BACKGROUND: The adapter protein c-Cbl has emerged as having a potential role in negative regulation of immune receptor signaling. The major platelet-signaling receptor for collagen, glycoprotein VI (GpVI), is associated with the Fc receptor (FcR) gamma-chain, and signals through a similar pathway to immune receptors. c-Cbl is tyrosine-phosphorylated in response to stimulation of GpVI, whereas phosphorylation of c-Cbl in thrombin-activated platelets is dependent on fibrinogen binding to the integrin GpIIb/IIIa. OBJECTIVE: To investigate the role of c-Cbl in platelet signaling. METHODS: Murine platelets lacking functional c-Cbl or Src family kinases were analyzed. RESULTS: Phosphorylation of c-Cbl through GpVI is reduced in murine platelets deficient in the Src-family kinases Fyn and Lyn, demonstrating that they lie upstream of c-Cbl phosphorylation. Phosphorylation of several proteins of the GpVI-signaling pathway, including the FcR gamma-chain, Syk and phospholipase Cgamma2 (PLCgamma2), is increased in the absence of c-Cbl. In line with this, aggregation is potentiated in response to the GpVI-specific collagen-related peptide (CRP) after a slight delay. A delay in potentiation is also seen in response to stimulation by thrombin. CONCLUSIONS: These observations demonstrate that c-Cbl negatively regulates platelet responses to GpVI agonists and to thrombin, with the latter effect possibly being mediated downstream of GpIIb/IIIa. c-Cbl may play a physiological role in helping to prevent unwanted platelet activation in vivo.
BACKGROUND: The adapter protein c-Cbl has emerged as having a potential role in negative regulation of immune receptor signaling. The major platelet-signaling receptor for collagen, glycoprotein VI (GpVI), is associated with the Fc receptor (FcR) gamma-chain, and signals through a similar pathway to immune receptors. c-Cbl is tyrosine-phosphorylated in response to stimulation of GpVI, whereas phosphorylation of c-Cbl in thrombin-activated platelets is dependent on fibrinogen binding to the integrin GpIIb/IIIa. OBJECTIVE: To investigate the role of c-Cbl in platelet signaling. METHODS:Murine platelets lacking functional c-Cbl or Src family kinases were analyzed. RESULTS: Phosphorylation of c-Cbl through GpVI is reduced in murine platelets deficient in the Src-family kinases Fyn and Lyn, demonstrating that they lie upstream of c-Cbl phosphorylation. Phosphorylation of several proteins of the GpVI-signaling pathway, including the FcR gamma-chain, Syk and phospholipase Cgamma2 (PLCgamma2), is increased in the absence of c-Cbl. In line with this, aggregation is potentiated in response to the GpVI-specific collagen-related peptide (CRP) after a slight delay. A delay in potentiation is also seen in response to stimulation by thrombin. CONCLUSIONS: These observations demonstrate that c-Cbl negatively regulates platelet responses to GpVI agonists and to thrombin, with the latter effect possibly being mediated downstream of GpIIb/IIIa. c-Cbl may play a physiological role in helping to prevent unwanted platelet activation in vivo.
Authors: M K Larson; G C Shearer; J H Ashmore; J M Anderson-Daniels; E L Graslie; J T Tholen; J L Vogelaar; A J Korth; V Nareddy; M Sprehe; W S Harris Journal: Prostaglandins Leukot Essent Fatty Acids Date: 2010-12-22 Impact factor: 4.006
Authors: James L Daniel; Carol A Dangelmaier; Sripal Mada; Lorena Buitrago; Jianguo Jin; Wallace Y Langdon; Alexander Y Tsygankov; Satya P Kunapuli; Archana Sanjay Journal: J Biol Chem Date: 2010-04-16 Impact factor: 5.157
Authors: Carol A Dangelmaier; Patricia G Quinter; Jianguo Jin; Alexander Y Tsygankov; Satya P Kunapuli; James L Daniel Journal: Blood Date: 2005-02-08 Impact factor: 22.113
Authors: Catherine J Pears; Kelly Thornber; Jocelyn M Auger; Craig E Hughes; Beata Grygielska; Majd B Protty; Andrew C Pearce; Steve P Watson Journal: PLoS One Date: 2008-11-24 Impact factor: 3.240
Authors: Joanne L Dunster; Francoise Mazet; Michael J Fry; Jonathan M Gibbins; Marcus J Tindall Journal: PLoS Comput Biol Date: 2015-11-19 Impact factor: 4.475