Selective impairment of platelet activation to collagen in the absence of GATA1
- 1 June 2005
- journal article
- Published by American Society of Hematology in Blood
- Vol. 105 (11), 4369-4376
- https://doi.org/10.1182/blood-2004-10-4098
Abstract
Defects in the X-linked DNA-binding megakaryocyte transcription factor GATA1 cause thrombocytopenia and abnormal platelet function. However, detailed studies of GATA1 function in platelet activation are lacking. Here, we studied platelets from GATA1-deficient mice and from a male patient (S14) with a bleeding diathesis attributed to a single amino acid substitution (R216Q) in the N-terminal GATA1 zinc finger that alters binding to DNA. In both cases there was inhibition of aggregation to collagen and decreased tyrosine phosphorylation of glycoprotein VI (GPVI)–signaling proteins. This effect was more marked in GATA1-deficient murine platelets, where it was associated with a significant reduction in surface GPVI expression. Moreover, both human and murine GATA1-mutant platelets showed reduced adhesion and aggregate formation on a collagen matrix at an intermediate rate of shear, although this could not be accounted solely by the thrombocytopenia and altered GPVI expression, indicating that GATA1 regulates additional factors important for platelet activation under shear. In contrast, there was no inhibition of responses to G protein–coupled receptor agonists in GATA1-perturbed platelets. Our results are consistent with GATA1 regulating some but not all pathways of platelet activation, leading to an impairment of aggregate formation under flow, which cannot be attributed solely to the thrombocytopenia.Keywords
This publication has 30 references indexed in Scilit:
- Tec regulates platelet activation by GPVI in the absence of BtkBlood, 2003
- A Critical Role for Phospholipase Cγ2 in αIIbβ3-mediated Platelet SpreadingPublished by Elsevier BV ,2003
- Murine GPVI stimulates weak integrin activation in PLCγ2–/– platelets: involvement of PLCγ1 and PI3-kinaseBlood, 2003
- Protein-Protein Interaction between Fli-1 and GATA-1 Mediates Synergistic Expression of Megakaryocyte-Specific Genes through Cooperative DNA BindingMolecular and Cellular Biology, 2003
- Integrin α2β1 mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLCγ2The Journal of cell biology, 2003
- Differential effects of reduced glycoprotein VI levels on activation of murine platelets by glycoprotein VI ligandsBiochemical Journal, 2002
- Characterization of Human Glycoprotein VI Gene 5′ Regulatory and Promoter RegionsArteriosclerosis, Thrombosis, and Vascular Biology, 2002
- X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interactionBlood, 2002
- Differential role of glycolipid-enriched membrane domains in glycoprotein VI- and integrin-mediated phospholipase Cγ2 regulation in plateletsBiochemical Journal, 2002
- Evidence of a Role for SHP-1 in Platelet Activation by the Collagen Receptor Glycoprotein VIPublished by Elsevier BV ,2000