Disease relevance of Gp6

• Activation-independent, antibody-mediated removal of GPVI from circulating human platelets: development of a novel NOD/SCID mouse model to evaluate the in vivo effectiveness of anti-human platelet agents [1].
• Platelet glycoprotein VI (GPVI) is now considered to be a major player in platelet-collagen adhesive interactions leading to thrombus formation [2].
• GPVI-deficient mice lack collagen responses and are protected against experimentally induced pulmonary thromboembolism [2].
• GPVI and alpha 2 beta 1 levels were found to be significantly decreased on platelets from patients with myeloproliferative disorders (MPDs) [3].
• FcRgamma and GPVI may be important therapeutic targets for myocardial ischemia-reperfusion injury [4].
• This route of GPVI loss is not associated with thrombocytopenia or altered thrombin responses [5].
• Our results indicate that one or more modifier genes in Mh control the extent to which in vivo platelet thrombus formation is disrupted by the absence of platelet GPVI [6].

High impact information on Gp6

• These findings reveal an unexpected role of GPVI in the initiation of platelet attachment at sites of vascular injury and unequivocally identify platelet-collagen interactions (via GPVI) as the major determinant of arterial thrombus formation [7].
• Here, we demonstrate by intravital fluorescence microscopy of the mouse carotid artery that inhibition or absence of the major platelet collagen receptor, GPVI, abolishes platelet-vessel wall interactions after endothelial denudation [7].
• Differential requirement for LAT and SLP-76 in GPVI versus T cell receptor signaling [8].
• These results suggest that GPVI might become a target for long-term prophylaxis of ischemic cardiovascular diseases and provide the first evidence that it is possible to specifically deplete an activating glycoprotein receptor from circulating platelets in vivo [9].
• The present study extends this model by demonstrating that engagement of alpha2beta1 by an integrin-specific sequence from within collagen or by collagen itself generates tyrosine kinase-based intracellular signals that lead to formation of filopodia and lamellipodia in the absence of the GPVI-FcR gamma-chain complex [10].

Chemical compound and disease context of Gp6

• The physiological importance of this GPVI pathway was shown in a FeCl3-induced in vivo murine thrombosis model [11].
• Collectively, these data indicate that integrin alpha2beta1 facilitates the central function of GPVI in the platelet activation processes that lead to thrombus formation, whereas the autocrine thromboxane A2 and ADP serve mainly to trigger aggregate formation [12].

Biological context of Gp6

• Tec regulates platelet activation by GPVI in the absence of Btk [13].
• GPVI cross-linking mediates activation through tyrosine phosphorylation of an ITAM (immunoreceptor tyrosine-based activation motif) in the FcR gamma-chain by Src family kinases [14].
• These observations clearly establish that blockade of GPVI may attenuate platelet-collagen interactions without adversely affecting the bleeding time [2].
• Animals from each genotype had essentially similar tail bleeding time, suggesting that a complete deficiency of GPVI, at least in mice, does not result in an enhanced bleeding tendency [2].
• This study demonstrates a minor role for the p110delta catalytic subunit in mediating platelet activation by the collagen receptor GPVI and integrin alphaIIbeta3 [15].

Anatomical context of Gp6

• It has been previously shown that a transmembrane arginine and the cytoplasmic domain of GPVI are required for association with the FcR gamma-chain in immortalized cell lines [14].
• The study also demonstrated that the soluble protein blocks Cvx and collagen-induced platelet aggregation and that GPVI expression is restricted to megakaryocytes and platelets [16].
• These results identify GPVI as a novel receptor for laminin and support a model in which integrin alpha6beta1 brings laminin to GPVI, which in turn mediates lamellipodia formation [17].
• In both venules and arterioles, signaling through GPVI, FcR gamma-chain, and Src kinases enhanced the formation of phosphatidylserine-exposing and fibrin-rich thrombi [11].
• Second, alborhagin induced GPVI-dependent responses in GPVI-transfected K562 and Jurkat cells [18].

Associations of Gp6 with chemical compounds

• GPVI is a 62-kDa membrane glycoprotein expressed in noncovalent association with the Fc receptor gamma chain on human and murine platelets and serves as the major activating receptor for collagen [1].
• GPVI(null) mice platelets failed to respond to a high dose of fibrillar collagen, or convulxin, a GPVI agonist, but showed a normal response to other agonists such as ADP, PMA and arachidonic acid [2].
• Both the proteolysis of GPVI and the loss of its activity were inhibited in the presence of the broad range metalloproteinase inhibitor, GM6001 [19].
• GPVI genotype had a significant effect on receptor levels with carriers of the proline 219 allele (approximately 22% of the population) having 10% lower GPVI levels than the more common serine homozygotes [3].
• Our results show that collagen-related peptide ¿CRP: [GCP*(GPP*)(10)GCP*G](n); P*=hydroxyproline¿, which is selective to GPVI, induces formation of phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P(3)] and phosphatidylinositol 3,4-bisphosphate [PI(3, 4)P(2)] in platelets [20].

Physical interactions of Gp6

• The platelet collagen receptor glycoprotein VI (GPVI) couples to the immune receptor adaptor Fc receptor gamma-chain (FcRgamma) and signals using many of the same intracellular signaling molecules as immune receptors [21].

Regulatory relationships of Gp6

• Activation of the collagen receptor glycoprotein VI (GPVI) by a collagen-related peptide (CRP) induces stimulation of platelets and megakaryocytes through the phosphatidylinositol (PI) 3-kinase-dependent pathway leading to activation of Bruton tyrosine kinase (Btk) and phospholipase Cgamma2 (PLCgamma2) [22].
• Glycoproteins GPVI and GPIb-IX-V stimulate robust tyrosine phosphorylation of Syk and PLCg2 (phospholipase Cg2) in washed platelets, but only the former stimulates pronounced activation of phospholipase [23].

Other interactions of Gp6

• This work demonstrates that lipid rafts orchestrate GPVI receptor signaling in platelets in a manner analogous to immune cell receptors and supports a model of GPVI signaling in which FcRgamma phosphorylation is controlled by ligand-dependent association with lipid rafts [21].
• Role of the adapter protein SLP-76 in GPVI-dependent platelet procoagulant responses to collagen [24].
• In the current study, the role of 2 Src family kinases, Fyn and Lyn, in GPVI signaling has been examined using murine platelets deficient in one or both kinases [25].
• Our results demonstrate fundamental differences between GPVI and GPIb-IX-V in the regulation of tyrosine phosphorylation of Syk and PLCg2 consistent with the functional impairment of phospholipase in signalling by GPIb-IX-V [23].

Analytical, diagnostic and therapeutic context of Gp6

• This study examined the expression of the platelet collagen receptor glycoprotein VI (GPVI) in megakaryocyte cell lines and primary megakaryocytes by reverse transcriptase-polymerase chain reaction and by flow cytometry and ligand blotting using the snake venom toxin convulxin [26].
• In both the MPD and the control group, GPVI levels were found not to affect platelet function under high shear in whole blood [3].
• To examine the functional significance of platelet FcR gamma/GPVI complex in the early phase of myocardial ischemia and reperfusion injury in mice, we performed coronary occlusion and reperfusion experiments using wild type mice and FcRgamma-deficient (FcRgamma(-/-)) mice that lack GPVI [4].
• Since mAb 204-11 reacts specifically with GPVI and is applicable for immunoblotting and immunoprecipitation, this antibody would be useful for studies on GPVI [27].

References