTPREACT_147836 (Reactome)
RAB8A/10/13/14:GTPmim-catalysisREACT_147836 (Reactome)
RALA:GDPArrowREACT_147722 (Reactome)
RALA:GDPREACT_147712 (Reactome)
RALA:GTP:MYO1C:Calmodulin:F-actinArrowREACT_147829 (Reactome)
RALA:GTP:MYO1C:Calmodulin:F-actinREACT_147776 (Reactome)
RALA:GTP:MYO1C:Calmodulin:F-actinmim-catalysisREACT_147776 (Reactome)
RALA:GTP:MYO1C:ExocystArrowREACT_147776 (Reactome)
RALA:GTPArrowREACT_147712 (Reactome)
RALA:GTPREACT_147722 (Reactome)
RALA:GTPREACT_147829 (Reactome)
RALA:GTPmim-catalysisREACT_147722 (Reactome)
REACT_147698 (Reactome) 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 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).
REACT_147700 (Reactome) TBC1D1 phosphorylated on serine-237 binds 14-3-3 proteins in assays with yeast 14-3-3 proteins BMH1 and BMH2 (Chen et al. 2008, Frosig et al. 2010). Binding with human 14-3-3 proteins is inferred.
REACT_147712 (Reactome) RALA releases GDP and binds GTP, producing the active form of RALA. The reaction is accelerated by guanine nucleotide exchange factors (GEFs) and opposed by GTPase-activating proteins (GAPs) which enhance the conversion of RALA:GTP back to RALA:GDP by activating the GTPase activity of RALA.
REACT_147722 (Reactome) RALA is a guanine nucleotide binding protein that hydrolyzes bound GTP to yield GDP and phosphate. RGC1 and RGC2 are GAPs (GTPase-activating proteins) that activate the GTPase activity of RALA. Insulin activates AKT, which phosphorylates RGC2, inactivating the GAP activity of RGC1:RGC2 and allowing RALA:GTP to accumulate.
REACT_147746 (Reactome) RAB8A/10/13/14 release GDP and bind GTP to yield the active complex. Guanine nucleotide exchange factors (GEFs) stimulate the reaction. GTPase-activating proteins (GAPs) oppose the reaction by stimulating the intrinsic GTPase activity of the RAB proteins.
REACT_147770 (Reactome) 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.
REACT_147776 (Reactome) As inferred from mouse, GLUT4 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. Myosins 2A, 2B, 5A, and 5B contribute to translocation and are presumed to be involved in this step. 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.
REACT_147780 (Reactome) After docking at the membrane VAMP2 on the vesicle interacts with SYNTAXIN-4 and SNAP23 on the plasma membrane to catalyze fusion of the vesicle with the plasma membrane. STXBP3 (MUNC18C) bound to STX4 prevents fusion until STXBP3 is phosphorylated.
REACT_147824 (Reactome) As inferred from mouse adipocytes, insulin signals via PKC-lambda to cause Rab4 to load GTP and associate with Kif3, which then has higher affinity for microtubules. Motor activity of Kif3 along microtubules is believed to transport vesicles containing Glut4 across the cytosol to the cortical actin network.
REACT_147829 (Reactome) As inferred from mouse, insulin causes phosphorylation and inactivation of the Ral GTPase activating complex RGC, causing RALA:GTP to accumulate and associate with the unconventional myosin MYO1C. MYO1C, with calmodulin as a light chain, motors across cortical actin and interacts with the exocyst complex to tether vesicles at the plasma membrane (Chen et al. 2007).
REACT_147836 (Reactome) RAB proteins have intrinsic weak GTPase activity that is enhanced by RAB-GTPase activating proteins (RAB-GAPs, Sano et al. 2007). The GTPase activity of RAB13 is inferred from other RAB proteins. AS160 (TBC1D4) and TBC1D1 are GAPs that activate the GTPase activity of RAB8A/10/13. Insulin signaling activates AKT, which phosphorylates and inactivates AS160 and TBC1D1, allowing GTP-bound (active) RABs to accumulate.
REACT_147852 (Reactome) As inferred from mouse, AKT2 (PKB-beta) phosphorylates RBC2 (RALGAPA2) on serine-486, serine-696, and threonine-715 in response to insulin. The phosphorylation prevents RBC1:RBC2 from activating RALA GTPase and allows RALA:GTP to accumulate.
REACT_147871 (Reactome) In response to muscle contraction and insulin signaling, AMPK-alpha2 phosphorylates TBC1D1 on serine 237 and probably other residues (Frosig et al. 2010, Vichaiwong et al. 2010). As inferred from rat L6 muscle cells TBC1D1 colocalizes with perinuclear vesicles bearing GLUT4 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).
REACT_147884 (Reactome) As inferred from mouse, AKT2 phosphorylates Myosin 5A on serine-1652. The phosphorylation promotes association of Myosin 5A with actin and ATPase activity of Myosin 5A.
RGC1:RGC2ArrowREACT_147722 (Reactome)
RGC1:RGC2REACT_147852 (Reactome)
RGC1:p-486,696-T715-RGC2ArrowREACT_147852 (Reactome)
SLC2A4ArrowREACT_147780 (Reactome)
SNAP23REACT_147780 (Reactome)
STX4:STXBP3 (MUNC18C)REACT_147780 (Reactome)
TBC1D1ArrowREACT_147836 (Reactome)
TBC1D1REACT_147871 (Reactome)
TBC1D4ArrowREACT_147836 (Reactome)
VAMP2:STX4:SNAP23ArrowREACT_147780 (Reactome)
VAMP2REACT_147780 (Reactome)
f-actin (ADP)REACT_147829 (Reactome)
f-actin (ADP)REACT_147884 (Reactome)
microtubuleREACT_147824 (Reactome)
mim-catalysisREACT_147770 (Reactome)
p-S1652-MYO5A:F-actinArrowREACT_147884 (Reactome)
p-S1652-MYO5A:F-actinmim-catalysisREACT_147776 (Reactome)
p-S237-TBC1D1:14-3-3ArrowREACT_147700 (Reactome)
p-S237-TBC1D1ArrowREACT_147871 (Reactome)
p-S237-TBC1D1REACT_147700 (Reactome)
p-T308,S473-AKT1mim-catalysisREACT_147770 (Reactome)
p-T309,S474-AKT2mim-catalysisREACT_147852 (Reactome)
p-T309,S474-AKT2mim-catalysisREACT_147884 (Reactome)
p-Y521-STXBP3ArrowREACT_147780 (Reactome)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP2777"
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