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Blood, 15 May 2005, Vol. 105, No. 10, pp. 3918-3924. Prepublished online as a Blood First Edition Paper on February 8, 2005; DOI 10.1182/blood-2004-09-3689. This Article Full Text (PDF) All Versions of this Article: 2004-09-3689v1 105/10/3918    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dangelmaier, C. A Articles by Daniel, J. L Search for Related Content PubMed PubMed Citation Articles by Dangelmaier, C. A Articles by Daniel, J. L Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 23, 2004 Accepted January 17, 2005 Rapid ubiquitination of Syk following GPVI activation in platelets Carol A Dangelmaier, Patricia G Quinter, Jianguo Jin, Alexander Y Tsygankov, Satya P Kunapuli, and James L Daniel* Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, USA Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA; Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA; Sol Sherry Thrombosis Center, Temple University School of Medicine, Philadelphia, PA, USA Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA; Sol Sherry Thrombosis Center, Temple University School of Medicine, Philadelphia, PA, USA * Corresponding author; email: jdaniel{at}temple.edu. Syk activation is a key intermediate step in the activation of platelets by the physiologic agonist collagen. We have found that Syk is rapidly ubiquitinated upon activation of platelets by collagen, CRP and convulxin. The Src family kinase inhibitors prevented Syk phosphorylation and its ubiquitination, indicating that the process is downstream of Src kinases. The ubiquitination of Syk did not cause degradation of the protein as evidenced by the lack of effect of proteasomal and lysosomal inhibitors. We separated ubiquitinated Syk from its non-ubiquitinated counterpart and used an in vitro kinase assay to compare their activities. We found that the ubiquitinated Syk appeared to be about five-fold more active. Using a phosphospecific antibody to Syk (Tyr525/Tyr526) that measures activated Syk, we found that the majority (60-75%) of the active Syk is in the ubiquitinated fraction. This result explains the apparent high specific activity of ubiquitinated Syk. In c-Cbl deficient mice, Syk is not ubiquitinated implicating c-Cbl as the E3 ligase involved in Syk ubiquitination. Furthermore, Syk is not dephosphorylated in these mice. We propose that c-Cbl plays a regulatory role in GPVI/FcR[[gamma]-chain-dependent platelet activation through its interaction with Syk. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Nakao, K. Hirasaka, J. Goto, K. Ishidoh, C. Yamada, A. Ohno, Y. Okumura, I. Nonaka, K. Yasutomo, K. M. Baldwin, et al. Ubiquitin Ligase Cbl-b Is a Negative Regulator for Insulin-Like Growth Factor 1 Signaling during Muscle Atrophy Caused by Unloading Mol. Cell. Biol., September 1, 2009; 29(17): 4798 - 4811. [Abstract] [Full Text] [PDF] Y. S. Bynagari, B. Nagy Jr., F. Tuluc, K. Bhavaraju, S. Kim, K. V. Vijayan, and S. P. Kunapuli Mechanism of Activation and Functional Role of Protein Kinase C{eta} in Human Platelets J. Biol. Chem., May 15, 2009; 284(20): 13413 - 13421. [Abstract] [Full Text] [PDF] X. Wang, L. Simeoni, J. A. Lindquist, J. Saez-Rodriguez, A. Ambach, E. D. Gilles, S. Kliche, and B. Schraven Dynamics of Proximal Signaling Events after TCR/CD8-Mediated Induction of Proliferation or Apoptosis in Mature CD8+ T Cells J. Immunol., May 15, 2008; 180(10): 6703 - 6712. [Abstract] [Full Text] [PDF] Z. A. Karim, W. Choi, and S. W. Whiteheart Primary Platelet Signaling Cascades and Integrin-mediated Signaling Control ADP-ribosylation Factor (Arf) 6-GTP Levels during Platelet Activation and Aggregation J. Biol. Chem., May 2, 2008; 283(18): 11995 - 12003. [Abstract] [Full Text] [PDF] T. Rabie, D. Varga-Szabo, M. Bender, R. Pozgaj, F. Lanza, T. Saito, S. P. Watson, and B. Nieswandt Diverging signaling events control the pathway of GPVI down-regulation in vivo Blood, July 15, 2007; 110(2): 529 - 535. [Abstract] [Full Text] [PDF]

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