IL-6 activates serum and glucocorticoid kinase via p38α mitogen-activated protein kinase pathway

Fanyin Meng, Yoko Yamagiwa, Silvia Taffetani, Jiahuai Han, Tushar Patel

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Interleukin-6 (IL-6) has been implicated as an autocrine factor involved in growth of several human cancers, such as tumors arising from the biliary tract or cholangiocarcinoma. In malignant biliary tract epithelia, IL-6 activates the p38 MAPK pathway, which mediates a dominant survival signaling pathway. Serum and glucocorticoid-stimulated kinase (SGK) has been implicated as a survival kinase, but its role in survival signaling by IL-6 is unknown. After IL-6 stimulation, p38 MAPK activation preceded phosphorylation of SGK at Ser 78. Pretreatment with the pharmacological inhibitors of p38 MAPK SB-203580 or SB-202190 blocked IL-6-induced SGK phosphorylation at Ser 78 and SGK activation. Overexpression of p38α increased constitutive SGK phosphorylation at Ser78, whereas dominant negative p38α MAPK blocked IL-6-induced SGK phosphorylation and nuclear translocation. Interestingly, in addition to stimulating SGK phosphorylation, both IL-6 stimulation and p38α MAPK overexpression increased SGK mRNA and protein expression. An increase in p38 MAPK and SGK occurred following enforced expression of IL-6 in vivo. Furthermore, inhibition of SGK expression by siRNA increased toxicity due to chemotherapeutic drugs. Taken together, these data identify SGK as both a downstream kinase substrate as well as a transcriptionally regulated gene target of p38 MAPK in response to IL-6 and support a role of SGK during survival signaling by IL-6 in human cancers, such as cholangiocarcinoma.

Original languageEnglish (US)
Pages (from-to)C971-C981
JournalAmerican Journal of Physiology - Cell Physiology
Volume289
Issue number4 58-4
DOIs
StatePublished - Oct 2005

Keywords

  • Cancer
  • Cytokines
  • Intracellular kinases

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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