A Rab10:RalA G protein cascade regulates insulin-stimulated glucose uptake in adipocytes.
Bottom Line: Once activated, Rab10 can increase the GTP binding of RalA by recruiting the Ral guanyl nucleotide exchange factor, Rlf/Rgl2.Overexpression of membrane-tethered Rlf compensates for the loss of Rab10 in Glut4 translocation, suggesting that Rab10 recruits Rlf to membrane compartments for RalA activation and that RalA is downstream of Rab10.Together these studies identify a new G protein cascade in the regulation of insulin-stimulated Glut4 trafficking and glucose uptake.
Affiliation: Life Sciences Institute, University of Michigan Medical School, Ann Arbor, MI 48109.Show MeSH
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Mentions: The activation of RalA by Rab10 could be due to inactivation of the RalGAP complex, activation of a RalGEF, or both. RGC1/2 is inactivated upon insulin stimulation through Akt phosphorylation of the catalytic subunit RGC2 (Chen et al., 2011b). Rab10 overexpression did not accelerate or affect the phosphorylation status of RGC2 (unpublished data). Moreover, a point mutation in RalA (F39L/FL) with increased nucleotide dissociation rates that quickly cycles between GDP and GTP (Reinstein et al., 1991; Lim et al., 2005), and thus does not require a GEF for activation, was not influenced by overexpression of Rab10 (QL), unlike what was observed for RalA (wild type [WT]; Figure 3A).
Affiliation: Life Sciences Institute, University of Michigan Medical School, Ann Arbor, MI 48109.