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

被引：51

作者：

Clarke, David C. ^{[1
,2
]}

Brown, Meredith L. ^{[1
]}

Erickson, Richard A. ^{[1
]}

Shi, Yigong ^{[3
]}

Liu, Xuedong ^{[1
]}

机构：

[1] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA

[2] Univ Colorado, Dept Chem & Biol Engn, Boulder, CO 80309 USA

[3] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA

来源：

MOLECULAR AND CELLULAR BIOLOGY | 2009年 / 29卷 / 09期

基金：

美国国家卫生研究院;

关键词：

BMP ACTIVITY GRADIENT; TGF-BETA; MORPHOGEN GRADIENT; MEDIATED ENDOCYTOSIS; TUMOR-SUPPRESSOR; XENOPUS CELLS; RECEPTOR; PROTEIN; TRANSDUCTION; ACTIVIN;

D O I：

10.1128/MCB.01443-08

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：2443 / 2455

页数：13

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