title: The Src substrate SKAP2 regulates actin assembly by interacting with WAVE2 and cortactin proteins.
abstract: In our attempt to screen for substrates of Src family kinases in glioblastoma, Src kinase-associated phosphoprotein 2 (SKAP2) was identified. Although SKAP2 has been suggested to be associated with integrin-mediated adhesion of hematopoietic cells, little is known about its molecular function and the effects in other types of cells and tumors. Here, we demonstrate that SKAP2 physically associates with actin assembly factors WAVE2 and cortactin and inhibits their interaction. Cortactin is required for the membrane localization of WAVE2, and SKAP2 suppresses actin polymerization mediated by WAVE2 and cortactin in vitro. Knockdown of SKAP2 in NIH3T3 accelerated cell migration and enhanced translocation of WAVE2 to the cell membrane, and those effects of SKAP2 depend on the binding activity of SKAP2 to WAVE2. Furthermore, reduction of SKAP2 in the glioblastoma promoted tumor invasion both in ex vivo organotypic rat brain slices and immune-deficient mouse brains. These results suggest that SKAP2 negatively regulates cell migration and tumor invasion in fibroblasts and glioblastoma cells by suppressing actin assembly induced by the WAVE2-cortactin complex, indicating that SKAP2 may be a novel candidate for the suppressor of tumor progression.
authors.affiliation: Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Shimamura
authors.forename: Kazuki
authors.initials: K
authors.lastname: Sasaki
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Tanaka
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D051356:Cortactin / Q000378:metabolism*; D017931:DNA Primers; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D041681:NIH 3T3 Cells; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000199:Actins; C495868:CTTN protein, human; D051356:Cortactin; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; C120152:WASF2 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; C116431:src kinase associated phosphoprotein 2; D019061:src-Family Kinases