Dominant role of the protein-tyrosine phosphatase CD148 in regulating platelet activation relative to protein-tyrosine phosphatase-1B.
OBJECTIVE
The receptor-like protein-tyrosine phosphatase (PTP) CD148 and the nontransmembrane PTP1-B have been shown to be net positive regulators of Src family kinases in platelets. In the present study, we compared the relative contributions of these PTPs in platelet activation by the major glycoprotein, glycoprotein VI, α(IIb)β(3), and C-type lectin-like receptor 2 (CLEC-2).


RESULTS
PTP-1B-deficient mouse platelets responded normally to the glycoprotein VI-specific agonist collagen-related peptide and antibody-mediated CLEC-2 activation. However, they exhibited a marginal reduction in α(IIb)β(3)-mediated Src family kinase activation and tyrosine phosphorylation. In contrast, CD148-deficient platelets exhibited a dramatic reduction in activation by glycoprotein VI and α(IIb)β(3) and a marginal reduction in response to activation by CLEC-2, which was further enhanced in the absence of PTP-1B. These defects were associated with reduced activation of Src family kinase and spleen tyrosine kinase, suggesting a causal relationship. Under arteriolar flow conditions, there was defective aggregate formation in the absence of PTP-1B and, to a greater extent, CD148 and a severe abrogation of both adhesion and aggregation in the absence of both PTPs.


CONCLUSIONS
Findings from this study demonstrate that CD148 plays a dominant role in activating Src family kinases in platelets relative to PTP-1B. Both PTPs are required for optimal platelet activation and aggregate formation under high arterial shear rates.
Centre for Cardiovascular Sciences, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Jun
J
Mori
Ying-Jie
YJ
Wang
Stuart
S
Ellison
Silke
S
Heising
Benjamin G
BG
Neel
Michel L
ML
Tremblay
Steve P
SP
Watson
Yotis A
YA
Senis
D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D005340:Fibrinogen; D006023:Glycoproteins / Q000502:physiology; D066298:In Vitro Techniques; D037181:Lectins, C-Type / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D015539:Platelet Activation / Q000502:physiology*; D010974:Platelet Aggregation / Q000502:physiology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology
C529518:CLEC-2 protein, mouse; D006023:Glycoproteins; D037181:Lectins, C-Type; D005340:Fibrinogen; D019061:src-Family Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; C098066:Ptprj protein, mouse; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3