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- Title
Stimulation of Ca<sup>2+</sup>-channel Orai1/STIM1 by serum- and glucocorticoid-inducible kinase 1 (SGK1).
- Authors
Eylenstein, Anja; Gehring, Eva-Maria; Heise, Nicole; Shumilina, Ekaterina; Schmidt, Sebastian; Szteyn, Kalina; Münzer, Patrick; Nurbaeva, Meerim K.; Eichenmüller, Melanie; Tyan, Leonid; Regel, Ivonne; Föller, Michael; Kuhl, Dietmar; Soboloff, Jonathan; Penner, Reinhold; Lang, Florian
- Abstract
Ca2+ signaling includes store-operated Ca2+ entry (SOCE) following depletion of endoplasmic reticulum (ER) Ca2+ stores. On store depletion, the ER Ca sensor STIM1 activates Orai1, the pore-forming unit of Ca2+ -release-activated Ca2+ (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, ICRAC, and SOCE in human embryonic kidney (HEK293) cells stably expressing Orai1 and transfected with STIM1 were each significantly enhanced by coexpression of constitutively active S422D SGK1 (by + 81, + 378, and +136%, respectively) but not by inactive SGK1. Coexpression of the ubiquitin ligase Nedd4-2, an established negatively regulated SGK1 target, down-regulated SOCE (by-48%) and ICRAC (by-60%), an effect reversed S422D by expression of SGK1 (by+175 and +173%, respectively). Orai1 protein abundance and SOCE were significantly lower in mast cells from SGK+1-/ knockout (sgk1-/- ) mice (by+37% and +52%, respectively) than in mast cells from wild-type (sgk1-/-) littermates. Activation of SOCE by sarcoplasmic endoplasmic reticulum Ca2+ -ATPase-inhibitor thapsigargin (2µM) stimulated migration, an effect significantly higher (by+306%) in SGK1-expressing K127N than in SGK1-expressing HEK293 cells, and also significantly higher (by + 108%) in sgk1+/+ than in sgk-1/- mast cells. SGK1+/+ is thus a novel key player in the regulation of SOCE.
- Subjects
CALCIUM channels; GLUCOCORTICOIDS; SERUM; ENDOPLASMIC reticulum; PROTEINS
- Publication
FASEB Journal, 2011, Vol 25, Issue 6, p2012
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.10-178210