title: Ribosomal S6 kinase (RSK) regulates phosphorylation of filamin A on an important regulatory site.
abstract: 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 Pak1-mediated membrane ruffling, our results suggest a novel role for RSK in the regulation of the actin cytoskeleton.
authors.affiliation: Department of Cell Biology, Brigham & Women's Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Michele S
authors.initials: MS
authors.lastname: Woo
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Ohta
authors.forename: Isaac
authors.initials: I
authors.lastname: Rabinovitz
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Stossel
authors.forename: John
authors.initials: J
authors.lastname: Blenis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002070:Butadienes / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D005576:Colforsin / Q000378:metabolism; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D064448:Filamins; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008545:Melanoma / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009570:Nitriles / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D016415:Sequence Alignment; D012694:Serine / Q000378:metabolism
chemical_list: D002070:Butadienes; D003285:Contractile Proteins; D004791:Enzyme Inhibitors; D064448:Filamins; D008840:Microfilament Proteins; D009570:Nitriles; D020033:Protein Isoforms; C113580:U 0126; D005576:Colforsin; D012694:Serine; D004815:Epidermal Growth Factor; D019893:Ribosomal Protein S6 Kinases