IL-6 activates serum and glucocorticoid kinase via p38alpha mitogen-activated protein kinase pathway.
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 Ser78. Pretreatment with the pharmacological inhibitors of p38 MAPK SB-203580 or SB-202190 blocked IL-6-induced SGK phosphorylation at Ser78 and SGK activation. Overexpression of p38alpha increased constitutive SGK phosphorylation at Ser78, whereas dominant negative p38alpha MAPK blocked IL-6-induced SGK phosphorylation and nuclear translocation. Interestingly, in addition to stimulating SGK phosphorylation, both IL-6 stimulation and p38alpha 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.
Meng
Fanyin
F
Department of Internal Medicine, Scott and White Clinic, Texas A&M University Health Science Center College of Medicine, 2401 South 31st St., Temple, Texas 76508, USA.
Yamagiwa
Yoko
Y
Taffetani
Silvia
S
Han
Jiahuai
J
Patel
Tushar
T
D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D017874:Immediate-Early Proteins; D015850:Interleukin-6 / Q000502:physiology*; D007527:Isoenzymes; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger; D015398:Signal Transduction; D000099184:Serum-Glucocorticoid Regulated Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D017874:Immediate-Early Proteins; D015850:Interleukin-6; D007527:Isoenzymes; D048308:Mitogen-Activated Protein Kinase 14; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D012333:RNA, Messenger; D000099184:Serum-Glucocorticoid Regulated Kinases; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole