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bioRxiv · 10.1101/870113

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

Rohena, C.·Kalogriopoulos, N.·Rajapakse, N.·Roy, S.·Lopez-Sanchez, I.·Ablack, J.·Sahoo, D.·Ghosh, P.
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Abstract

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 Gi, GIV (a.k.a Girdin), directly binds the integrin adaptor Kindlin-2. A non-canonical short linear motif within GIVs C-terminus 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-2s affinity for {beta}1-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 {beta}1-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*{beta}1-integrin on time to progression to metastasis. The eTOC blurbIntegrins mediate cell adhesion to the extracellular matrix; their dysregulation fuels inflammation, cancer cell invasion and metastasis. Authors show how two pro-metastatic scaffold proteins, Kindlin and GIV/Girdin bind and cooperatively enhance their allosteric coupling to integrins, and their subsequent activation. Findings reveal novel interfaces in integrin signaling for pharmacologic manipulation. HIGHLIGHTSO_LIGIV and Kindlin(K2), two integrin adaptors that promote metastasis, bind each other C_LIO_LIBinding of GIV or integrin to K2 allosterically enhances GIV*K2*integrin complexes C_LIO_LIBinding is required for the maximal recruitment of GIV and K2 to active integrins C_LIO_LIBinding facilitates integrin clustering, activation, tumor cell adhesion, invasion. C_LI

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Rohena, C., Kalogriopoulos, N., Rajapakse, N., Roy, S., Lopez-Sanchez, I., Ablack, J., Sahoo, D., Ghosh, P.. 2019-12-10. GIV-Kindlin interaction is required for Kindlin-Mediated Integrin Recognition and Activation. https://doi.org/10.1101/870113

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