Insulin-stimulated Phosphorylation of a Rab GTPase-activating Protein Regulates GLUT4 Translocation*

By H. Sano, S. Kane, Eiko Sano, C. Mîinea, J. Asara, William Arbuthnot Sir Lane, C. W. Garner, G. Lienhard. Journal of Biological Chemistry, 2003

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Insulin stimulates the rapid translocation of intracellular glucose transporters of the GLUT4 isotype to the plasma membrane in fat and muscle cells. The connections between known insulin signaling pathways and the protein machinery of this membrane-trafficking process have not been fully defined. Recently, we identified a 160-kDa protein in adipocytes, designated AS160, that is phosphorylated by the insulin-activated kinase Akt. This protein contains a GTPase-activating domain (GAP) for Rabs, which are small G proteins required for membrane trafficking. In the present study we have identified six sites of in vivo phosphorylation on AS160. These sites lie in the motif characteristic of Akt phosphorylation, and insulin treatment increased phosphorylation at five of the sites. Expression of AS160 with two or more of these sites mutated to alanine markedly inhibited insulin-stimulated GLUT4 translocation in 3T3-L1 adipocytes. Moreover, this inhibition did not occur when the GAP function in the phosphorylation site mutant was inactivated by a point mutation. These findings strongly indicate that insulin-stimulated phosphorylation of AS160 is required for GLUT4 translocation and that this phosphorylation signals translocation through inactivation of the Rab GAP function.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d1d4b6165325902d8ba3277099d677c8a838d2bb

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Citations in the corpus

AKT/PKB signaling: navigating downstream. (2007, positive): “Although the precise molecular mechanisms by which Akt stimulates Glut4 translocation are still being intensely studied, the Rab-GAP AS160 (also known as TBC1 domain family member 4; TBC1D4) has emerged as an important direct target of Akt involved in this process (Eguez et al., 2005; Sano et al., 2”
PI3K/Akt: getting it right matters (2008, background): “Other substrates of Akt with a possible involvement in metabolic regulation include Akt substrate of 160 kDa (AS160), which may mediate the regulation of GLUT4 translocation by Akt (Sano et al., 2003), phosphoinositide kinase for five position containing a Fyve finger (PIKfyve) (Berwick et al.”
The nuts and bolts of AGC protein kinases (2010, background): “This allows vesicles containing the GLUT4 glucose transporter to translocate to the plasma membran”
The PTEN–PI3K pathway: of feedbacks and cross-talks (2008, background): “AKT phosphorylates and inactivates GSK3b (Cross et al., 1995), increases glucose transporter Glut4 translocation to plasma membrane by blocking AS160 (Sano et al., 2003) and, through FOXO inactivation, inhibits phosphoenolpyruvate carboxykinase and glucose-6-phosphatase (Burgering, 2008).”
Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training (2013, neutral): “AS160 undergoes phosphorylation in response to insulin and contains multiple Akt phosphorylation sites: Ser318, Ser341, Ser570, Ser588, Thr642, and Ser751 (330, 565).”
Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. (2010, background): “Among these, the phosphorylation of an Akt substrate of 160 kDa (AS160) has been found to be particularly important for GLUT4 translocation (367, 483).”
Insulin receptor signaling in normal and insulin-resistant states. (2014, background): “The GTPase-activating protein Akt substrate of 160 kDa (AS160), also called TBC1D4, and its homolog TBC1D1, are phosphorylated by Akt and are involved in insulin- and contraction-mediated glucose uptake (Sano et al. 2003; Sakamoto and Holman 2008; Taylor et al. 2008; An et al. 2010).”