摘要：SummaryCells 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.Graphical AbstractDisplay OmittedHighlights•GIV and Kindlin (K2), two integrin adaptors that promote metastasis, bind each other•Binding of GIV or integrin to K2 allosterically enhances GIV•K2•integrin complexes•Binding is required for the maximal recruitment of GIV and K2 to active integrins•Binding facilitates integrin clustering, activation, tumor cell adhesion, invasionBiological Sciences; Molecular Biology; Cell Biology
