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PMID:21148297

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Citation

Chen, XW, Leto, D, Xiong, T, Yu, G, Cheng, A, Decker, S and Saltiel, AR (2011) A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action. Mol. Biol. Cell 22:141-52

Abstract

Insulin stimulates glucose transport in muscle  and adipose tissue by translocation of glucose transporter 4 (GLUT4) to the plasma membrane. We previously reported that activation of the small GTPase RalA downstream of PI 3-kinase plays a critical role in this process by mobilizing the exocyst complex for GLUT4 vesicle targeting in adipocytes. Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. Knockdown of RGC proteins leads to increased RalA activity and glucose uptake in adipocytes. Insulin inhibits the GAP complex through Akt2-catalyzed phosphorylation of RGC2 in vitro and in vivo, while activated Akt relieves the inhibitory effect of RGC proteins on RalA activity. The RGC complex thus connects PI 3-kinase/Akt activity to the transport machineries responsible for GLUT4 translocation.

Links

PubMed PMC3016972 Online version:10.1091/mbc.E10-08-0665

Keywords

Adipocytes/metabolism; Animals; Blotting, Western; COS Cells; Catalytic Domain; Cercopithecus aethiops; GTPase-Activating Proteins/metabolism; Gene Knockdown Techniques; Glucose/metabolism; Glucose Transporter Type 4/metabolism; Humans; Insulin/metabolism; Mice; NIH 3T3 Cells; Phosphatidylinositol 3-Kinases/metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt/metabolism; Signal Transduction; ral GTP-Binding Proteins/genetics; ral GTP-Binding Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:RGPA2

enables

GO:0005096: GTPase activator activity

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2444531

F

  • has_input:(MGI:MGI:1927244)|has_input:(MGI:MGI:1927243)

Seeded From UniProt

complete

MOUSE:RGPA2

acts_upstream_of_or_within

GO:0032880: regulation of protein localization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RGPA2

acts_upstream_of_or_within

GO:0032484: Ral protein signal transduction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RGPA2

acts_upstream_of_or_within

GO:0060178: regulation of exocyst localization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RGPA2

acts_upstream_of_or_within

GO:0090630: activation of GTPase activity

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2444531

P

Seeded From UniProt

complete

MOUSE:EXOC7

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P63321

F

Seeded From UniProt

complete

MOUSE:EXOC4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P63321

F

Seeded From UniProt

complete

MOUSE:RALA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:O35250
PR:O35382

F

Seeded From UniProt

complete

MOUSE:AKT2

acts_upstream_of_or_within

GO:0008286: insulin receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AKT2

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(MGI:MGI:3036245)

Seeded From UniProt

complete

MOUSE:AKT2

acts_upstream_of_or_within

GO:0090630: activation of GTPase activity

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2444531
MGI:MGI:3036245

P

Seeded From UniProt

complete

MOUSE:RLGPB

enables

GO:0005096: GTPase activator activity

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:3036245

F

Seeded From UniProt

complete

MOUSE:RLGPB

acts_upstream_of_or_within

GO:0032880: regulation of protein localization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RLGPB

acts_upstream_of_or_within

GO:0032484: Ral protein signal transduction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RLGPB

acts_upstream_of_or_within

GO:0060178: regulation of exocyst localization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RLGPB

acts_upstream_of_or_within

GO:0090630: activation of GTPase activity

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:3036245

P

Seeded From UniProt

complete

MOUSE:RALA

enables

GO:0003924: GTPase activity

ECO:0000269: experimental evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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