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a common ligand with GPVI and requires previous activating signals to adopt a high-affinity conformation needed for colla-gen adhesion. Mazzucato et al make an important contribution by showing that, as platelets interact with collagen under flow, ␣2␤1 receptors generate calcium signals that are distinct from those generated by GPVI. Surprisingly, ␣2␤1-dependent calcium signals are even generated in the absence of GPVI, forcing us to reexamine the concept of strict dependence on previous inside-out integrin activation for ␣2␤1 ligand binding and whether GPVI is a major source of these inside-out signals. Even more unexpected is the finding that GPVI-associated calcium signals do not take place in the absence of ␣2␤1, suggesting a stronger synergy between ␣2␤1 and GPVI than previously appreciated. These intriguing results are significant because they document integrin-dependent signals during the actual process of platelet interaction with collagen under flow, a response believed to faithfully reproduce the in vivo interaction between platelets and vessel wall collagen. A major question raised by this and previous studies is the functional importance of these integrin-generated signals. Various studies have suggested that ␣2␤1 can syner-gize with GPVI during platelet collagen responses , 7,11,12 but defining a direct signaling role for ␣2␤1 has been more difficult. Mazzu-cato et al note that more than half of platelets successfully adhere to collagen under flow without generating such ␣2␤1-mediated calcium signals, and GPVI-deficient platelets do not exhibit robust collagen signaling despite the presence of ␣2␤1 integrins. Thus, one possibility is that these integrin signals are either not functionally significant or not sufficient to support platelet activation. Alternatively , as suggested by the authors, the signals generated by GPVI and ␣2␤1, like similar signals generated by GPIb and integrin aIIbb3 during platelet rolling on von Willebrand factor , 13 may function in an interactive and even reciprocal fashion as platelets interact with matrix ligands such as collagen that are both activating and adhesive. Such interdependent molecular interactions are particularly difficult to unravel using standard loss-of-function experiments, and a more detailed understanding of molecular mechanisms by which inte-grins trigger such signaling events will be needed to test their biological roles. Conflict-of-interest disclosure: The authors declare no competing financial interests. ■ REFERENCES 1. Mazzucato M, Cozzi MR, Battiston M, et al. Distinct spatio-temporal Ca2ϩ signaling elicited by integrin {alpha}2{beta}1 and glycoprotein VI under flow.protein VI but not alpha2beta1 integrin is essential for platelet interaction with collagen. The contribution of glycoprotein …