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Blood, 27 August 2009, Vol. 114, No. 9, pp. 1893-1899. Prepublished online as a Blood First Edition Paper on May 22, 2009; DOI 10.1182/blood-2009-03-209510. This Article Full Text Full Text (PDF) Supplemental Methods, Tables, and Figures All Versions of this Article: blood-2009-03-209510v1 114/9/1893    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Trifiro, E. Articles by Kunicki, T. J. PubMed PubMed Citation Articles by Trifiro, E. Articles by Kunicki, T. J. Related Collections Platelets and Thrombopoiesis Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLATELETS AND THROMBOPOIESIS The low-frequency isoform of platelet glycoprotein VIb attenuates ligand-mediated signal transduction but not receptor expression or ligand binding Elisabetta Trifiro1,2, Shirley A. Williams3, Yann Cheli1, Kenichi Furihata1, Fabio M. Pulcinelli2, Diane J. Nugent3, and Thomas J. Kunicki1 1 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; 2 Department of Experimental Medicine and Pathology, University La Sapienza, Rome, Italy; and 3 Children's Hospital of Orange County, Orange, CA The 2 most common haplotypes of human GP6, GP6a and GP6b, generate the allelic isoforms glycoprotein VI (GPVI)a and GPVIb that differ by 5 amino acids: S219P, K237E, and T249A in the ectodomains, and Q317L and H322N in the cytoplasmic domain. By quantitative Western blot, we found no association between GP6 genotype and total platelet GPVI content among 132 normal subjects. When expressed as soluble products or as membrane-associated receptors, GPVIa and GPVIb have identical affinities for type I collagen, collagen-related peptide, or convulxin. However, the cytoplasmic domain substitutions in GPVIb have a significant effect on GPVI-dependent subcellular associations and ligand-induced signal transduction. L317 increases binding to calmodulin, whereas N322 attenuates binding to Fyn/Lyn. Consistent with the latter finding, convulxin-induced Syk phosphorylation is significantly attenuated in Dami cells stably transfected with GPVIb, relative to GPVIa. This represents direct evidence that haplotype-related GPVI functional differences are inherent in the cytoplasmic domain substitutions, whereby GPVIb binds less strongly to Fyn/Lyn and attenuates the rate and extent of Syk phosphorylation. These allelic differences in GP6a and GP6b explain functional differences in the respective isoforms, but the molecular basis for the several-fold range in GPVI levels of human platelets remains to be determined. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: GPVI: the inside story Alan Nurden Blood 2009 114: 1723-1724. [Abstract] [Full Text] [PDF] This article has been cited by other articles: A. Nurden GPVI: the inside story Blood, August 27, 2009; 114(9): 1723 - 1724. [Abstract] [Full Text] [PDF]

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