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Negative regulation of SEK1 signaling by serum‐ and glucocorticoid‐inducible protein kinase 1
Author(s) -
Kim Myung Jin,
Chae Ji Soo,
Kim Kwang Je,
Hwang Sang Gil,
Yoon Kyoung Wan,
Kim Eun Kyung,
Yun Hee Jae,
Cho JunHo,
Kim Jeehyun,
Kim BongWoo,
Kim Hyungchul,
Kang Sang Sun,
Lang Florian,
Cho SsangGoo,
Choi EuiJu
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601755
Subject(s) - biology , glucocorticoid , signal transduction , protein kinase a , kinase , glucocorticoid receptor , microbiology and biotechnology , immunology
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.