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

doi:10.1016/j.isci.2020.101209

GIV•Kindlin Interaction Is Required for Kindlin-Mediated Integrin Recognition and Activation

iScience. 2020 Jun 26;23(6):101209. doi: 10.1016/j.isci.2020.101209. Epub 2020 May 28.

Authors

Cristina Rohena¹, Nicholas Kalogriopoulos², Navin Rajapakse³, Suchismita Roy³, Inmaculada Lopez-Sanchez¹, Jailal Ablack¹, Debashis Sahoo⁴, Pradipta Ghosh⁵

Affiliations

¹ Department of Medicine, University of California San Diego, 9500 Gilman Drive (MC 0651), George E. Palade Bldg, Rm 239, La Jolla, CA 92093, USA.
² 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.
³ Department of Cellular and Molecular Medicine, University of California San Diego, CA 92093, USA.
⁴ 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.
⁵ 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. Electronic address: prghosh@ucsd.edu.

Abstract

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.

Keywords: Biological Sciences; Cell Biology; Molecular Biology.

Abstract

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