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Gp6  -  glycoprotein 6 (platelet)

Mus musculus

Synonyms: 9830166G18Rik, GPVI, Glycoprotein 5, Gm469, Gpvi, ...
 
 
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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

 

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

References

  1. 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. Boylan, B., Berndt, M.C., Kahn, M.L., Newman, P.J. Blood (2006) [Pubmed]
  2. GPVI-deficient mice lack collagen responses and are protected against experimentally induced pulmonary thromboembolism. Lockyer, S., Okuyama, K., Begum, S., Le, S., Sun, B., Watanabe, T., Matsumoto, Y., Yoshitake, M., Kambayashi, J., Tandon, N.N. Thromb. Res. (2006) [Pubmed]
  3. GPVI levels in platelets: relationship to platelet function at high shear. Best, D., Senis, Y.A., Jarvis, G.E., Eagleton, H.J., Roberts, D.J., Saito, T., Jung, S.M., Moroi, M., Harrison, P., Green, F.R., Watson, S.P. Blood (2003) [Pubmed]
  4. Platelets activated by collagen through the immunoreceptor tyrosine-based activation motif in the Fc receptor gamma-chain play a pivotal role in the development of myocardial ischemia-reperfusion injury. Takaya, N., Katoh, Y., Iwabuchi, K., Hayashi, I., Konishi, H., Itoh, S., Okumura, K., Ra, C., Nagaoka, I., Daida, H. J. Mol. Cell. Cardiol. (2005) [Pubmed]
  5. Diverging signaling events control the pathway of GPVI down-regulation in vivo. Rabie, T., Varga-Szabo, D., Bender, M., Pozgaj, R., Lanza, F., Saito, T., Watson, S.P., Nieswandt, B. Blood (2007) [Pubmed]
  6. The Modifier of hemostasis (Mh) locus on chromosome 4 controls in vivo hemostasis of Gp6-/- mice. Cheli, Y., Jensen, D., Marchese, P., Habart, D., Wiltshire, T., Cooke, M., Fernandez, J.A., Ware, J., Ruggeri, Z.M., Kunicki, T.J. Blood (2008) [Pubmed]
  7. A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo. Massberg, S., Gawaz, M., Grüner, S., Schulte, V., Konrad, I., Zohlnhöfer, D., Heinzmann, U., Nieswandt, B. J. Exp. Med. (2003) [Pubmed]
  8. Differential requirement for LAT and SLP-76 in GPVI versus T cell receptor signaling. Judd, B.A., Myung, P.S., Obergfell, A., Myers, E.E., Cheng, A.M., Watson, S.P., Pear, W.S., Allman, D., Shattil, S.J., Koretzky, G.A. J. Exp. Med. (2002) [Pubmed]
  9. Long-term antithrombotic protection by in vivo depletion of platelet glycoprotein VI in mice. Nieswandt, B., Schulte, V., Bergmeier, W., Mokhtari-Nejad, R., Rackebrandt, K., Cazenave, J.P., Ohlmann, P., Gachet, C., Zirngibl, H. J. Exp. Med. (2001) [Pubmed]
  10. Integrin alpha2beta1 mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLCgamma2. Inoue, O., Suzuki-Inoue, K., Dean, W.L., Frampton, J., Watson, S.P. J. Cell Biol. (2003) [Pubmed]
  11. The glycoprotein VI-phospholipase Cgamma2 signaling pathway controls thrombus formation induced by collagen and tissue factor in vitro and in vivo. Munnix, I.C., Strehl, A., Kuijpers, M.J., Auger, J.M., van der Meijden, P.E., van Zandvoort, M.A., oude Egbrink, M.G., Nieswandt, B., Heemskerk, J.W. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
  12. Complementary roles of glycoprotein VI and alpha2beta1 integrin in collagen-induced thrombus formation in flowing whole blood ex vivo. Kuijpers, M.J., Schulte, V., Bergmeier, W., Lindhout, T., Brakebusch, C., Offermanns, S., Fässler, R., Heemskerk, J.W., Nieswandt, B. FASEB J. (2003) [Pubmed]
  13. Tec regulates platelet activation by GPVI in the absence of Btk. Atkinson, B.T., Ellmeier, W., Watson, S.P. Blood (2003) [Pubmed]
  14. Delineation of the region in the glycoprotein VI tail required for association with the Fc receptor gamma-chain. Bori-Sanz, T., Inoue, K.S., Berndt, M.C., Watson, S.P., Tulasne, D. J. Biol. Chem. (2003) [Pubmed]
  15. Role of the p110delta PI 3-kinase in integrin and ITAM receptor signalling in platelets. Senis, Y.A., Atkinson, B.T., Pearce, A.C., Wonerow, P., Auger, J.M., Okkenhaug, K., Pearce, W., Vigorito, E., Vanhaesebroeck, B., Turner, M., Watson, S.P. Platelets (2005) [Pubmed]
  16. Cloning, characterization, and functional studies of human and mouse glycoprotein VI: a platelet-specific collagen receptor from the immunoglobulin superfamily. Jandrot-Perrus, M., Busfield, S., Lagrue, A.H., Xiong, X., Debili, N., Chickering, T., Le Couedic, J.P., Goodearl, A., Dussault, B., Fraser, C., Vainchenker, W., Villeval, J.L. Blood (2000) [Pubmed]
  17. Laminin stimulates spreading of platelets through integrin alpha6beta1-dependent activation of GPVI. Inoue, O., Suzuki-Inoue, K., McCarty, O.J., Moroi, M., Ruggeri, Z.M., Kunicki, T.J., Ozaki, Y., Watson, S.P. Blood (2006) [Pubmed]
  18. A novel viper venom metalloproteinase, alborhagin, is an agonist at the platelet collagen receptor GPVI. Andrews, R.K., Gardiner, E.E., Asazuma, N., Berlanga, O., Tulasne, D., Nieswandt, B., Smith, A.I., Berndt, M.C., Watson, S.P. J. Biol. Chem. (2001) [Pubmed]
  19. GPVI down-regulation in murine platelets through metalloproteinase-dependent shedding. Bergmeier, W., Rabie, T., Strehl, A., Piffath, C.L., Prostredna, M., Wagner, D.D., Nieswandt, B. Thromb. Haemost. (2004) [Pubmed]
  20. A collagen-related peptide regulates phospholipase Cgamma2 via phosphatidylinositol 3-kinase in human platelets. Pasquet, J.M., Bobe, R., Gross, B., Gratacap, M.P., Tomlinson, M.G., Payrastre, B., Watson, S.P. Biochem. J. (1999) [Pubmed]
  21. Lipid rafts orchestrate signaling by the platelet receptor glycoprotein VI. Locke, D., Chen, H., Liu, Y., Liu, C., Kahn, M.L. J. Biol. Chem. (2002) [Pubmed]
  22. Phosphatidylinositol 3-kinase-dependent translocation of phospholipase Cgamma2 in mouse megakaryocytes is independent of Bruton tyrosine kinase translocation. Bobe, R., Wilde, J.I., Maschberger, P., Venkateswarlu, K., Cullen, P.J., Siess, W., Watson, S.P. Blood (2001) [Pubmed]
  23. Glycoproteins VI and Ib-IX-V stimulate tyrosine phosphorylation of tyrosine kinase Syk and phospholipase Cgamma2 at distinct sites. Suzuki-Inoue, K., Wilde, J.I., Andrews, R.K., Auger, J.M., Siraganian, R.P., Sekiya, F., Rhee, S.G., Watson, S.P. Biochem. J. (2004) [Pubmed]
  24. Role of the adapter protein SLP-76 in GPVI-dependent platelet procoagulant responses to collagen. Leo, L., Di Paola, J., Judd, B.A., Koretzky, G.A., Lentz, S.R. Blood (2002) [Pubmed]
  25. Fyn and Lyn phosphorylate the Fc receptor gamma chain downstream of glycoprotein VI in murine platelets, and Lyn regulates a novel feedback pathway. Quek, L.S., Pasquet, J.M., Hers, I., Cornall, R., Knight, G., Barnes, M., Hibbs, M.L., Dunn, A.R., Lowell, C.A., Watson, S.P. Blood (2000) [Pubmed]
  26. Expression of the collagen receptor glycoprotein VI during megakaryocyte differentiation. Berlanga, O., Bobe, R., Becker, M., Murphy, G., Leduc, M., Bon, C., Barry, F.A., Gibbins, J.M., Garcia, P., Frampton, J., Watson, S.P. Blood (2000) [Pubmed]
  27. A new monoclonal antibody, mAb 204-11, that influences the binding of platelet GPVI to fibrous collagen. Moroi, M., Mizuguchi, J., Kawashima, S., Nagamatsu, M., Miura, Y., Nakagaki, T., Ito, K., Jung, S.M. Thromb. Haemost. (2003) [Pubmed]
 
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