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Molecular and Cellular Biology, July 2003, p. 4764-4777, Vol. 23, No. 14
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.14.4764-4777.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Reciprocal Signaling by Integrin and Nonintegrin Receptors during Collagen Activation of Platelets

Hong Chen and Mark L. Kahn*

Division of Cardiology and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Received 11 December 2002/ Returned for modification 24 February 2003/ Accepted 21 April 2003

Activation of platelets by exposed collagen after vessel wall injury is a primary event in the pathogenesis of stroke and myocardial infarction. Two collagen receptors, integrin {alpha}2ß1 and glycoprotein VI (GPVI), are expressed at similar levels on human and mouse platelets, but their individual roles during collagen activation remain poorly defined. Recent genetic and pharmacologic experiments have revealed an essential role for GPVI but have failed to define the role of {alpha}2ß1 or explain how two structurally distinct collagen receptors might function together to mediate platelet collagen responses. Discriminating the roles of these two collagen receptors is complicated by evidence suggesting that GPVI and platelet integrins may activate a common intracellular signaling pathway. To determine how {alpha}2ß1 and GPVI activate platelets in response to collagen, we have (i) examined collagen signaling conferred by expression of these receptors in hematopoietic cell lines; (ii) determined the effect of blocking each receptor on the activation of human platelets by collagen; (iii) generated low-GPVI mice in which the {alpha}2ß1/GPVI receptor ratio has been altered from 1:1 to 50:1 to expose {alpha}2ß1 function; (iv) studied the collagen responses of mouse platelets lacking LAT, an adaptor protein critical for GPVI but not integrin signaling; and (v) addressed the mechanism by which soluble collagens activate wild-type platelets. These studies demonstrate that {alpha}2ß1 requires inside-out signals to participate in collagen signaling and that {alpha}2ß1 is required for collagen activation of platelets when GPVI signals are reduced by blocking anti-GPVI antibody, low receptor number, specific disruption of the GPVI signaling pathway, or forms of collagen that bind weakly to GPVI relative to {alpha}2ß1. We propose a reciprocal two-receptor model of collagen signaling in platelets in which the nonintegrin receptor GPVI provides the primary collagen signal that activates and recruits the integrin receptor {alpha}2ß1 to further amplify collagen signals and fully activate platelets through a common intracellular signaling pathway. This model explains many of the genetic and pharmacologic observations regarding collagen signaling in platelets and demonstrates a novel mechanism by which hematopoietic cells integrate signaling by structurally distinct receptors that share a common ligand.

* Corresponding author. Mailing address: Division of Cardiology, Department of Medicine, University of Pennsylvania, BRB II/III Rm. 952, 421 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 898-9007. Fax: (215) 573-2094. E-mail: markkahn{at}mail.med.upenn.edu.

Molecular and Cellular Biology, July 2003, p. 4764-4777, Vol. 23, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.14.4764-4777.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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