Clarke David C, Brown Meredith L, Erickson Richard A, Shi Yigong, Liu Xuedong
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309-0215, USA.
Mol Cell Biol. 2009 May;29(9):2443-55. doi: 10.1128/MCB.01443-08. Epub 2009 Feb 17.
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.
细胞针对转化生长因子β(TGF-β)超家族配体做出生长停滞、凋亡或分化的决定取决于配体浓度。细胞如何感知细胞外可利用的TGF-β浓度仍知之甚少。因此,我们对TGF-β配体浓度如何转化为下游磷酸化Smad2动力学进行了系统的定量分析,发现TGF-β配体消耗速率是Smad信号持续时间的主要决定因素。TGF-β消耗由两种机制引起:(i)通过依赖TGF-β II型受体的机制进行细胞对TGF-β的摄取,以及(ii)TGF-β与细胞表面的可逆结合。我们的结果表明,细胞通过组成性的TGF-β II型受体运输过程消耗TGF-β来感知TGF-β剂量。我们的结果还对TGF-β II型受体在疾病中的作用具有启示意义,因为携带TGF-β II型受体突变的肿瘤细胞表现出TGF-β消耗受损,这可能导致TGF-β过度产生,进而导致癌症预后不良。