HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Platelet glycoprotein (GP) VI and integrin α2β1 cooperate to mediate effective adhesion of platelets to collagens. When platelets engage collagen, it is thought that GPVI predominantly mediates outside-in signaling leading to activation of α2β1 that then mediates a more stable adhesion. While debate remains as to the relative contribution of each receptor, it is clear that in mice the genetic elimination of either receptor alone does not completely inhibit collagen-induced platelet responses.1,2 

The independent function of α2β1 and its potential role in collagen-induced signal transduction may be underestimated. Recently, Inoue et al3  looked more carefully at the role of α2β1 in adhesion and spreading of platelets on a collagen-coated surface. A key observation was that the intracellular signaling cascade used by α2β1 shares many of the features of the GPVI signaling cascade, including participation of Src kinases, Syk, SLP-76, and PLCγ2. The only component that is apparently not involved is LAT. Moreover, engagement of α2β1 initiates signals through an independent pathway involving FAK, PMCA, and Ca2+ mobilization that is not detectable when collagen binds to platelets in suspension.

For several years, it has been known that platelet α2β1 levels in humans can vary by roughly 4-fold due to the inheritance of 1 or more of 3 major human ITGA2 haplotypes.4  Haplotype 1 (T807; G1648) is associated with the highest density of α2β1; haplotype 2 (C807; G1648) confers the lowest density; and the low-frequency haplotype 3 (C807; A1648) is associated with intermediate receptor density. The molecular basis for differences in expression associated with each of these haplotypes remains to be precisely determined. In addition, 2 single nucleotide polymorphisms (SNPs) within the promoter region of human ITGA2 can decrease binding of the transcription factor Sp1, resulting in decreased transcription of ITGA2 and further reductions in densities of platelet α2β1.5 

Until now, these genetic differences in α2β1 expression had been thought to be unique to humans. However, Li and colleagues (page 3396) in this issue of Blood describe yet another experiment of nature that adds a new perspective to the study of platelet integrin α2β1 expression and its role in platelet function in vivo. They have made the very intriguing observation that genetic variation in α2 expression exists between mouse strains and accounts for differences in platelet responses to collagen. Compared with 4 other common strains, platelets from FVB/N mice show a 50% reduction in expression of α2β1 but normal levels of other key receptors, including GPVI, GPIb, and the integrin αIIbβ3. Platelets from FVB/N mice exhibit reduced aggregation and a prolonged lag phase in their response to collagen. Linkage analysis demonstrates that the reduction in α2β1 levels is linked to the D13mit260 marker that is upstream from the α2 gene. The discovery of differences in α2β1 expression in mouse strains provides a new vehicle to investigate the molecular basis of this phenomenon and its importance to platelet function in vivo.

1
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
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2003
;
102
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1701
-1707.
2
Holtkotter O, Nieswandt B, Smyth N, et al. Integrin α2-deficient mice develop normally, are fertile, but display partially defective platelet interaction with collagen.
J Biol Chem
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2002
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277
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3
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
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2003
;
160
:
769
-780.
4
Kritzik M, Savage B, Nugent DJ, et al. Nucleotide polymorphisms in the alpha 2 gene define multiple alleles which are associated with differences in platelet alpha 2 beta 1.
Blood
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1998
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92
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2382
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5
Jacquelin B, Rozenshteyn D, Kanaji S, et al. Characterization of inherited differences in transcription of the human integrin alpha 2 gene.
J Biol Chem
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2001
;
276
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23518
-23524.