Negative regulation of SEK1 signaling by serum- and glucocorticoid-inducible protein kinase 1.
Serum- and glucocorticoid-inducible protein kinase 1 (SGK1) has been implicated in diverse cellular activities including the promotion of cell survival. The molecular mechanism of the role of SGK1 in protection against cellular stress has remained unclear, however. We have now shown that SGK1 inhibits the activation of SEK1 and thereby negatively regulates the JNK signaling pathway. SGK1 was found to physically associate with SEK1 in intact cells. Furthermore, activated SGK1 mediated the phosphorylation of SEK1 on serine 78, resulting in inhibition of the binding of SEK1 to JNK1, as well as to MEKK1. Replacement of serine 78 of SEK1 with alanine abolished SGK1-mediated SEK1 inhibition. Oxidative stress upregulated SGK1 expression, and depletion of SGK1 by RNA interference potentiated the activation of SEK1 induced by oxidative stress in Rat2 fibroblasts. Moreover, such SGK1 depletion prevented the dexamethasone-induced increase in SGK1 expression, as well as the inhibitory effects of dexamethasone on paclitaxel-induced SEK1-JNK signaling and apoptosis in MDA-MB-231 breast cancer cells. Together, our results suggest that SGK1 negatively regulates stress-activated signaling through inhibition of SEK1 function.
Kim
Myung Jin
MJ
School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
Chae
Ji Soo
JS
Kim
Kwang Je
KJ
Hwang
Sang Gil
SG
Yoon
Kyoung Wan
KW
Kim
Eun Kyung
EK
Yun
Hee Jae
HJ
Cho
Jun-Ho
JH
Kim
Jeehyun
J
Kim
Bong-Woo
BW
Kim
Hyung-Chul
HC
Kang
Sang Sun
SS
Lang
Florian
F
Cho
Ssang-Goo
SG
Choi
Eui-Ju
EJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D000099184:Serum-Glucocorticoid Regulated Kinases
D003907:Dexamethasone; D006861:Hydrogen Peroxide; D017874:Immediate-Early Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D017239:Paclitaxel; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases