Mechanisms of regulatory cell volume increase following cell shrinkage include accumulation of organic osmolytes such as betaine, taurine, sorbitol, glycerophosphorylcholine (GPC) and myo-inositol. Myo-inositol is taken up by the sodium-myo-inositol-transporter SMIT1 (SLC5A3) expressed in a wide variety of cell types. Hypertonicity induces the transcription of the SMIT1 gene upon binding of the transcription factor Tonicity Enhancer Binding Protein (TonEBP) to Tonicity Responsive Enhancers (TonE) in the SMIT1 promoter region. However, little is known about posttranslational regulation of the carrier protein. In this study we show, that SMIT1 is modulated by the serum and glucocorticoid inducible kinase SGK1, a protein genomically upregulated by hypertonicity. As demonstrated by two-electrode voltage clamp in the Xenopus oocyte expression system, SMIT1 mediated myo-inositol induced currents are upregulated by coexpression of wild type SGK1 and constitutively active S422DSGK1 but not by inactive K127NSGK1. The increase in SMIT1 activity is due to an elevated cell surface expression of the carrier while its kinetic properties remain unaffected. According to the decay of SMIT1 activity in the presence of brefeldin A, SGK1 stabilizes the SMIT1 protein in the plasma membrane. The SGK isoforms SGK2, SGK3 and the closely related protein kinase B (PKB) are similarly capable to activate SMIT1 activity. SMIT1 mediated currents are decreased by coexpression of the ubiquitin-ligase Nedd4-2, an effect counteracted by additional coexpression of SGK1. In conclusion, the present observations disclose SGK isoforms and protein kinase B as novel regulators of SMIT1 activity.