An Acquired Defect Associated with Abnormal Signaling of the Platelet Collagen Receptor Glycoprotein VI

作者：Qiao Jianlin; Arthur Jane F; Collecutt Margaret; Shen Yang; Mu Fi Tjen; Berndt Michael C; Davis Amanda K; Andrews Robert K; Gardiner Elizabeth E^*

来源：Acta Haematologica, 2012, 128(4): 233-241.

DOI：10.1159/000340048

• Collagen
• Glycoprotein VI
• Myelodysplastic syndrome
• Platelets
• Shedding
• Syk

Introduction: Ligands acting at the platelet collagen receptor, glycoprotein (GP) VI, induce intracellular FcR gamma/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 similar to 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.

• 出版日期2012