The Rab GTPase-Activating Protein TBC1D4/AS160 Contains an Atypical Phosphotyrosine-Binding Domain That Interacts with Plasma Membrane Phospholipids To Facilitate GLUT4 Trafficking in Adipocytes

被引：60

作者：

Tan, Shi-Xiong ^{[1
]}

Ng, Yvonne ^{[1
]}

Burchfield, James G. ^{[1
]}

Ramm, Georg ^{[3
]}

Lambright, David G. ^{[4
]}

Stoeckli, Jacqueline ^{[1
]}

James, David E. ^{[1
,2
]}

机构：

[1] Garvan Inst Med Res, Diabet & Obes Res Program, Sydney, NSW, Australia

[2] Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia

[3] Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Melbourne, Vic 3004, Australia

[4] Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA USA

来源：

MOLECULAR AND CELLULAR BIOLOGY | 2012年 / 32卷 / 24期

基金：

美国国家卫生研究院; 澳大利亚国家健康与医学研究理事会;

关键词：

INSULIN-REGULATED AMINOPEPTIDASE; AKT SUBSTRATE; 3T3-L1; ADIPOCYTES; MUSCLE-CELLS; KINASE-B; TRANSLOCATION; AS160; PHOSPHORYLATION; PATHWAY; FUSION;

D O I：

10.1128/MCB.00761-12

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The Rab GTPase-activating protein TBC1D4/AS160 regulates GLUT4 trafficking in adipocytes. Nonphosphorylated AS160 binds to GLUT4 vesicles and inhibits GLUT4 translocation, and AS160 phosphorylation overcomes this inhibitory effect. In the present study we detected several new functional features of AS160. The second phosphotyrosine-binding domain in AS160 encodes a phospholipid-binding domain that facilitates plasma membrane (PM) targeting of AS160, and this function is conserved in other related RabGAP/Tre-2/Bub2/Cdc16 (TBC) proteins and an AS160 ortholog in Drosophila. This region also contains a non-overlapping intracellular GLUT4-containing storage vesicle (GSV) cargo-binding site. The interaction of AS160 with GSVs and not with the PM confers the inhibitory effect of AS160 on insulin-dependent GLUT4 translocation. Constitutive targeting of AS160 to the PM increased the surface GLUT4 levels, and this was attributed to both enhanced AS160 phosphorylation and 14-3-3 binding and inhibition of AS160 GAP activity. We propose a model wherein AS160 acts as a regulatory switch in the docking and/or fusion of GSVs with the PM.

引用

页码：4946 / 4959

页数：14

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