Serum- and glucocorticoid-induced protein kinase 1 (SGK1) is regulated by store-operated Ca2+ entry and mediates cytoprotection against necrotic cell death

J Biol Chem. 2013 Nov 8;288(45):32708-32719. doi: 10.1074/jbc.M113.507210. Epub 2013 Sep 16.


Serum and glucocorticoid-regulated kinase 1 (SGK1) encodes a phosphatidylinositol 3-kinase-dependent serine/threonine kinase that is rapidly induced in response to cellular stressors and is an important cell survival signal. Previous studies have suggested that an increase in cytoplasmic Ca(2+) concentration ([Ca(2+)]c) is required for increased SGK1 expression, but the subcellular source of Ca(2+) regulating SGK1 transcription remains uncertain. Activation of endoplasmic reticulum stress (ERS) with thapsigargin (TG) increased SGK1 mRNA and protein expression in MDA-MB-231 cells. Intracellular Ca(2+) imaging revealed that store-operated Ca(2+) entry played a prominent role in SGK1 induction by TG. Neither ERS nor release of Ca(2+) from the ER was sufficient to activate SGK1. Prolonged elevation of intracellular Ca(2+) levels, however, triggered cell death with a much greater proportion of the cells undergoing necrosis rather than apoptosis. A relative increase in the percentage of cells undergoing necrosis was observed in cells expressing a short hairpin RNA targeted to the SGK1 gene. Necrotic cell death evoked by cytoplasmic Ca(2+) overloading was associated with persistent hyperpolarization of the inner mitochondrial membrane and a modest increase in calpain activation, but did not involve detectable caspase 3 or caspase 7 activation. The effects of cytoplasmic Ca(2+) overloading on mitochondrial membrane potential were significantly reduced in cells expressing SGK1 compared with SGK1-depleted cells. Our findings indicate that store-operated Ca(2+) entry regulates SGK1 expression in epithelial cells and suggest that SGK1-dependent cytoprotective signaling involves effects on maintaining mitochondrial function.

Keywords: Apoptosis; Calcium Signaling; Cytoprotection; Mitochondrial Apoptosis; Mitochondrial Membrane Potential; Necrosis (Necrotic Death); SGK1; Signal Transduction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Calcium / metabolism*
  • Calcium Signaling*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Caspase 7 / genetics
  • Caspase 7 / metabolism
  • Cell Line, Tumor
  • Enzyme Induction / genetics
  • Epithelial Cells / enzymology*
  • Epithelial Cells / pathology
  • Female
  • Humans
  • Immediate-Early Proteins / biosynthesis*
  • Immediate-Early Proteins / genetics
  • Membrane Potential, Mitochondrial*
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Membranes / pathology
  • Necrosis / enzymology
  • Necrosis / genetics
  • Necrosis / pathology
  • Protein Serine-Threonine Kinases / biosynthesis*
  • Protein Serine-Threonine Kinases / genetics
  • Up-Regulation*


  • Immediate-Early Proteins
  • Protein Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase
  • CASP3 protein, human
  • CASP7 protein, human
  • Caspase 3
  • Caspase 7
  • Calcium