Cbl-b Is a Novel Physiologic Regulator of Glycoprotein VI-dependent Platelet Activation

Department of Anatomy, Sol Sherry Thrombosis Research Center, Temple University, Philadelphia, Pennsylvania 19140, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2010; 285(23):17282-91. DOI: 10.1074/jbc.M109.080200
Source: PubMed


Cbl-b, a member of the Cbl family of E3 ubiquitin ligases, plays an important role in the activation of lymphocytes. However, its function in platelets remains unknown. We show that Cbl-b is expressed in human platelets along with c-Cbl, but in contrast to c-Cbl, it is not tyrosine-phosphorylated upon glycoprotein VI (GPVI) stimulation. Cbl-b, unlike c-Cbl, is not required for Syk ubiquitylation downstream of GPVI activation. Phospholipase Cgamma2 (PLCgamma2) and Bruton's tyrosine kinase (BTK) are constituently associated with Cbl-b. Cbl-b-deficient (Cbl-b(-/-)) platelets display an inhibition in the concentration-response curve for GPVI-specific agonist-induced aggregation, secretion, and Ca(2+) mobilization. A parallel inhibition is found for activation of PLCgamma2 and BTK. However, Syk activation is not affected by the absence of Cbl-b, indicating that Cbl-b acts downstream of Syk but upstream of BTK and PLCgamma2. When Cbl-b(-/-) mice were tested in the ferric chloride thrombosis model, occlusion time was increased and clot stability was reduced compared with wild type controls. These data indicate that Cbl-b plays a positive modulatory role in GPVI-dependent platelet signaling, which translates to an important regulatory role in hemostasis and thrombosis in vivo.

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Available from: Alexander Y Tsygankov, May 14, 2014
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    • "ist is shorter than that for Cbl ( Tsygankov et al . , 2001 ; Swaminathan and Tsygankov , 2006 ; Tsygankov , 2008 ) . Moreover , tyrosine phosphorylation of Cbl and Cbl - b is sometimes differential ; thus , stimulation of the GPVI receptor on platelets causes tyrosine phosphorylation of Cbl , but not that of Cbl - b ( Dangelmaier et al . , 2005 ; Daniel et al . , 2010 ) . Major tyrosine phosphorylation sites of Cbl are located in its C - terminal half and include Tyr - 674 , - 700 , - 731 , and - 774 ( Andoniou et al . , 1996 ; Feshchenko et al . , 1998 ; Hunter et al . , 1999 ; Steen et al . , 2002 ; Liu et al . , 2002a ; Salomon et al . , 2003 ; Grossmann et al . , 2004 ) . These sites when phospho"
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