Insulin stimulates glucose transport into muscle and fat cells by enhancing GLUT4 abundance in the plasma membrane through activation of phosphatidylinositol 3-kinase (Pl3K). Protein kinase B (PKB) and PKCC are known PI3K downstream targets in the regulation of GLUT4. The serum- and glucocorticoid-inducible kinase SGKI is similarly activated by insulin and capable to regulate cell surface expression of several metabolite transporters. In this study, we evaluated the putative role of SGK1 in the modulation of GLUT4. Co-expression of the kinase along with GLUT4 in Xenopus oocytes stimulated glucose transport. The enhanced GLUT4 activity was paralleled by increased transporter abundance in the plasma membrane. Disruption of the SGKI phosphorylation site on GLUT4 ((S274A)GLUT4) abrogated the stimulating effect of SGKI. In summary, SGKI promotes glucose transporter membrane abundance via GLUT4 phosphorylation at Ser274. Thus, SGKI may contribute to the insulin and GLUT4-dependent regulation of cellular glucose uptake. (c) 2007 Elsevier Inc. All rights reserved.