The integrin αVβ3 has been implicated in regulating endothelial cell adhesion, migration and survival, as well as angiogenesis, but its exact role is debated as both pro- and anti-angiogenic effects have been described in different studies. Kindlin-2, which directly interacts with integrin β-subunits, has also been linked to angiogenesis, but the underlying molecular mechanisms are not clear. In their study on page 3532, Sanford Shattil and colleagues develop an elegant optogenetics approach to interrogate the interaction between kindlin-2 and αVβ3 in a spatiotemporal manner and address its effect on cell migration and angiogenetic sprout formation. Their assay allows them to use blue light to force the interaction of kindlin-2 with an integrin β3 mutant that normally is unable to bind to it in endothelial cells they derived from β3-null mice. Using this system, the authors show that the specific interaction of kindlin-2 with αVβ3 increases endothelial cell migration, podosome formation and angiogenic sprouting. Furthermore, kindlin-2 mutants that lack binding sites for other interaction partners do not promote endothelial cell adhesion or migration, suggesting that angiogenic function requires the simultaneous interaction of kindlin-2 with several factors, in accordance with its described adaptor function. This work thus clearly demonstrates the usefulness of optogenetic approaches to elucidate functional protein–protein interactions at the subcellular level.
