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

iScience (Jun 2020)

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

Journal volume & issue: Vol. 23, no. 6
p. 101209

Abstract

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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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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