Transforming growth factor beta depletion is the primary determinant of Smad signaling kinetics
Authors: David C Clarke
Richard A Erickson
Xuedong Liu
Meredith L Brown
Yigong Shi
Journal: Molecular and Cellular Biology (2009)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: TGF-beta; ligand concentration; phospho-Smad2 kinetics; TGF-beta depletion; type II receptor
Affiliations: Departments of Chemistry and Biochemistry, Chemical and Biological Engineering, University of Colorado at Boulder, Boulder, Colorado 80309-0215, Department of Molecular Biology, Princeton University, Washington Road, Princeton, New Jersey 08544

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

Retracted: No

PubPeer comments:
 Figure 4A: * Red boxes: Two Smad2 blots look similar to each other, but represent different TGF-b concentrations. Reported to the journal in September 2016, but not addressed because the paper was already more than six years old. ![file] , 
 We confirmed the analysis of the ASM team that the images were duplicates. We retrieved the original files and determined that the first author (DCC) erroneously used the blot image showing Smad2 expression from the 200 pM samples for the 10 pM samples as well. Volume 29, no. 9, p. 2443-2455, 2009. Page 2448, Figure 4A. The Smad2 immunoblot image for the 10 pM sample was an inadvertent duplication of 200 pM blot image. The corrected image should appear as shown below. We regret this error. The correction does not affect the conclusions of the study. ![file] , 
 Dear Dr. Liu, Thank you for checking and confirming that these were duplicates. Will you and the journal be issuing a correction, so that other readers can be made aware as well? , 
 Author correction has been submitted. , 
 2021 correction. https: journals.asm.org doi 10.1128 MCB.00255-21 AUTHOR CORRECTION Volume 29, no. 9, p. 2443-2455, 2009, https: doi.org 10.1128 MCB.01443-08. Page 2448, Fig. 4A: The Smad2 immunoblot image for the 10 pM sample was an inadvertent duplication of the 200 pM image. The corrected image should appear as shown below. We regret this error. The correction does not affect the conclusions of the study. ,