An acquired defect associated with abnormal signaling of the platelet collagen receptor glycoprotein VI

Jian Lin Qiao, Jane Frances Arthur, Margaret Collecutt, Yang Shen, Fi-Tjen Mu, Michael Claude Berndt, Amanda Davis, Robert Keith Andrews, Elizabeth Ellen Gardiner

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6 Citations (Scopus)


Ligands acting at the platelet collagen receptor, glycoprotein (GP)VI, induce intracellular FcR?/Syk-dependent signaling pathways and Syk-dependent or Syk-independent generation of intracellular reactive oxygen species (ROS). Additional signaling-dependent or signaling-independent pathways lead to metalloproteinase-mediated shedding of GPVI. Aim: Analysis of platelet GPVI expression and signaling in a patient with a collagen-selective defect associated with myelodysplastic syndrome (MDS) uniquely demonstrates divergent pathways leading to ROS generation and Syk phosphorylation in human platelets. Methods: Surface expression of GPVI and ligand-induced ROS generation was quantitated by flow cytometry. GPVI shedding and Syk phosphorylation were analyzed by Western blot. Results: Despite platelet count/size and GPVI surface expression within normal ranges, platelet-rich plasma showed no aggregation in response to collagen or GPVI-selective agonist collagen-related peptide, but aggregated in response to other agonists, consistent with dysfunctional GPVI signaling. We observed rapid GPVI-dependent Syk-independent ROS generation and disulfide-dependent GPVI homodimerization, but not Syk-dependent ROS or ligand-induced shedding. Temporal analysis showed a gradual decline in platelet count and the appearance of ligand-induced phosphorylation of an 40-kDa Syk fragment. Conclusions: These studies show that GPVI ligation in platelets induces intracellular ROS production independent of either Syk activation or divergent pathways leading to platelet aggregation or ectodomain shedding. Copyright ? 2012 S. Karger AG, Basel.
Original languageEnglish
Pages (from-to)233 - 241
Number of pages9
JournalActa Haematologica
Issue number4
Publication statusPublished - 2012

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