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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1248-1249.
New role for the GPVI/FcR
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1 and a platelet-specific, heterotrimeric receptor composed of the Ig-superfamily member, GPVI, in noncovalent association with a homodimer of the FcR
chain.2 Upon binding collagen, signals emanating from 21 and the GPVI/FcR chain complex reinforce each other, ultimately leading to conformational changes in the major platelet integrin, IIb3, which in its activated state associates with bridging proteins like fibrinogen and VWF. Although the nature of 21-mediated signals is not as well understood, numerous studies using GPVI-deficient mice, FcR chain-deficient mice, and antibodies that either block the interaction of GPVI with collagen or deplete GPVI from the platelet surface, have shown that engagement of the GPVI/FcR chain complex works via Src family kinase-mediated phosphorylation of specific immunoreceptor tyrosine-based inhibitory motifs (ITAMs) that are present on the cytoplasmic domain of the FcR chain. These ITAMs, when phosphorylated, serve as docking sites for the protein-tyrosine kinase Syk, which, when recruited and activated, initiates the rapid assembly of a series of adaptor proteins and protein-tyrosine kinases that are crucial for platelet activation responses, including cytoskeletal rearrangements that mediate platelet shape change and spreading and coalescence and secretion of intracellular granules, as well as activation of additional adhesion receptors that are required for adhesion strengthening and thrombus formation to occur.
In 2003, Gruner and colleagues3 reported in this journal the somewhat surprising observation that platelets from 21-deficient mice adhere quite normally to the wall of a ligation-injured murine carotid artery, and that their adhesion was only partially reduced when IIb3 was additionally blocked by a monoclonal antibody. When IIb3 was inhibited in murine platelets missing all 3 1 integrins (21, 51, and 61), however, adhesion and thrombus formation were absent, implicating 51 and/or 61 as integrins capable of mediating platelet-vessel wall interactions under conditions of arterial shear. Interestingly, GPVI was found to be indispensable for platelet adhesion and aggregation to occur, strongly suggesting that it might be involved in regulating platelet interactions with the vessel wall.
In this issue of Blood, Inoue and colleagues report the novel observation that the GPVI/FcR chain complex, in addition to its crucial role as a collagen receptor, is also an important component of platelet activation following interaction of 61 with laminin—a prominent component of the basal lamina that underlies epithelial and endothelial cell monolayers and also surrounds individual muscle cells. The interaction of GPVI with laminin was found to be too weak by itself to support adhesion; however, in conjunction with 61, expression of the GPVI/FcR chain complex strongly potentiated formation of lamellipodia, and to a lesser extent filopodia, during the platelet spreading process. Interestingly, platelet activation by laminin was found to enlist the signaling, rather than the adhesive, properties of the GPVI/FcR chain complex, as both platelet spreading and tyrosine phosphorylation of several key downstream components of the GPVI/FcR chain-mediated signaling were markedly reduced in FcR chain-deficient platelets following their interaction with immobilized laminin.
Similar to the interplay between 21 and the GPVI/FcR chain complex following platelet interactions with collagen, the chicken-and-egg question as to whether (1) 61 first binds laminin and presents it to the GPVI/FcR chain for signaling to the cell interior, or (2) GPVI-laminin interactions first activate the 61 integrin to facilitate platelet spreading, remains controversial. Both probably occur. Finally, since the GPVI/FcR chain has now been identified as a central component of both collagen- and laminin-mediated platelet activation, it may be of future interest to determine whether the threshold for cellular activation in response to these prominent components of the extracellular matrix might be regulated by the same inhibitory signaling receptor.4 
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61–dependent activation of GPVI
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  B. Boylan, C. Gao, V. Rathore, J. C. Gill, D. K. Newman, and P. J. Newman Identification of Fc{gamma}RIIa as the ITAM-bearing receptor mediating {alpha}IIb{beta}3 outside-in integrin signaling in human platelets Blood, October 1, 2008; 112(7): 2780 - 2786. [Abstract] [Full Text] [PDF]
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| Copyright © 2006 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
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