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1 Department of Physiology I, University of Tubingen, Tubingen, Germany
2 Department of Anatomy, University of Tubingen, Tubingen, Germany
3 Department of Pathology, University of Tubingen, Tubingen, Germany
4 Department of Physiology I, University of Zurich, Zurich, Switzerland
5 Department of Pharmacology, University of Mainz, Mainz, Germany
* To whom correspondence should be addressed. E-mail: florian.lang{at}uni-tuebingen.de.
The serum and glucocorticoid inducible kinase SGK1 is highly expressed in enterocytes. The significance of the kinase in the regulation of intestinal function has, however, remained elusive. In Xenopus laevis oocytes SGK1 stimulates the epithelial Na+ channel ENaC by phosphorylating the ubiquitin ligase Nedd4-2 which regulates channels by ubiquitination leading to subsequent degradation of the channel protein. Thus, the present study has been performed to explore whether SGK1 regulates transport systems expressed in intestinal epithelial cells, specifically the phosphate transporter NaPi IIb. Immunohistochemistry in human small intestine revealed SGK1 colocalization with Nedd4-2 in villus enterocytes. For functional analysis cRNA encoding NaPi IIb, the SGK isoforms and/or the ubiquitin ligase Nedd4-2 were injected into Xenopus laevis oocytes and transport activity quantified as the substrate induced current. Exposure to 3 mM phosphate induces an inward current (IP) in NaPi IIb expressing oocytes. The coinjection of Nedd4-2, but not the catalytically inactive mutant C938SNedd4-2, significantly downregulates IP whereas the coinjection of S422DSGK1 markedly stimulates IP and even fully reverses the effect of Nedd4-2 on IP. The effect of S422DSGK1 on NaPi IIb is mimicked by wild type SGK3, but not by wild type SGK2, constitutively active T308D,S473DPKB or inactive K127NSGK1. Moreover, S422DSGK1 and SGK3 phosphorylate Nedd4-2. In conclusion, SGK1 stimulates the intestinal phosphate transporter NaPi IIb at least in part by phosphorylating and thereby inhibiting Nedd4-2 binding to its target. Thus, the present study reveals a novel signaling pathway in the regulation of intestinal phosphate transport which may be important for the regulation of phosphate balance.
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