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An Acquired Defect Associated with Abnormal Signaling of the Platelet Collagen Receptor Glycoprotein VI.
MedLine Citation:
PMID:  22922528     Owner:  NLM     Status:  Publisher    
Introduction: Ligands acting at the platelet collagen receptor, glycoprotein (GP)VI, induce intracellular FcRγ/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.
Jianlin Qiao; Jane F Arthur; Margaret Collecutt; Yang Shen; Fi-Tjen Mu; Michael C Berndt; Amanda K Davis; Robert K Andrews; Elizabeth E Gardiner
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-8-24
Journal Detail:
Title:  Acta haematologica     Volume:  128     ISSN:  1421-9662     ISO Abbreviation:  Acta Haematol.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-8-27     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0141053     Medline TA:  Acta Haematol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  233-241     Citation Subset:  -    
Copyright Information:
Copyright © 2012 S. Karger AG, Basel.
Australian Centre for Blood Diseases, Monash University, Melbourne, Vic., Australia.
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