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c-Cbl negatively regulates platelet activation by glycoprotein VI
1Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK. jma299@bham.ac.uk
Journal of Thrombosis and Haemostasis : JTH
|November 25, 2003
Summary
The adapter protein c-Cbl negatively regulates platelet activation. Its absence potentiates platelet aggregation in response to collagen and thrombin, suggesting a role in preventing excessive platelet response in vivo.
Area of Science:
- Hematology
- Immunology
- Cell Signaling
Background:
- The adapter protein c-Cbl is implicated in the negative regulation of immune receptor signaling.
- Platelet collagen receptor glycoprotein VI (GpVI) signals similarly to immune receptors.
- c-Cbl phosphorylation occurs upon GpVI stimulation and thrombin activation-dependent fibrinogen binding.
Purpose of the Study:
- To investigate the function of c-Cbl in platelet signaling pathways.
- To elucidate the role of c-Cbl in platelet responses to agonists.
Main Methods:
- Analysis of murine platelets lacking functional c-Cbl.
- Assessment of platelets deficient in Src family kinases (Fyn and Lyn).
Main Results:
- Src family kinases (Fyn, Lyn) are upstream of c-Cbl phosphorylation.
- Absence of c-Cbl increases phosphorylation of GpVI pathway proteins (FcR gamma-chain, Syk, PLCgamma2).
- Platelet aggregation is potentiated in c-Cbl deficient platelets upon stimulation with collagen-related peptide (CRP) and thrombin.
Conclusions:
- c-Cbl negatively regulates platelet responses to GpVI agonists and thrombin.
- c-Cbl may prevent excessive platelet activation in vivo, potentially acting downstream of GpIIb/IIIa in thrombin signaling.