GIV-Kindlin interaction is required for Kindlin-Mediated Integrin Recognition and Activation

Cells perceive and respond to the extracellular matrix (ECM) 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 Galphai, 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 the affinity of Kindlin-2 for beta1-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 two-fold impact: it allosterically synergizes integrin activation and enables beta1-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/beta1-integrin on time to progression to metastasis.