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

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8, 9, 17, 18, 27...24, 31212, 226, 253, 231214, 19, 24, 311, 3, 5, 7, 1128cytosolcytoplasmic vesicle lumenKIF3B Microtubule protofilament GGC-RALA:GDPEXOC7 STX4 ADPp-S237-TBC1D1:14-3-3GGC-RAB10 p-Y521-STXBP3YWHAB YWHAG ATPRAC1:GTPRALGAPB p-S1652-MYO5A GGC-RAB8A,10,13,14:GDPCa2+ EXOC7 p-S197-C2CD5 YWHAE GGC-RAB8A LNPEP ADP14-3-3 dimerGGC-RAB14 p-S1652-MYO5A dimerp-AKT1,p-AKT2p-S237-TBC1D1 GTP PRKAG1 14-3-3 dimerGTP PRKAG3 EXOC1 AMP p-5S,T642-AS160:IRAPGGC-RAB4A YWHAQ GTP MYO5A dimerEXOC5 YWHAH PiGGC-RAB4A MYO5A RHOQ YWHAE p-5S,T642-TBC1D4 VAMP2ADPGGC-RAB10 RHOQ:GTPEXOC3 LNPEP GGC-RAB4A:GTPCa2+ YWHAQ AS160:IRAPMYO1C MYO1C LNPEP GGC-RALA:GTP:MYO1C:Calmodulin:F-actinYWHAZ SLC2A4YWHAH YWHAH YWHAE EXOC2 C2CD5 p-T309,S474-AKT2YWHAB C2CD5:2xCa2+ASPSCR1 GTP GTP GGC-RAB13 VAMP2:STX4:SNAP23GGC-RALA:GTP:MYO1C:ExocystEXOC8 YWHAQ GTP KIFAP3 p-S197-C2CD5:2xCa2+GDPKIF3A EXOC2 MYO1C:CALM1CALM1 GTPGGC-RALA GTP GTP Exocyst ComplexATPf-actin (ADP) RALGAPA2 PRKAB2 EXOC6 GGC-RALA:GTPMYH9ATPMicrotubule protofilament GGC-RAB11A SLC2A4:ASPSCR1ADPSTXBP3 VAMP2 RALGAPB YWHAB MicrotubuleATPYWHAG KIF3EXOC4 GGC-RAB8A,10,13,14:GTPATPKIF3B SFN f-actin (ADP) SFN YWHAH MYO1C TBC1D4 GGC-PalmC-RAC1 GDP GGC-RAB14 YWHAZ KIFAP3 YWHAB GGC-RAB13 YWHAE GGC-RALA GDPYWHAZ GGC-RALA GGC-RALA YWHAG GGC-RAB4A:GTP:KIF3:microtubuleCALM1 EXOC6 GTP STX4:STXBP3(MUNC18C)YWHAG SFN GGC-RAB11A:GTPKIF3A PRKAG2 PRKAB1 p-T308,S473-AKT1 p-5S,T642-AS160:14-3-3:IRAPAMPK-alpha2:AMPK-beta:AMPK-gamma:AMPADPEXOC5 p-T172-PRKAA2 TBC1D1EXOC4 GDP RGC1:RGC2YWHAZ SFN p-S486,S696,T715-RALGAPA2 ATPCALM1 EXOC3 EXOC1 ASPSCR1EXOC8 SNAP23 p-5S,T642-TBC1D4 GTPADPYWHAQ SNAP23p-S237-TBC1D1GGC-RAB8A f-actin (ADP)RGC1:p-486,696-T715-RGC2STX4 GTP SLC2A4 p-T309,S474-AKT2 15, 2614, 3110413, 16, 20426519, 3114, 31


Description

In adipocytes and myocytes insulin signaling causes intracellular vesicles carrying the GLUT4 (SLC2A4) glucose transporter to translocate to the plasma membrane, allowing the cells to take up glucose from the bloodstream (reviewed in Zaid et al. 2008, Leney and Tavare 2009, Bogan and Kandror 2010, Foley et al. 2011, Hoffman and Elmendorf 2011, Kandror and Pilch 2011, Jaldin-Fincati et al. 2017). In myocytes muscle contraction alone can also cause translocation of GLUT4.
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. View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 1445148
Reactome-version 
Reactome version: 74
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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  1. 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
  2. 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
  3. 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
  4. Meier R, Alessi DR, Cron P, Andjelković M, Hemmings BA.; ''Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta.''; PubMed Europe PMC Scholia
  5. 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
  6. Yoshimura S, Gerondopoulos A, Linford A, Rigden DJ, Barr FA.; ''Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors.''; PubMed Europe PMC Scholia
  7. 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
  8. Bogan JS, Kandror KV.; ''Biogenesis and regulation of insulin-responsive vesicles containing GLUT4.''; PubMed Europe PMC Scholia
  9. Hoffman NJ, Elmendorf JS.; ''Signaling, cytoskeletal and membrane mechanisms regulating GLUT4 exocytosis.''; PubMed Europe PMC Scholia
  10. Pessin JE, Bell GI.; ''Mammalian facilitative glucose transporter family: structure and molecular regulation.''; PubMed Europe PMC Scholia
  11. 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
  12. 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
  13. 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
  14. Vichaiwong K, Purohit S, An D, Toyoda T, Jessen N, Hirshman MF, Goodyear LJ.; ''Contraction regulates site-specific phosphorylation of TBC1D1 in skeletal muscle.''; PubMed Europe PMC Scholia
  15. Kinsella BT, Erdman RA, Maltese WA.; ''Carboxyl-terminal isoprenylation of ras-related GTP-binding proteins encoded by rac1, rac2, and ralA.''; PubMed Europe PMC Scholia
  16. 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
  17. Foley K, Boguslavsky S, Klip A.; ''Endocytosis, recycling, and regulated exocytosis of glucose transporter 4.''; PubMed Europe PMC Scholia
  18. Leney SE, Tavaré JM.; ''The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targets.''; PubMed Europe PMC Scholia
  19. 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
  20. 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
  21. Bhullar RP, Seneviratne HD.; ''Characterization of human platelet GTPase activating protein for the Ral GTP-binding protein.''; PubMed Europe PMC Scholia
  22. Albright CF, Giddings BW, Liu J, Vito M, Weinberg RA.; ''Characterization of a guanine nucleotide dissociation stimulator for a ras-related GTPase.''; PubMed Europe PMC Scholia
  23. 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
  24. Frøsig C, Pehmøller C, Birk JB, Richter EA, Wojtaszewski JF.; ''Exercise-induced TBC1D1 Ser237 phosphorylation and 14-3-3 protein binding capacity in human skeletal muscle.''; PubMed Europe PMC Scholia
  25. Murga-Zamalloa CA, Atkins SJ, Peranen J, Swaroop A, Khanna H.; ''Interaction of retinitis pigmentosa GTPase regulator (RPGR) with RAB8A GTPase: implications for cilia dysfunction and photoreceptor degeneration.''; PubMed Europe PMC Scholia
  26. Navarro-Lérida I, Sánchez-Perales S, Calvo M, Rentero C, Zheng Y, Enrich C, Del Pozo MA.; ''A palmitoylation switch mechanism regulates Rac1 function and membrane organization.''; PubMed Europe PMC Scholia
  27. Kandror KV, Pilch PF.; ''The sugar is sIRVed: sorting Glut4 and its fellow travelers.''; PubMed Europe PMC Scholia
  28. 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
  29. Zaid H, Antonescu CN, Randhawa VK, Klip A.; ''Insulin action on glucose transporters through molecular switches, tracks and tethers.''; PubMed Europe PMC Scholia
  30. 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
  31. Chen S, Murphy J, Toth R, Campbell DG, Morrice NA, Mackintosh C.; ''Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
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 dimerComplexR-HSA-1445138 (Reactome)
ADPMetaboliteCHEBI:456216 (ChEBI)
AMP MetaboliteCHEBI:16027 (ChEBI)
AMPK-alpha2:AMPK-beta:AMPK-gamma:AMPComplexR-HSA-1454683 (Reactome)
AS160:IRAPComplexR-HSA-1445125 (Reactome)
ASPSCR1 ProteinQ9BZE9 (Uniprot-TrEMBL)
ASPSCR1ProteinQ9BZE9 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:30616 (ChEBI)
C2CD5 ProteinQ86YS7 (Uniprot-TrEMBL)
C2CD5:2xCa2+ComplexR-HSA-5260209 (Reactome)
CALM1 ProteinP0DP23 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
EXOC1 ProteinQ9NV70 (Uniprot-TrEMBL)
EXOC2 ProteinQ96KP1 (Uniprot-TrEMBL)
EXOC3 ProteinO60645 (Uniprot-TrEMBL)
EXOC4 ProteinQ96A65 (Uniprot-TrEMBL)
EXOC5 ProteinO00471 (Uniprot-TrEMBL)
EXOC6 ProteinQ8TAG9 (Uniprot-TrEMBL)
EXOC7 ProteinQ9UPT5 (Uniprot-TrEMBL)
EXOC8 ProteinQ8IYI6 (Uniprot-TrEMBL)
Exocyst ComplexComplexR-HSA-264974 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GGC-PalmC-RAC1 ProteinP63000 (Uniprot-TrEMBL)
GGC-RAB10 ProteinP61026 (Uniprot-TrEMBL)
GGC-RAB11A ProteinP62491 (Uniprot-TrEMBL)
GGC-RAB11A:GTPComplexR-HSA-1458542 (Reactome)
GGC-RAB13 ProteinP51153 (Uniprot-TrEMBL)
GGC-RAB14 ProteinP61106 (Uniprot-TrEMBL)
GGC-RAB4A ProteinP20338 (Uniprot-TrEMBL)
GGC-RAB4A:GTP:KIF3:microtubuleComplexR-HSA-1458522 (Reactome)
GGC-RAB4A:GTPComplexR-HSA-1458538 (Reactome)
GGC-RAB8A ProteinP61006 (Uniprot-TrEMBL)
GGC-RAB8A,10,13,14:GDPComplexR-HSA-1445130 (Reactome)
GGC-RAB8A,10,13,14:GTPComplexR-HSA-1445137 (Reactome)
GGC-RALA ProteinP11233 (Uniprot-TrEMBL)
GGC-RALA:GDPComplexR-HSA-1458466 (Reactome)
GGC-RALA:GTP:MYO1C:Calmodulin:F-actinComplexR-HSA-2316344 (Reactome)
GGC-RALA:GTP:MYO1C:ExocystComplexR-HSA-2316343 (Reactome)
GGC-RALA:GTPComplexR-HSA-1458506 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
KIF3A ProteinQ9Y496 (Uniprot-TrEMBL)
KIF3B ProteinO15066 (Uniprot-TrEMBL)
KIF3ComplexR-HSA-2316334 (Reactome)
KIFAP3 ProteinQ92845 (Uniprot-TrEMBL)
LNPEP ProteinQ9UIQ6 (Uniprot-TrEMBL)
MYH9ProteinP35579 (Uniprot-TrEMBL)
MYO1C ProteinO00159 (Uniprot-TrEMBL)
MYO1C:CALM1ComplexR-HSA-2316345 (Reactome)
MYO5A ProteinQ9Y4I1 (Uniprot-TrEMBL)
MYO5A dimerComplexR-HSA-9605111 (Reactome)
Microtubule protofilament R-HSA-8982424 (Reactome)
MicrotubuleComplexR-HSA-190599 (Reactome)
PRKAB1 ProteinQ9Y478 (Uniprot-TrEMBL)
PRKAB2 ProteinO43741 (Uniprot-TrEMBL)
PRKAG1 ProteinP54619 (Uniprot-TrEMBL)
PRKAG2 ProteinQ9UGJ0 (Uniprot-TrEMBL)
PRKAG3 ProteinQ9UGI9 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:43474 (ChEBI)
RAC1:GTPComplexR-HSA-217289 (Reactome)
RALGAPA2 ProteinQ2PPJ7 (Uniprot-TrEMBL)
RALGAPB ProteinQ86X10 (Uniprot-TrEMBL)
RGC1:RGC2ComplexR-HSA-1458509 (Reactome)
RGC1:p-486,696-T715-RGC2ComplexR-HSA-1458472 (Reactome)
RHOQ ProteinP17081 (Uniprot-TrEMBL)
RHOQ:GTPComplexR-HSA-2316453 (Reactome)
SFN ProteinP31947 (Uniprot-TrEMBL)
SLC2A4 ProteinP14672 (Uniprot-TrEMBL)
SLC2A4:ASPSCR1ComplexR-HSA-1449566 (Reactome)
SLC2A4ProteinP14672 (Uniprot-TrEMBL)
SNAP23 ProteinO00161 (Uniprot-TrEMBL)
SNAP23ProteinO00161 (Uniprot-TrEMBL)
STX4 ProteinQ12846 (Uniprot-TrEMBL)
STX4:STXBP3 (MUNC18C)ComplexR-HSA-2263479 (Reactome)
STXBP3 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 ProteinO60343 (Uniprot-TrEMBL)
VAMP2 ProteinP63027 (Uniprot-TrEMBL)
VAMP2:STX4:SNAP23ComplexR-HSA-1449628 (Reactome)
VAMP2ProteinP63027 (Uniprot-TrEMBL)
YWHAB ProteinP31946 (Uniprot-TrEMBL)
YWHAE ProteinP62258 (Uniprot-TrEMBL)
YWHAG ProteinP61981 (Uniprot-TrEMBL)
YWHAH ProteinQ04917 (Uniprot-TrEMBL)
YWHAQ ProteinP27348 (Uniprot-TrEMBL)
YWHAZ ProteinP63104 (Uniprot-TrEMBL)
f-actin (ADP) R-HSA-202998 (Reactome)
f-actin (ADP)R-HSA-202998 (Reactome)
p-5S,T642-AS160:14-3-3:IRAPComplexR-HSA-1445124 (Reactome)
p-5S,T642-AS160:IRAPComplexR-HSA-1445133 (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 (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).
p-5S,T642-TBC1D4 ProteinO60343 (Uniprot-TrEMBL)
p-AKT1,p-AKT2ComplexR-HSA-9023954 (Reactome)
p-S1652-MYO5A ProteinQ9Y4I1 (Uniprot-TrEMBL)
p-S1652-MYO5A dimerComplexR-HSA-9605106 (Reactome)
p-S197-C2CD5 ProteinQ86YS7 (Uniprot-TrEMBL)
p-S197-C2CD5:2xCa2+ComplexR-HSA-5260210 (Reactome)
p-S237-TBC1D1 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-TBC1D1:14-3-3ComplexR-HSA-1454696 (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 ProteinQ2PPJ7 (Uniprot-TrEMBL)
p-T172-PRKAA2 ProteinP54646 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-T309,S474-AKT2ProteinP31751 (Uniprot-TrEMBL)
p-Y521-STXBP3ProteinO00186 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
14-3-3 dimerR-HSA-1445149 (Reactome)
14-3-3 dimerR-HSA-1454689 (Reactome)
ADPArrowR-HSA-1445144 (Reactome)
ADPArrowR-HSA-1449574 (Reactome)
ADPArrowR-HSA-1449597 (Reactome)
ADPArrowR-HSA-1454699 (Reactome)
ADPArrowR-HSA-1458463 (Reactome)
ADPArrowR-HSA-5260201 (Reactome)
AMPK-alpha2:AMPK-beta:AMPK-gamma:AMPmim-catalysisR-HSA-1454699 (Reactome)
AS160:IRAPArrowR-HSA-1445143 (Reactome)
AS160:IRAPR-HSA-1445144 (Reactome)
ASPSCR1ArrowR-HSA-1449574 (Reactome)
ATPR-HSA-1445144 (Reactome)
ATPR-HSA-1449574 (Reactome)
ATPR-HSA-1449597 (Reactome)
ATPR-HSA-1454699 (Reactome)
ATPR-HSA-1458463 (Reactome)
ATPR-HSA-5260201 (Reactome)
ArrowR-HSA-2316352 (Reactome)
C2CD5:2xCa2+R-HSA-5260201 (Reactome)
Exocyst ComplexR-HSA-2316352 (Reactome)
GDPArrowR-HSA-2255342 (Reactome)
GDPArrowR-HSA-2255343 (Reactome)
GGC-RAB11A:GTPArrowR-HSA-2316352 (Reactome)
GGC-RAB4A:GTP:KIF3:microtubuleArrowR-HSA-2316347 (Reactome)
GGC-RAB4A:GTPR-HSA-2316347 (Reactome)
GGC-RAB8A,10,13,14:GDPArrowR-HSA-1445143 (Reactome)
GGC-RAB8A,10,13,14:GDPR-HSA-2255343 (Reactome)
GGC-RAB8A,10,13,14:GTPArrowR-HSA-2255343 (Reactome)
GGC-RAB8A,10,13,14:GTPArrowR-HSA-2316352 (Reactome)
GGC-RAB8A,10,13,14:GTPR-HSA-1445143 (Reactome)
GGC-RAB8A,10,13,14:GTPmim-catalysisR-HSA-1445143 (Reactome)
GGC-RALA:GDPArrowR-HSA-1458485 (Reactome)
GGC-RALA:GDPR-HSA-2255342 (Reactome)
GGC-RALA:GTP:MYO1C:Calmodulin:F-actinArrowR-HSA-2316349 (Reactome)
GGC-RALA:GTP:MYO1C:Calmodulin:F-actinR-HSA-2316352 (Reactome)
GGC-RALA:GTP:MYO1C:Calmodulin:F-actinmim-catalysisR-HSA-2316352 (Reactome)
GGC-RALA:GTP:MYO1C:ExocystArrowR-HSA-2316352 (Reactome)
GGC-RALA:GTPArrowR-HSA-2255342 (Reactome)
GGC-RALA:GTPR-HSA-1458485 (Reactome)
GGC-RALA:GTPR-HSA-2316349 (Reactome)
GGC-RALA:GTPmim-catalysisR-HSA-1458485 (Reactome)
GTPR-HSA-2255342 (Reactome)
GTPR-HSA-2255343 (Reactome)
KIF3R-HSA-2316347 (Reactome)
MYH9ArrowR-HSA-2316352 (Reactome)
MYO1C:CALM1R-HSA-2316349 (Reactome)
MYO5A dimerR-HSA-1449597 (Reactome)
MicrotubuleR-HSA-2316347 (Reactome)
PiArrowR-HSA-1458485 (Reactome)
R-HSA-1445143 (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.
R-HSA-1445144 (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 (SLC2A4).
R-HSA-1445149 (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 (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).
R-HSA-1449574 (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.
R-HSA-1449597 (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.
R-HSA-1454689 (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.
R-HSA-1454699 (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 (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).
R-HSA-1458463 (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.
R-HSA-1458485 (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.
R-HSA-2255342 (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.
R-HSA-2255343 (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.
R-HSA-2316347 (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 (Slc2a4) across the cytosol to the cortical actin network.
R-HSA-2316349 (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).
R-HSA-2316352 (Reactome) As inferred from mouse, GLUT4 (SLC2A4) initially translocates from endosomes to insulin-responsive vesicles (IRVs, GSVs). RAB11 appears to play a role in this process. IRVs bearing GLUT4 are then translocated across the cortical actin network to the plasma membrane. Unconventional myosin 5A (MYO5A) interacts with RAB10 or RAB8A on the vesicle and participates in transport of the IRV. Myosin 1C appears to act close to the plasma membrane and may facilitate fusion of the vesicle with the plasma membrane. RAB:GTP complexes coupled to the vesicles may interact with myosins to regulate their activity. Non-muscle myosin IIA (MYH9) appears to interact with the SNAP23 complex to dock the IRV at the inner membrane face.
R-HSA-5260201 (Reactome) The protein kinase B beta (AKT) pathway mediates insulin-stimulated glucose transport by increasing glucose transporter GLUT4 translocation from intracellular stores to the plasma membrane. C2 domain-containing protein 5 (C2CD5 aka C2 domain-containing phosphoprotein 138kDa) has been shown to be required for optimal insulin-stimulated GLUT4 translocation and fusion of GLUT4 vesicles with the plasma membrane in adipocytes. It is also able to bind Ca2+ and lipid membranes in its C2 domain. C2CD5 is a substrate for RAC-beta serine/threonine-protein kinase (AKT2), which phosphorylates C2CD5 at serine 197. Phosphorylated C2CD5 optimises GLUT4 translocation to the plasma membrane. The role of human C2CD5 is inferred from the role of the orthologous mouse protein (Xie et al. 2011).
RGC1:RGC2ArrowR-HSA-1458485 (Reactome)
RGC1:RGC2R-HSA-1458463 (Reactome)
RGC1:p-486,696-T715-RGC2ArrowR-HSA-1458463 (Reactome)
SLC2A4:ASPSCR1R-HSA-1449574 (Reactome)
SLC2A4ArrowR-HSA-1449574 (Reactome)
SNAP23R-HSA-1449574 (Reactome)
STX4:STXBP3 (MUNC18C)R-HSA-1449574 (Reactome)
TBC1D1ArrowR-HSA-1445143 (Reactome)
TBC1D1R-HSA-1454699 (Reactome)
VAMP2:STX4:SNAP23ArrowR-HSA-1449574 (Reactome)
VAMP2R-HSA-1449574 (Reactome)
f-actin (ADP)R-HSA-2316349 (Reactome)
p-5S,T642-AS160:14-3-3:IRAPArrowR-HSA-1445149 (Reactome)
p-5S,T642-AS160:IRAPArrowR-HSA-1445144 (Reactome)
p-5S,T642-AS160:IRAPR-HSA-1445149 (Reactome)
p-AKT1,p-AKT2mim-catalysisR-HSA-1445144 (Reactome)
p-S1652-MYO5A dimerArrowR-HSA-1449597 (Reactome)
p-S1652-MYO5A dimerArrowR-HSA-2316352 (Reactome)
p-S197-C2CD5:2xCa2+ArrowR-HSA-2316352 (Reactome)
p-S197-C2CD5:2xCa2+ArrowR-HSA-5260201 (Reactome)
p-S237-TBC1D1:14-3-3ArrowR-HSA-1454689 (Reactome)
p-S237-TBC1D1ArrowR-HSA-1454699 (Reactome)
p-S237-TBC1D1R-HSA-1454689 (Reactome)
p-T309,S474-AKT2mim-catalysisR-HSA-1449597 (Reactome)
p-T309,S474-AKT2mim-catalysisR-HSA-1458463 (Reactome)
p-T309,S474-AKT2mim-catalysisR-HSA-5260201 (Reactome)
p-Y521-STXBP3ArrowR-HSA-1449574 (Reactome)
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