This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Clarke, D. C.
Right arrow Articles by Liu, X.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Clarke, D. C.
Right arrow Articles by Liu, X.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, May 2009, p. 2443-2455, Vol. 29, No. 9
0270-7306/09/$08.00+0     doi:10.1128/MCB.01443-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Transforming Growth Factor β Depletion Is the Primary Determinant of Smad Signaling Kinetics{triangledown}

David C. Clarke,1,2,{dagger} Meredith L. Brown,1 Richard A. Erickson,1,{ddagger} Yigong Shi,3 and Xuedong Liu1*

Departments of Chemistry and Biochemistry,1 Chemical and Biological Engineering, University of Colorado at Boulder, Boulder, Colorado 80309-0215,2 Department of Molecular Biology, Princeton University, Washington Road, Princeton, New Jersey 085443

Received 13 September 2008/ Returned for modification 25 October 2008/ Accepted 6 February 2009

A cell's decision to growth arrest, apoptose, or differentiate in response to transforming growth factor β (TGF-β) superfamily ligands depends on the ligand concentration. How cells sense the concentration of extracellular bioavailable TGF-β remains poorly understood. We therefore undertook a systematic quantitative analysis of how TGF-β ligand concentration is transduced into downstream phospho-Smad2 kinetics, and we found that the rate of TGF-β ligand depletion is the principal determinant of Smad signal duration. TGF-β depletion is caused by two mechanisms: (i) cellular uptake of TGF-β by a TGF-β type II receptor-dependent mechanism and (ii) reversible binding of TGF-β to the cell surface. Our results indicate that cells sense TGF-β dose by depleting TGF-β via constitutive TGF-β type II receptor trafficking processes. Our results also have implications for the role of the TGF-β type II receptor in disease, as tumor cells harboring TGF-β type II receptor mutations exhibit impaired TGF-β depletion, which may contribute to the overproduction of TGF-β and a consequently poor prognosis in cancer.

* Corresponding author. Mailing address: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309-0215. Phone and fax: (303) 735-6161. E-mail: Xuedong.Liu{at}Colorado.edu

{triangledown} Published ahead of print on 17 February 2009.

{dagger} Present address: Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139.

{ddagger} Present address: JILA, University of Colorado at Boulder, Boulder, CO 80309-0440.

Molecular and Cellular Biology, May 2009, p. 2443-2455, Vol. 29, No. 9
0270-7306/09/$08.00+0     doi:10.1128/MCB.01443-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Moustakas, A., Heldin, C.-H. (2009). The regulation of TGF{beta} signal transduction. Development 136: 3699-3714 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»