title: SH3P2 is a negative regulator of cell motility whose function is inhibited by ribosomal S6 kinase-mediated phosphorylation.
abstract: Although the extracellular signal-regulated kinase (ERK) pathway functions downstream of Ras in induction of the cell motility response, the detailed molecular mechanism by which this pathway regulates cell motility has remained elusive. The application of a functional expression cloning strategy to discover proteins that regulate cell motility has resulted in the identification of an SH3 domain-containing protein, SH3P2. Overexpression of SH3P2 in HeLa S3 cells inhibited cell motility, whereas RNA interference-mediated depletion of SH3P2 enhanced motility in various tumor cell lines, suggesting that SH3P2 functions as a negative regulator of cell motility. The expression level of SH3P2 alone did not correlate well with the motility of tumor cells, however. SH3P2 was phosphorylated on Ser(202) by ribosomal S6 kinase (RSK) in an ERK pathway-dependent manner, and such phosphorylation inhibited the ability of SH3P2 to suppress cell motility. The RSK inhibitor BI-D1870 suppressed SH3P2 phosphorylation and tumor cell motility as effectively as did the MEK inhibitor PD184352. Furthermore, expression of the unphosphorylatable SH3P2 mutant SH3P2(S202A) inhibited tumor cell motility, indicating that phosphorylation of SH3P2 at Ser(202) is a key determinant of such motility. These results suggest that SH3P2 is an essential molecule that functions downstream of the ERK pathway to modulate cell motility.
authors.affiliation: Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Bunkyo-machi, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Tanimura
authors.forename: Junya
authors.initials: J
authors.lastname: Hashizume
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kurosaki
authors.forename: Kanako
authors.initials: K
authors.lastname: Sei
authors.forename: Aiko
authors.initials: A
authors.lastname: Gotoh
authors.forename: Rika
authors.initials: R
authors.lastname: Ohtake
authors.forename: Michihiro
authors.initials: M
authors.lastname: Kawano
authors.forename: Kazushi
authors.initials: K
authors.lastname: Watanabe
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kohno
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011621:Pteridines / Q000494:pharmacology; D034622:RNA Interference; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism*
chemical_list: C516541:BI D1870; D047908:Intracellular Signaling Peptides and Proteins; C118408:OSTF1 protein, human; D011506:Proteins; D011621:Pteridines; D012694:Serine; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D020928:Mitogen-Activated Protein Kinases