title: Focal adhesion kinase-dependent focal adhesion recruitment of SH2 domains directs SRC into focal adhesions to regulate cell adhesion and migration.
abstract: Directed cell migration requires dynamical control of the protein complex within focal adhesions (FAs) and this control is regulated by signaling events involving tyrosine phosphorylation. We screened the SH2 domains present in tyrosine-specific kinases and phosphatases found within FAs, including SRC, SHP1 and SHP2, and examined whether these enzymes transiently target FAs via their SH2 domains. We found that the SRC_SH2 domain and the SHP2_N-SH2 domain are associated with FAs, but only the SRC_SH2 domain is able to be regulated by focal adhesion kinase (FAK). The FAK-dependent association of the SRC_SH2 domain is necessary and sufficient for SRC FA targeting. When the targeting of SRC into FAs is inhibited, there is significant suppression of SRC-mediated phosphorylation of paxillin and FAK; this results in an inhibition of FA formation and maturation and a reduction in cell migration. This study reveals an association between FAs and the SRC_SH2 domain as well as between FAs and the SHP2_N-SH2 domains. This supports the hypothesis that the FAK-regulated SRC_SH2 domain plays an important role in directing SRC into FAs and that this SRC-mediated FA signaling drives cell migration.
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Jui-Chung
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Chih-Ting
authors.initials: CT
authors.lastname: Kuo
authors.affiliation: Institute of Biophotonics, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Helen
authors.initials: H
authors.lastname: Wenshin Yu
authors.affiliation: Institute of Biophotonics, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Yin-Quan
authors.initials: YQ
authors.lastname: Chen
authors.affiliation: Institute of Biophotonics, National Yang-Ming University, Taipei 11221, Taiwan.|Biophotonics and Molecular Imaging Research Center, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Arthur
authors.initials: A
authors.lastname: Chiou
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan.|Biophotonics and Molecular Imaging Research Center, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Jean-Cheng
authors.initials: JC
authors.lastname: Kuo
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D036681:Fluorescence Recovery After Photobleaching; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D008856:Microscopy, Fluorescence; D051419:Paxillin / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D059008:Time-Lapse Imaging; D018909:src Homology Domains
chemical_list: D051419:Paxillin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D010744:Phosphoric Monoester Hydrolases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases