Serum- and glucocorticoid-inducible kinase SGK phosphorylates and negatively regulates B-Raf.
Phosphorylation can both positively and negatively regulate activity of the Raf kinases. Akt has been shown to phosphorylate and inhibit C-Raf activity. We have recently reported that Akt negatively regulates B-Raf kinase activation by phosphorylating multiple residues within its amino-terminal regulatory domain. Here we investigated the regulation of B-Raf by serum and glucocorticoid-inducible kinase, SGK, which shares close sequence identity with the catalytic domain of Akt but lacks the pleckstrin homology domain. We observed that SGK inhibits B-Raf activity. A comparison of substrate specificity between SGK and Akt indicates that SGK is a potent negative regulator of B-Raf. In contrast to Akt, SGK negatively regulates B-Raf kinase activity by phosphorylating only a single Akt consensus site, Ser(364). Under similar experimental conditions, SGK displays a measurably stronger inhibitory effect on B-Raf kinase activity than Akt, whereas Akt exhibits a more inhibitory effect on the forkhead transcription factor, FKHR. The selective substrate specificity is correlated with an enhanced association between Akt or SGK and their preferred substrates, FKHR and B-Raf, respectively. These results indicate that B-Raf kinase activity is negatively regulated by Akt and SGK, suggesting that the cross-talk between the B-Raf and other signaling pathways can be mediated by both Akt and SGK.
Zhang
B H
BH
Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109-0606, USA.
Tang
E D
ED
Zhu
T
T
Greenberg
M E
ME
Vojtek
A B
AB
Guan
K L
KL
D001769:Blood; D002460:Cell Line; D006801:Humans; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D012694:Serine; D014157:Transcription Factors; D000099184:Serum-Glucocorticoid Regulated Kinases