Serum- and Glucocorticoid-inducible Kinase SGK Phosphorylates and Negatively Regulates B-Raf

• Published in: The Journal of biological chemistry Vol. 276; no. 34; pp. 31620 - 31626
• Main Authors: Zhang, B H, Tang, E D, Zhu, T, Greenberg, M E, Vojtek, A B, Guan, K L
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 24.08.2001
• Subjects: Blood; Cell Line; Humans; Immediate-Early Proteins; Nuclear Proteins; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-raf - antagonists & inhibitors; Proto-Oncogene Proteins c-raf - chemistry; Proto-Oncogene Proteins c-raf - metabolism; Serine - metabolism; Transcription Factors - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M102808200

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 s erum and g lucocorticoid-inducible k inase, 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.