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

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3, 9, 14, 16, 23...13292, 124, 11, 18, 2124, 288, 201, 6, 10, 17, 243011, 21cytosolcytoplasmic vesicle lumenLNPEP GTP GTPC2CD5:2xCa2+ADPYWHAH EXOC7 GTP YWHAE ADPp-Y521-STXBP3PRKAB1 f-actin (ADP) RALGAPA2 p-5S,T642-AS160:14-3-3:IRAPGTP MYH9ATPGTP p-S197-C2CD5:2xCa2+GGC-RALA:GDPGGC-RAB8A EXOC4 GGC-RAB8A,10,13,14:GDPEXOC3 RGC1:RGC2GTP EXOC8 p-T309,S474-AKT2 GGC-PalmC-RAC1 MYO1C SNAP23ATPKIFAP3 YWHAZ GTPLNPEP KIFAP3 GGC-RAB8A,10,13,14:GTPKIF3A GGC-RALA:GTP:MYO1C:Calmodulin:F-actinYWHAZ RGC1:p-486,696-T715-RGC2YWHAH AS160:IRAPEXOC6 ATPGGC-RALA KIF3B TBC1D1PiGGC-RALA Ca2+ ADPGGC-RAB10 AMP p-T309,S474-AKT2f-actin (ADP)ADPGGC-RALA YWHAZ EXOC1 STX4 GTP PRKAB2 ASPSCR1CALM1 RHOQ:GTPSFN YWHAQ p-AKT1,p-AKT2YWHAB Ca2+ p-S237-TBC1D1 MicrotubuleKIF3B 14-3-3 dimerRHOQ GGC-RALA GGC-RAB4A:GTP:KIF3:microtubulep-S197-C2CD5 EXOC8 GGC-RALA:GTP:MYO1C:ExocystMicrotubule protofilament ADPGGC-RAB4A:GTPCALM1 EXOC7 STX4:STXBP3(MUNC18C)GTP Microtubule protofilament GGC-RAB11A:GTPp-S237-TBC1D1:14-3-3p-T308,S473-AKT1 SNAP23 p-S486,S696,T715-RALGAPA2 EXOC5 Exocyst ComplexKIF3MYO5A STXBP3 CALM1 VAMP2YWHAG C2CD5 ATPp-5S,T642-TBC1D4 YWHAQ MYO1C:CALM1p-T172-PRKAA2 YWHAZ MYO1C GGC-RAB13 SLC2A4 ASPSCR1 EXOC4 RALGAPB PRKAG3 GGC-RAB8A YWHAB YWHAE ADPRALGAPB ATPp-5S,T642-AS160:IRAPf-actin (ADP) STX4 YWHAH SLC2A4:ASPSCR1YWHAB YWHAG SFN SFN YWHAQ GTP EXOC6 YWHAE GDPSFN p-5S,T642-TBC1D4 YWHAH MYO5A dimer14-3-3 dimerGTP GDPEXOC3 EXOC5 GGC-RAB4A VAMP2 p-S1652-MYO5A dimerp-S237-TBC1D1YWHAG YWHAB GGC-RAB11A YWHAQ GGC-RALA:GTPYWHAG ATPGTP PRKAG1 GDP LNPEP GGC-RAB4A GGC-RAB10 p-S1652-MYO5A VAMP2:STX4:SNAP23AMPK-alpha2:AMPK-beta:AMPK-gamma:AMPYWHAE GGC-RAB13 TBC1D4 EXOC1 SLC2A4EXOC2 EXOC2 KIF3A GDP PRKAG2 GGC-RAB14 GGC-RAB14 RAC1:GTPMYO1C 19195, 7, 2615, 2511, 1822154, 111011, 18


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: 66
Reactome Author 
Reactome Author: May, Bruce

Quality Tags

Ontology Terms

 

Bibliography

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  1. 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
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  3. Bogan JS, Kandror KV.; ''Biogenesis and regulation of insulin-responsive vesicles containing GLUT4.''; PubMed Europe PMC
  4. 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
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  6. 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
  7. 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
  8. 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
  9. Kandror KV, Pilch PF.; ''The sugar is sIRVed: sorting Glut4 and its fellow travelers.''; PubMed Europe PMC
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  13. Bhullar RP, Seneviratne HD.; ''Characterization of human platelet GTPase activating protein for the Ral GTP-binding protein.''; PubMed Europe PMC
  14. Leney SE, Tavaré JM.; ''The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targets.''; PubMed Europe PMC
  15. 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
  16. Foley K, Boguslavsky S, Klip A.; ''Endocytosis, recycling, and regulated exocytosis of glucose transporter 4.''; PubMed Europe PMC
  17. 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
  18. 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
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  21. 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
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  26. 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
  27. Zaid H, Antonescu CN, Randhawa VK, Klip A.; ''Insulin action on glucose transporters through molecular switches, tracks and tethers.''; PubMed Europe PMC
  28. 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
  29. 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
  30. 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
  31. Hoffman NJ, Elmendorf JS.; ''Signaling, cytoskeletal and membrane mechanisms regulating GLUT4 exocytosis.''; PubMed Europe PMC

History

View all...
CompareRevisionActionTimeUserComment
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:16761 (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:15422 (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:18367 (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 dimermim-catalysisR-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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