GIV•Kindlin Interaction Is Required for Kindlin-Mediated Integrin Recognition and Activation
Cristina Rohena,
Nicholas Kalogriopoulos,
Navin Rajapakse,
Suchismita Roy,
Inmaculada Lopez-Sanchez,
Jailal Ablack,
Debashis Sahoo,
Pradipta Ghosh
Affiliations
Cristina Rohena
Department of Medicine, University of California San Diego, 9500 Gilman Drive (MC 0651), George E. Palade Bldg, Rm 239, La Jolla, CA 92093, USA
Nicholas Kalogriopoulos
Department of Medicine, University of California San Diego, 9500 Gilman Drive (MC 0651), George E. Palade Bldg, Rm 239, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California San Diego, CA 92093, USA
Navin Rajapakse
Department of Cellular and Molecular Medicine, University of California San Diego, CA 92093, USA
Suchismita Roy
Department of Cellular and Molecular Medicine, University of California San Diego, CA 92093, USA
Inmaculada Lopez-Sanchez
Department of Medicine, University of California San Diego, 9500 Gilman Drive (MC 0651), George E. Palade Bldg, Rm 239, La Jolla, CA 92093, USA
Jailal Ablack
Department of Medicine, University of California San Diego, 9500 Gilman Drive (MC 0651), George E. Palade Bldg, Rm 239, La Jolla, CA 92093, USA
Debashis Sahoo
Department of Pediatrics, University of California San Diego, CA 92093, USA; Department of Computer Science and Engineering, Jacob's School of Engineering, University of California San Diego, CA 92093, USA; Rebecca and John Moore Comprehensive Cancer Center, University of California San Diego, CA 92093, USA
Pradipta Ghosh
Department of Medicine, University of California San Diego, 9500 Gilman Drive (MC 0651), George E. Palade Bldg, Rm 239, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California San Diego, CA 92093, USA; Rebecca and John Moore Comprehensive Cancer Center, University of California San Diego, CA 92093, USA; Veterans Affairs Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161, USA; Corresponding author
Summary: Cells perceive and respond to the extracellular matrix via integrin receptors; their dysregulation has been implicated in inflammation and cancer metastasis. Here we show that a guanine nucleotide-exchange modulator of trimeric-GTPase Gαi, GIV (a.k.a Girdin), directly binds the integrin adaptor Kindlin-2. A non-canonical short linear motif within the C terminus of GIV binds Kindlin-2-FERM3 domain at a site that is distinct from the binding site for the canonical NPxY motif on the -integrin tail. Binding of GIV to Kindlin-2 allosterically enhances Kindlin-2's affinity for β1-integrin. Consequently, integrin activation and clustering are maximized, which augments cell adhesion, spreading, and invasion. Findings elucidate how the GIV•Kindlin-2 complex has a 2-fold impact: it allosterically synergizes integrin activation and enables β1-integrins to indirectly access and modulate trimeric GTPases via the complex. Furthermore, Cox proportional-hazard models on tumor transcriptomics provide trans-scale evidence of synergistic interactions between GIV•Kindlin-2•β1-integrin on time to progression to metastasis.
