GIV•Kindlin Interaction Is Required for Kindlin-Mediated Integrin Recognition and Activation
Year: 2020
Type: article
Abstract: 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 Gαi, GIV ( a . k . a Girdin), 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 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. The eTOC blurb Integrins 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. HIGHLIGHTS 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, invasion.
Source: iScience
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,000
Funders: National Institutes of Health, University of California, San Diego, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences
Awards: G1081931513, G122547126, G1359535963, G1443061497, G155987337, G2478754673, The structural plasticity of chemokine and gp120 recognition by CCR5, G3795641072, G3880607359, Trimeric G proteins as Novel Targets in Cancer Progression, Modulation of Macrophage Polarization by Heterotrimeric G proteins: Implications of Gastrointestinal Inflammation, G5520316217, G5882061030, Spatial Regulation of RGS and G Protein Signaling, G6607237905, G6641989055, Integrators of Metastatic Potential, G819730897, G8436895423, G9000030157, G9000054877, G9000131308, G9000185698, G9000316310, G9000317936, G9000336338, Cancer Biology, Informatics & Omics (CBIO) Training Program, Modulation of G proteins by Growth Factors
OpenAlex ID: W3029629154