Rab10, a Target of the AS160 Rab GAP, Is Required for Insulin-Stimulated Translocation of GLUT4 to the Adipocyte Plasma Membrane

Sano, Hiroyuki; Eguez, Lorena; Teruel, Mary N.; Fukuda, Mitsunori; Chuang, Tuan Daniel; Chavez, Jose A.; Lienhard, Gustav E.; McGraw, Timothy E.

doi:10.1016/j.cmet.2007.03.001

Cited by 313 publications

(367 citation statements)

References 56 publications

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“…These data all support the hypothesis that AS160 negatively regulates the activity of Rab protein(s) involved in GLUT4 translocation. Recently, it has been suggested that Rab10 is the Rab protein downstream of AS160, since introduction of the constitutively active Rab10 (Rab10 Q67L ) increases the PM fraction of GLUT4 in the absence of insulin stimulation, and knockdown of Rab10 retards insulin-stimulated GLUT4 translocation [8,9]. These findings further support the existence of a negative regulatory mechanism between AS160 and Rab protein(s).…”

Section: Introductionsupporting

confidence: 70%

RUVBL2, a novel AS160-binding protein, regulates insulin-stimulated GLUT4 translocation

et al. 2009

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In fat and muscle cells, insulin-stimulated glucose uptake is mainly mediated by glucose transporter 4 (GLUT4), which translocates from intracellular compartments to the cell surface in response to insulin stimulation. AS160 is one of the substrates of Akt and plays important roles in insulin-regulated GLUT4 translocation. In this study, RuvBlike protein 2 (RUVBL2) is identified as a new AS160-binding protein using mammalian tandem affinity purification (TAP) combined with mass spectrometry. In 3T3-L1 adipocytes, RUVBL2 is highly expressed and is mainly distributed in the cytosol. Depletion of RUVBL2 in adipocytes inhibits insulin-stimulated GLUT4 translocation and glucose uptake through reducing insulin-stimulated AS160 phosphorylation. However, introduction of human RUVBL2 can reverse this inhibitory effect. These data suggest that RUVBL2 plays an important role in insulin-stimulated GLUT4 translocation through its interaction with AS160.

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Section: Introductionsupporting

confidence: 70%

RUVBL2, a novel AS160-binding protein, regulates insulin-stimulated GLUT4 translocation

et al. 2009

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“…Four Rabs, Rab2, Rab8a, Rab10, and Rab14, have been shown as substrates of AS160 in an in vitro assay (6), among which Rab10 and Rab8a regulate GLUT4 exocytosis in 3T3-L1 adipocytes (43) and L6 myocytes (44), respectively. Interestingly, a recent report (45) shows that Rab14 may regulate the endocytic trafficking of GLUT4 in 3T3-L1 adipocytes.…”

mentioning

confidence: 99%

The Inactivation of RabGAP Function of AS160 Promotes Lysosomal Degradation of GLUT4 and Causes Postprandial Hyperglycemia and Hyperinsulinemia

Xie

Chen

et al. 2016

Diabetes

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The AS160 (Akt substrate of 160 kDa) is a Rab-GTPase activating protein (RabGAP) with several other functional domains, and its deficiency in mice or human patients lowers GLUT4 protein levels and causes severe insulin resistance. How its deficiency causes diminished GLUT4 proteins remains unknown. We found that the deletion of AS160 decreased GLUT4 levels in a cell/ tissue-autonomous manner. Consequently, skeletal muscle-specific deletion of AS160 caused postprandial hyperglycemia and hyperinsulinemia. The pathogenic effects of AS160 deletion are mainly, if not exclusively, due to the loss of its RabGAP function since the RabGAP-inactive AS160 R917K mutant mice phenocopied the AS160 knockout mice. The inactivation of RabGAP of AS160 promotes lysosomal degradation of GLUT4, and the inhibition of lysosome function could restore GLUT4 protein levels. Collectively, these findings demonstrate that the RabGAP activity of AS160 maintains GLUT4 protein levels in a cell/tissue-autonomous manner and its inactivation causes lysosomal degradation of GLUT4 and postprandial hyperglycemia and hyperinsulinemia.

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“…AS160 has a Rab GTPase-activating protein (GAP) domain that plays a critical role in regulating vesicle formation, vesicle movement, and membrane fusion [11] . Phosphorylation of AS160 is suspected to exhibit impairments in its Rab GAP activity, which permits target Rabs to return to their active GTP-bound forms and initiate GLUT4 exocytotic trafficking [12,13] . AS160 phosphorylation is reduced in T2DM patients, which is accompanied by impaired GLUT4 translocation [14] .…”

Section: Introductionmentioning

confidence: 99%

Astragalus polysaccharide stimulates glucose uptake in L6 myotubes through AMPK activation and AS160/TBC1D4 phosphorylation

Liu

Zhang

et al. 2012

Acta Pharmacol Sin

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Aim: To establish the mechanism responsible for the stimulation of glucose uptake by Astragalus polysaccharide (APS), extracted from Astragalus membranaceus Bunge, in L6 myotubes in vitro. Methods: APS-stimulated glucose uptake in L6 myotubes was measured using the 2-deoxy-[ 3 H]-D-glucose method. The adenine nucleotide contents in the cells were measured by HPLC. The phosphorylation of AMP-activated protein kinase (AMPK) and Akt substrate of 160 kDa (AS160) was examined using Western blot analysis. The cells transfected with 4P mutant AS160 (AS160-4P) were constructed using gene transfer approach. Results: Treatment of L6 myotubes with APS (100−1600 µg/mL) significantly increased glucose uptake in time-and concentration-dependent manners. The maximal glucose uptake was reached in the cells treated with APS (400 μg/mL) for 36 h. The APS-stimulated glucose uptake was significantly attenuated by pretreatment with Compound C, a selective AMPK inhibitor or in the cells overexpressing AS160-4P. Treatment of L6 myotubes with APS strongly promoted the activation of AMPK. We further demonstrated that either Ca 2+ /calmodulin-dependent protein kinase kinase β (CaMKKβ) or liver kinase B1 (LKB1) mediated APS-induced activation of AMPK in L6 myotubes, and the increased cellular AMP: ATP ratio was also involved. Treatment of L6 myotubes with APS robustly enhanced the phosphorylation of AS160, which was significantly attenuated by pretreatment with Compound C. Conclusion: Our results demonstrate that APS stimulates glucose uptake in L6 myotubes through the AMP-AMPK-AS160 pathway, which may contribute to its hypoglycemic effect.

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Rab10, a Target of the AS160 Rab GAP, Is Required for Insulin-Stimulated Translocation of GLUT4 to the Adipocyte Plasma Membrane

Cited by 313 publications

References 56 publications

RUVBL2, a novel AS160-binding protein, regulates insulin-stimulated GLUT4 translocation

RUVBL2, a novel AS160-binding protein, regulates insulin-stimulated GLUT4 translocation

The Inactivation of RabGAP Function of AS160 Promotes Lysosomal Degradation of GLUT4 and Causes Postprandial Hyperglycemia and Hyperinsulinemia

Astragalus polysaccharide stimulates glucose uptake in L6 myotubes through AMPK activation and AS160/TBC1D4 phosphorylation

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