Huang Shuan S, Huang Jung S
Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.
J Cell Biochem. 2005 Oct 15;96(3):447-62. doi: 10.1002/jcb.20558.
This article focuses on recent findings that the type V TGF-beta receptor (TbetaR-V), which co-expresses with other TGF-beta receptors (TbetaR-I, TbetaR-II, and TbetaR-III) in all normal cell types studied, is involved in growth inhibition by IGFBP-3 and TGF-beta and that TGF-beta activity is regulated by two distinct endocytic pathways (clathrin- and caveolar/lipid-raft-mediated). TGF-beta is a potent growth inhibitor for most cell types, including epithelial and endothelial cells. The signaling by which TGF-beta controls cell proliferation is not well understood. Many lines of evidence indicate that other signaling pathways, in addition to the prominent TbetaR-I/TbetaR-II/Smad2/3/4 signaling cascade, are required for mediating TGF-beta-induced growth inhibition. Recent studies revealed that TbetaR-V, which is identical to LRP-1, mediates IGF-independent growth inhibition by IGFBP-3 and mediates TGF-beta-induced growth inhibition in concert with TbetaR-I and TbetaR-II. In addition, IRS proteins and a Ser/Thr-specific protein phosphatase(s) are involved in the TbetaR-V-mediated growth inhibitory signaling cascade. The TbetaR-V signaling cascade appears to cross-talk with the TbetaR-I/TbetaR-II, insulin receptor (IR), IGF-I receptor (IGF-IR), integrin and c-Met signaling cascades. Attenuation or loss of the TbetaR-V signaling cascade may enable carcinoma cells to escape from TGF-beta growth control and may contribute to the aggressiveness and invasiveness of these cells via promoting epithelial-to-mesenchymal transdifferentiation (EMT). Finally, the ratio of TGF-beta binding to TbetaR-II and TbetaR-I is a signal controlling TGF-beta partitioning between two distinct endocytosis pathways and resultant TGF-beta responsiveness. These recent studies have provided new insights into the molecular mechanisms underlying TGF-beta-induced cellular growth inhibition, cross-talk between the TbetaR-V and other signaling cascades, the signal that controls TGF-beta responsiveness and the role of TbetaR-V in tumorigenesis.
本文聚焦于近期的研究发现，即V型转化生长因子β受体（TβR-V）在所有研究的正常细胞类型中均与其他转化生长因子β受体（TβR-I、TβR-II和TβR-III）共表达，它参与胰岛素样生长因子结合蛋白-3（IGFBP-3）和转化生长因子β介导的生长抑制，且转化生长因子β的活性受两种不同的内吞途径（网格蛋白介导和小窝/脂筏介导）调控。转化生长因子β对大多数细胞类型，包括上皮细胞和内皮细胞，是一种有效的生长抑制剂。转化生长因子β控制细胞增殖的信号传导机制尚未完全清楚。许多证据表明，除了显著的TβR-I/TβR-II/Smad2/3/4信号级联反应外，还需要其他信号通路来介导转化生长因子β诱导的生长抑制。最近的研究表明，与低密度脂蛋白受体相关蛋白1（LRP-1）相同的TβR-V介导IGFBP-3非依赖的生长抑制，并与TβR-I和TβR-II协同介导转化生长因子β诱导的生长抑制。此外，胰岛素受体底物（IRS）蛋白和一种丝氨酸/苏氨酸特异性蛋白磷酸酶参与TβR-V介导的生长抑制信号级联反应。TβR-V信号级联反应似乎与TβR-I/TβR-II、胰岛素受体（IR）、胰岛素样生长因子-I受体（IGF-IR）、整合素和c-Met信号级联反应相互作用。TβR-V信号级联反应的减弱或缺失可能使癌细胞逃避转化生长因子β的生长控制，并可能通过促进上皮-间充质转化（EMT）导致这些细胞的侵袭性和转移性增加。最后，转化生长因子β与TβR-II和TβR-I结合的比例是控制转化生长因子β在两种不同内吞途径之间分配以及由此产生的转化生长因子β反应性的信号。这些最新研究为转化生长因子β诱导细胞生长抑制的分子机制、TβR-V与其他信号级联反应之间的相互作用、控制转化生长因子β反应性的信号以及TβR-V在肿瘤发生中的作用提供了新的见解。
