Author:
Rohena Cristina,Kalogriopoulos Nicholas,Rajapakse Navin,Roy Suchismita,Lopez-Sanchez Inmaculada,Ablack Jailal,Sahoo Debashis,Ghosh Pradipta
Abstract
ABSTRACTCells perceive and respond to the extracellular matrix (ECM)viaintegrin 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.aGirdin), directly binds the integrin adaptor Kindlin-2. A non-canonical short linear motif within GIV’s 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-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 two-fold impact: it allosterically synergizes integrin activation and enables β1-integrins to indirectly access and modulate trimeric GTPasesviathe 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.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.HIGHLIGHTSGIV and Kindlin(K2), two integrin adaptors that promote metastasis, bind each otherBinding of GIV or integrin to K2 allosterically enhances GIV•K2•integrin complexesBinding is required for the maximal recruitment of GIV and K2 to active integrinsBinding facilitates integrin clustering, activation, tumor cell adhesion, invasion.
Publisher
Cold Spring Harbor Laboratory