Stimulation of Ca ²⁺ ‐channel Orai1/STIM1 by serum‐and glucocorticoid‐inducible kinase 1 (SGK1)

Abstract

Ca 2+ signaling includes store‐operated Ca 2+ entry (SOCE) following depletion of endoplas‐mic reticulum (ER) Ca 2+ stores. On store depletion, the ER Ca 2+ sensor STIM1 activates Orai1, the pore‐forming unit of Ca 2+ ‐release‐activated Ca 2+ (CRAC) channels. Here, we show that Orai1 is regulated by serum‐ and glucocorticoid‐inducible kinase 1 (SGK1), a growth factor‐regulated kinase. Membrane Orai1 protein abundance, / CRAC , and SOCE in human embryonic kidney (HEK293) cells stably expressing Orai1 and transfected with STIM1 were each significantly enhanced by coexpression of constitutively active SGK1 (by+81, +378, and+136%, respectively) but not by inactive K12 N SGK1. Coexpression of the ubiquitin ligase Nedd4‐2, an established negatively regulated SGK1 target, down‐regulated SOCE (by –48%) and / CRA c (by –60%), an effect reversed by expression of SGK1 (by +175 and +173%, respectively). Orai1 protein abundance and SOCE were significantly lower in mast cells from SGK1‐knockout ( sgk1 ) mice (by –37% and –52%, respectively) than in mast cells from wild‐type ( sgk1 +/+ ) littermates. Activation of SOCE by sarcoplasmic/endoplasmic reticulum Ca 2+ ‐ATPase‐inhibitor thapsi‐gargin (2 μΜ) stimulated migration, an effect significantly higher (by +306%) in SGKl‐expressing than in SGKl‐expressing HEK293 cells, and also significantly higher (by +108%) in sgk1 +/+ than in sgk1 −/− mast cells. SGK1 is thus a novel key player in the regulation of SOCE.—Eylenstein, A., Geh‐ring, E.‐M., Heise, N., Shumilina, E., Schmidt, S., Szteyn, K., Münzer, P., Nurbaeva, M. K., Eichenmüller, M., Tyan, L., Regel, I., Föller, M., Kuhl, D., Soboloff, J., Penner, R., Lang, R. Stimulation of Ca 2+ ‐channel Orai1/STIM1 by serum‐ and glucocorticoid‐inducible kinase 1 (SGK1). FASEB J. 25, 2012‐2021 (2011). www.fasebj.org