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Blood, 24 September 2009, Vol. 114, No. 13, pp. 2571-2572.
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PLATELETS & THROMBOPOIESIS
Comments on Mazzucato et al, page 2793
Platelet integrin signaling: wherefore art thou?
Alec A. Schmaier, and
Mark L. Kahn
UNIVERSITY OF PENNSYLVANIA
In this issue of Blood, Mazzucato and colleagues demonstrate that collagen receptors GPVI and  2β1 integrin generate qualitatively distinct, independent calcium signals during platelet tethering and adhesion to collagen under flow conditions.1
Rapid-spiking, short-lived, calcium signals using intracellular calcium stores are generated by 2β1 signaling in a glycoprotein (GP)VI-independent fashion. GPVI is responsible for sustained calcium mobilization dependent on extracellular calcium influx but requires the presence of 2β1 signaling. These findings add complexity to our understanding of how 2β1 and GPVI interact in response to collagen and provide additional evidence that platelet activation and platelet adhesion are not distinct and independent events.
Collagen-induced platelet adhesion and activation under flow conditions are considered primary events in the formation of the intra-arterial thrombi that cause stroke and heart attack. Studies in the past decade have identified 2 platelet collagen receptors, the immune-type receptor GPVI and the integrin 2β1, as critical for the formation of platelet thrombi on collagen under flow ex vivo and for arterial thrombus formation under some circumstances in vivo. A widely accepted model of platelet collagen responses assigns GPVI the role of generating platelet activation signals, including "inside-out" signals required to conformationally activate integrins on the platelet surface, and 2β1 the role of mediating firm adhesion to collagen in the face of powerful shear forces.2,3 This model is supported by genetic and pharmacologic loss-of-function studies demonstrating that GPVI signaling is required for platelet activation by collagen, a prerequisite for platelet adhesion to collagen under flow.4,5 In contrast, 2β1 is required for platelet adhesion to collagen under flow but not for platelet activation by collagen.6,7
This clean division of labor suggested by loss-of-function studies has been challenged by findings that have identified roles for 2β1 in the generation of intracellular signals that might initiate or prolong platelet activation. A significant report in the literature, mostly focused on IIbβ3, supports "outside-in" signaling by integrins through the same pathway used by GPVI.8,9 The ability of 2β1 to activate this pathway has been demonstrated and, like GPVI, uses Src-family kinases, Syk, Slp-76, and PLCg2.10 However, unmasking a role for 2β1 signaling in physiologic platelet-collagen responses has been difficult because it shares a common ligand with GPVI and requires previous activating signals to adopt a high-affinity conformation needed for collagen adhesion. Mazzucato et al make an important contribution by showing that, as platelets interact with collagen under flow, 2β1 receptors generate calcium signals that are distinct from those generated by GPVI. Surprisingly, 2β1-dependent calcium signals are even generated in the absence of GPVI, forcing us to re-examine the concept of strict dependence on previous inside-out integrin activation for 2β1 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 2β1, suggesting a stronger synergy between 2β1 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 2β1 can synergize with GPVI during platelet collagen responses,7,11,12 but defining a direct signaling role for 2β1 has been more difficult. Mazzucato et al note that more than half of platelets successfully adhere to collagen under flow without generating such 2β1-mediated calcium signals, and GPVI-deficient platelets do not exhibit robust collagen signaling despite the presence of 2β1 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 2β1, 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 integrins trigger such signaling events will be needed to test their biological roles.
Footnotes
Conflict-of-interest disclosure: The authors declare no competing financial interests. 
REFERENCES
- Mazzucato M, Cozzi MR, Battiston M, et al. Distinct spatio-temporal Ca2+ signaling elicited by integrin {alpha}2{beta}1 and glycoprotein VI under flow. Blood. 2009;114(13):2793–2801.[Abstract/Free Full Text]
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- Varga-Szabo D, Pleines I, Nieswandt B. Cell adhesion mechanisms in platelets. Arterioscler Thromb Vasc Biol. 2008;28(3):403–412.[Abstract/Free Full Text]
- Nieswandt B, Brakebusch C, Bergmeier W, et al. Glycoprotein VI but not alpha2beta1 integrin is essential for platelet interaction with collagen. EMBO J. 2001;20(9):2120–2130.[CrossRef][Medline]
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- Kato K, Kanaji T, Russell S, et al. The contribution of glycoprotein VI to stable platelet adhesion and thrombus formation illustrated by targeted gene deletion. Blood. 2003;102(5):1701–1707.[Abstract/Free Full Text]
- Sarratt KL, Chen H, Zutter MM, Santoro SA, Hammer DA, Kahn ML. GPVI and alpha2beta1 play independent critical roles during platelet adhesion and aggregate formation to collagen under flow. Blood. 2005;106(4):1268–1277.[Abstract/Free Full Text]
- Kuijpers MJ, Schulte V, Bergmeier W, et al. Complementary roles of glycoprotein VI and alpha2beta1 integrin in collagen-induced thrombus formation in flowing whole blood ex vivo. FASEB J. 2003;17(6):685–687.[Abstract/Free Full Text]
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- Obergfell A, Eto K, Mocsai A, et al. Coordinate interactions of Csk, Src, and Syk kinases with [alpha]IIb[beta]3 initiate integrin signaling to the cytoskeleton. J Cell Biol. 2002;157(2):265–275.[Abstract/Free Full Text]
- Inoue O, Suzuki-Inoue K, Dean WL, Frampton J, Watson SP. Integrin alpha2beta1 mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLCgamma2. J Cell Biol. 2003;160(5):769–780.[Abstract/Free Full Text]
- Auger JM, Kuijpers MJ, Senis YA, Watson SP, Heemskerk JW. Adhesion of human and mouse platelets to collagen under shear: a unifying model. FASEB J. 2005;19(7):825–827.[Abstract/Free Full Text]
- Chen H, Kahn ML. Reciprocal signaling by integrin and nonintegrin receptors during collagen activation of platelets. Mol Cell Biol. 2003;23(14):4764–4777.[Abstract/Free Full Text]
- Mazzucato M, Pradella P, Cozzi MR, De Marco L, Ruggeri ZM. Sequential cytoplasmic calcium signals in a 2-stage platelet activation process induced by the glycoprotein Ibalpha mechanoreceptor. Blood. 2002;100(8):2793–2800.[Abstract/Free Full Text]
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Related Article in Blood Online:
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Distinct spatio-temporal Ca2+ signaling elicited by integrin 2β1 and glycoprotein VI under flow
- Mario Mazzucato, Maria Rita Cozzi, Monica Battiston, Martine Jandrot-Perrus, Maurizio Mongiat, Patrizia Marchese, Thomas J. Kunicki, Zaverio M. Ruggeri, and Luigi De Marco
Blood 2009 114: 2793-2801.
[Abstract]
[Full Text]
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