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

  1. Cristina Rohena
  2. Nicholas Kalogriopoulos
  3. Navin Rajapakse
  4. Suchismita Roy
  5. Inmaculada Lopez-Sanchez
  6. Jailal Ablack
  7. Debashis Sahoo
  8. Pradipta Ghosh
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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 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.

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