期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 24, 期 7, 页码 3025-3035出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.24.7.3025-3035.2004
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资金
- NCI NIH HHS [CA09595, T32 CA009595, R01 CA46595, R01 CA046595] Funding Source: Medline
- NHLBI NIH HHS [R01 HL019429, HL19429] Funding Source: Medline
- NIGMS NIH HHS [R01 GM51405, R01 GM051405] Funding Source: Medline
The Ras-mitogen-activated protein (Ras-MAP) kinase pathway regulates various cellular processes, including gene expression, cell proliferation, and survival. Ribosomal S6 kinase (RSK), a key player in this pathway, modulates the activities of several cytoplasmic and nuclear proteins via phosphorylation. Here we report the characterization of the cytoskeletal protein filamin A (FLNa) as a membrane-associated RSK target. We show that the N-terminal kinase domain of RSK phosphorylates FLNa on Ser(2152) in response to mitogens. Inhibition of MAP kinase signaling with UO126 or mutation of Ser(2152) to Ala on FLNa prevents epidermal growth factor (EGF) -stimulated phosphorylation of FLNa in vivo. Furthermore, phosphorylation of FLNa on Ser(2152) is significantly enhanced by the expression of wild-type RSK and antagonized by kinase-inactive RSK or specific reduction of endogenous RSK. Strikingly, EGF-induced, FLNa-dependent migration of human melanoma cells is significantly reduced by Uo126 treatment. Together, these data provide substantial evidence that RSK phosphorylates FLNa on Ser(2152) in vivo. Given that phosphorylation of FLNa on Ser(2152) is required for Pakl-mediated membrane ruffling, our results suggest a novel role for RSK in the regulation of the actin cytoskeleton.
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