The serum- and glucocorticoid-inducible kinase SGK1 and the protein kinase PKB/Akt presumably phosphorylate and, by this means, activate the mammalian phosphatidylinositol-3-phosphate-5-kinase PIKfyve (PIP5K3), which has in turn been shown to regulate transporters and channels. SGK1-regulated channels include the Ca2+ channel TRPV6, which is expressed in a variety of epithelial and nonepithelial cells including tumor cells. SGK1 and protein kinase B PKB/Akt foster tumor growth. The present study thus explored whether TRPV6 is regulated by PIKfyve. TRPV6 was expressed in Xenopus laevis oocytes with or without additional coexpression of constitutively active S422DSGK1, constitutively active T308D,S473DPKB, wild-type PIKfyve, and S318APIKfyve lacking the SGK1 phosphorylation site. TRPV6 activity was determined from the current (ICa) resulting from TRPV6-induced Ca2+ entry and subsequent activation of Ca2+-sensitive endogenous Cl− channels. TRPV6 protein abundance in the cell membrane was determined utilizing immunohistochemistry and Western blotting. In TRPV6-expressing oocytes IH was increased by coexpression of S422DSGK1 and by T308D,S473DPKB. Coexpression of wild-type PIKfyve further increased IH in TRPV6 + S422DSGK1-expressing oocytes but did not significantly modify ICa in oocytes expressing TRPV6 alone. S318APIKfyve failed to significantly modify ICa in the presence and absence of S422DSGK1. S422DSGK1 increased the TRPV6 protein abundance in the cell membrane, an effect augmented by additional expression of wild-type PIKfyve. We conclude that PIKfyve participates in the regulation of TRPV6.
The Journal of Membrane Biology – Springer Journals
Published: Dec 30, 2009
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