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Blood, 1 November 2008, Vol. 112, No. 9, pp. 3650-3660. Prepublished online as a Blood First Edition Paper on June 10, 2008; DOI 10.1182/blood-2008-04-151753. This Article Full Text (PDF) All Versions of this Article: blood-2008-04-151753v1 112/9/3650    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 Ahamed, J. Articles by Coller, B. S Search for Related Content PubMed PubMed Citation Articles by Ahamed, J. Articles by Coller, B. S Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 16, 2008 Accepted May 27, 2008 In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-1 (TGF-1) Jasimuddin Ahamed*, Nathalie Burg, Keiji Yoshinaga, Christin A Janczak, Daniel B Rifkin, and Barry S Coller Blood and Vascular Biology, The Rockefeller University, New York, NY, United States Departments of Cell Biology and Medicine, The New York University School of Medicine, New York, NY, United States * Corresponding author; email: jahamed{at}rockefeller.edu. Transforming growth factor-1 (TGF-1) has potent physiologic and pathologic effects on a variety of cell types at subnanomolar concentrations. Platelets contain 40 times as much TGF-1 as other cells and secrete it as an inactive (latent) form in complex with latency-associated peptide (LAP), which is disulfide bonded via Cys33 to latent TGF- binding protein 1 (LTBP-1). Little is known about how latent TGF-1 becomes activated in vivo. Here we show that TGF-1 released from platelets or fibroblasts undergoes dramatic activation when subjected to stirring or shear forces, providing a potential mechanism for physiologic control. Thiol-disulfide exchange appears to contribute to the process based on the effects of thiol-reactive reagents and differences in thiol labeling of TGF-1 before and after stirring or shear. Activation required the presence of LTBP, as TGF-1 contained in complex with only LAP could not be activated by stirring when studied as either a recombinant purified protein complex or in the platelet releasates or sera of mice engineered to contain an LAP C33S mutation. Release and activation of latent TGF-1 in vivo was demonstrated in a mouse model 5 min after thrombus formation. These data potentially provide a novel mechanism for in vivo activation of TGF-1. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Shear activates platelet-derived latent TGF-β Kohei Miyazono Blood 2008 112: 3533-3534. [Full Text] [PDF] This article has been cited by other articles: H.-G. Kopp, T. Placke, and H. R. Salih Platelet-Derived Transforming Growth Factor-{beta} Down-Regulates NKG2D Thereby Inhibiting Natural Killer Cell Antitumor Reactivity Cancer Res., October 1, 2009; 69(19): 7775 - 7783. [Abstract] [Full Text] [PDF] K. Yoshinaga, H. Obata, V. Jurukovski, R. Mazzieri, Y. Chen, L. Zilberberg, D. Huso, J. Melamed, P. Prijatelj, V. Todorovic, et al. Perturbation of transforming growth factor (TGF)-ss1 association with latent TGF-{beta} binding protein yields inflammation and tumors PNAS, December 2, 2008; 105(48): 18758 - 18763. [Abstract] [Full Text] [PDF]

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