Integrin's new partner

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Integrins are heterodimeric membrane receptors that mediate cell adhesion and typically perform bidirectional signalling. Signals from inside the cell activate the binding of integrin to extracellular ligands (inside–out signalling), which triggers intracellular signalling initiated by ligand-bound integrin (outside–in signalling). Outside–in signalling can initiate cell spreading, retraction, migration and proliferation, but its mechanism remains unclear. Reporting in Science, Gong et al. now show that intracellular signalling downstream of integrins is mediated by their direct binding to G proteins.

Cell spreading — an early consequence of outside–in signalling — requires activation of the protein kinase SRC, and the SRC-dependent transient inhibition of the small GTPase RHOA, which affects actin cytoskeleton dynamics. Although it is known that integrin engagement leads to SRC-dependent RHOA inhibition, the molecular mechanisms that link integrin to these signalling events have been unclear.

“integrins are non-canonical Gα13 protein-coupled receptors”

Heterotrimeric G proteins consist of the subunits Gα and the tightly associated Gβγ and they bind to the intracellular domain of G protein-coupled receptors (GPCRs). G proteins are activated when extracelluar ligands bind GPCRs and induce the exchange of GDP for GTP on Gα. The authors find that knockdown of Gα₁₃ in platelets inhibits their spreading on fibrinogen — an αIIbβ3 integrin ligand. Depletion of Gα₁₃ also abolishes SRC phosphorylation at Tyr416 (which is indicative of SRC activation) and accelerates RHOA activation. This suggests that Gα₁₃ functions in signalling from ligand-occupied integrins and mediates the downstream inhibition of RHOA, which promotes cell spreading.

Gα₁₃ and β3 integrin co-immunoprecipitate and purified Gα₁₃ binds to a recombinant β3 or β1 integrin cytoplasmic domain fusion protein in vitro, showing that Gα₁₃ binds directly to the integrin cytoplasmic domain. Using truncated versions of Gα₁₃, the authors also show that β3 integrin binds to the switch region I (SRI) of Gα₁₃. Treatment of platelets with a myristoylated SRI peptide inhibits the Gα₁₃–β3 integrin interaction in vitro and prevents integrin-mediated SRC activation, RHOA inhibition and platelet spreading.

These results show that integrins are non-canonical Gα₁₃ protein-coupled receptors and that their interaction with Gα₁₃ mediates integrin signalling to SRC and RHOA, and thus regulates cell spreading.