title: Direct interactions with the integrin β1 cytoplasmic tail activate the Abl2/Arg kinase.
abstract: Integrins are heterodimeric α/β extracellular matrix adhesion receptors that couple physically to the actin cytoskeleton and regulate kinase signaling pathways to control cytoskeletal remodeling and adhesion complex formation and disassembly. β1 integrins signal through the Abl2/Arg (Abl-related gene) nonreceptor tyrosine kinase to control fibroblast cell motility, neuronal dendrite morphogenesis and stability, and cancer cell invasiveness, but the molecular mechanisms by which integrin β1 activates Arg are unknown. We report here that the Arg kinase domain interacts directly with a lysine-rich membrane-proximal segment in the integrin β1 cytoplasmic tail, that Arg phosphorylates the membrane-proximal Tyr-783 in the β1 tail, and that the Arg Src homology domain then engages this phosphorylated region in the tail. We show that these interactions mediate direct binding between integrin β1 and Arg in vitro and in cells and activate Arg kinase activity. These findings provide a model for understanding how β1-containing integrins interact with and activate Abl family kinases.
authors.affiliation: From the Departments of Molecular Biophysics and Biochemistry.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Simpson
authors.affiliation: From the Departments of Molecular Biophysics and Biochemistry.
authors.forename: William D
authors.initials: WD
authors.lastname: Bradley
authors.affiliation: Pharmacology.
authors.forename: David
authors.initials: D
authors.lastname: Harburger
authors.affiliation: the Randall Division of Cell and Molecular Biophysics, Kings College, London WC2R 2LS, United Kingdom.
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
authors.affiliation: Pharmacology, Cell Biology, and.
authors.forename: David A
authors.initials: DA
authors.lastname: Calderwood
authors.affiliation: From the Departments of Molecular Biophysics and Biochemistry, Neurobiology, Yale University, New Haven, Connecticut 06510 and anthony.koleske@yale.edu.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Koleske
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D019012:Integrin beta1 / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D019012:Integrin beta1; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases
keywords: Abl Tyrosine Kinase; Integrin; Phosphorylation; Protein-Protein Interaction; Src Homology 2 Domain (SH2 Domain)