Direct Interactions with the Integrin β1 Cytoplasmic Tail Activate the Abl2/Arg Kinase

Integrins are heterodimeric alpha/beta 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. beta 1 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 beta 1 activates Arg are unknown. We report here that the Arg kinase domain interacts directly with a lysine-rich membraneproximal segment in the integrin beta 1 cytoplasmic tail, that Arg phosphorylates the membrane-proximal Tyr-783 in the beta 1 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 beta 1 and Arg in vitro and in cells and activate Arg kinase activity. These findings provide a model for understanding how beta 1-containing integrins interact with and activate Abl family kinases.