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

iScience

Navin Rajapakse¹  Inmaculada Lopez-Sanchez²  Suchismita Roy²  Jailal Ablack³  Debashis Sahoo³  Cristina Rohena³  Nicholas Kalogriopoulos³  Pradipta Ghosh⁴ 

[1] Department of Cellular and Molecular Medicine, University of California San Diego, CA 92093, USA;Department of Cellular and Molecular Medicine, University of California San Diego, CA 92093, USA;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 Pediatrics, University of California San Diego, CA 92093, USA;

关键词: Biological Sciences;    Molecular Biology;    Cell Biology;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown