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Blood, 1 March 2005, Vol. 105, No. 5, pp. 1977-1985. Prepublished online as a Blood First Edition Paper on November 2, 2004; DOI 10.1182/blood-2004-08-3308. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: 2004-08-3308v1 105/5/1977    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 Tang, H. Articles by Hao, Q. Search for Related Content PubMed PubMed Citation Articles by Tang, H. Articles by Hao, Q. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 25, 2004 Accepted October 24, 2004 Thrombin induces endocytosis of endoglin and type-II TGF- receptor and downregulation of TGF- signaling in endothelial cells Hua Tang*, Brad Low, Stacey A Rutherford, and Qin Hao Department of Biochemistry, The University of Texas Health Center at Tyler, Tyler, TX, USA * Corresponding author; email: hua.tang{at}uthct.edu. Thrombin activates protease-activated receptor 1 (PAR1) on endothelial cells (ECs) and is critical for angiogenesis and vascular development. However, the mechanism underlying the proangiogenic effect of thrombin has not been elucidated yet. Here, we report the discovery of a novel functional link between thrombin-PAR1 and transforming growth factor- (TGF-) signaling pathways. We showed that thrombin via PAR1 induced the internalization of endoglin and type-II TGF- receptor (TRII) but not type-I receptors in human ECs. This effect was mediated by protein kinase C- (PKC-) since specific inhibition of PKC- caused an aggregation of endoglin or TRII on cell surface and blocked their internalization by thrombin. Furthermore, acute and long-term pretreatment of ECs with thrombin or PAR1 peptide agonist suppressed the TGF--induced serine phosphorylation of Smad2, a critical mediator of TGF- signaling. Moreover, activation of PAR1 led to a profound and spread cytosolic clustering formation of Smad2/3 and markedly prevented Smad2/3 nuclear translocation evoked by TGF-1. Since TGF- plays a crucial role in the resolution phase of angiogenesis, the downregulation of TGF- signaling by thrombin-PAR1 pathway may provide a new insight into the mechanism of the proangiogenic effect of thrombin. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. K. Mandal, U. R. Pendurthi, and L. V. M. Rao Tissue factor trafficking in fibroblasts: involvement of protease-activated receptor-mediated cell signaling Blood, July 1, 2007; 110(1): 161 - 170. [Abstract] [Full Text] [PDF] R. I. Koleva, B. A. Conley, D. Romero, K. S. Riley, J. A. Marto, A. Lux, and C. P. H. Vary Endoglin Structure and Function: DETERMINANTS OF ENDOGLIN PHOSPHORYLATION BY TRANSFORMING GROWTH FACTOR-beta RECEPTORS J. Biol. Chem., September 1, 2006; 281(35): 25110 - 25123. [Abstract] [Full Text] [PDF] F. Syeda, J. Grosjean, R. A. Houliston, R. J. Keogh, T. D. Carter, E. Paleolog, and C. P. D. Wheeler-Jones Cyclooxygenase-2 Induction and Prostacyclin Release by Protease-activated Receptors in Endothelial Cells Require Cooperation between Mitogen-activated Protein Kinase and NF-{kappa}B Pathways J. Biol. Chem., April 28, 2006; 281(17): 11792 - 11804. [Abstract] [Full Text] [PDF] A. Zhang, X. Liu, J. G. Cogan, M. D. Fuerst, J. A. Polikandriotis, R. J. Kelm Jr., and A. R. Strauch YB-1 Coordinates Vascular Smooth Muscle {alpha}-Actin Gene Activation by Transforming Growth Factor {beta}1 and Thrombin during Differentiation of Human Pulmonary Myofibroblasts Mol. Biol. Cell, October 1, 2005; 16(10): 4931 - 4940. [Abstract] [Full Text] [PDF] M. Belting, J. Ahamed, and W. Ruf Signaling of the Tissue Factor Coagulation Pathway in Angiogenesis and Cancer Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1545 - 1550. [Abstract] [Full Text] [PDF] H. Tang, Q. Hao, S. A. Rutherford, B. Low, and Z. J. Zhao Inactivation of Src Family Tyrosine Kinases by Reactive Oxygen Species in Vivo J. Biol. Chem., June 24, 2005; 280(25): 23918 - 23925. [Abstract] [Full Text] [PDF]

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