Reciprocal signaling by integrin and nonintegrin receptors during collagen activation of platelets.
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 alpha2beta1 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 alpha2beta1 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 alpha2beta1 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 alpha2beta1/GPVI receptor ratio has been altered from 1:1 to 50:1 to expose alpha2beta1 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 alpha2beta1 requires inside-out signals to participate in collagen signaling and that alpha2beta1 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 alpha2beta1. 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 alpha2beta1 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.
Chen
Hong
H
Division of Cardiology and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Kahn
Mark L
ML
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D003435:Crotalid Venoms / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D038982:Integrin alpha2beta1 / Q000235:genetics / Q000378:metabolism*; D037181:Lectins, C-Type; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012995:Solubility
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D002352:Carrier Proteins; D003435:Crotalid Venoms; D038982:Integrin alpha2beta1; C110810:LAT protein, human; C491734:Lat protein, mouse; D037181:Lectins, C-Type; D008565:Membrane Proteins; D010455:Peptides; D010750:Phosphoproteins; D010980:Platelet Membrane Glycoproteins; C435908:collagen-related peptide; C098341:platelet membrane glycoprotein VI; C028890:convulxin; D003094:Collagen