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.

Highlights

  • Integrin adhesion drives Arg kinase activity-dependent changes in cell motility and morphogenesis

  • A Lysine-rich Region in the Integrin ␤1 Cytoplasmic Tail Binds to the Arg Kinase Domain—Full-length Arg and the Arg kinase domain alone bind with micromolar affinity to a GST

  • We evaluated which residues in integrin ␤1 and Arg mediate the direct interactions in cells

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Summary

Background

Integrin adhesion drives Arg kinase activity-dependent changes in cell motility and morphogenesis. ␤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 ␤1 activates Arg are unknown. We have previously reported that Arg, but not Abl, is enriched in invadopodia of highly metastatic breast cancer cells, that its kinase activity is required for efficient matrix degradation and invasion, and that integrin ␤1 signaling through Arg is critical for these processes [10, 13] Despite these central roles for integrin ␤1-Arg interactions in cell morphogenesis and motility, the molecular mechanism by which integrins control Abl family kinase activation is unknown. 5 Supported by National Institutes of Health Grant RO1 GM068600.

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