TGF BETA RECEPTORS AND CELL PROLIFERATION

细胞增殖受刺激因子和抑制因子的综合作用控制。转化生长因子β (tgf - β)在这方面是独一无二的，因为它可以根据细胞环境刺激或抑制细胞生长。一般来说，间充质来源的细胞生长受到刺激，而大多数其他类型的细胞则受到抑制。目前尚不清楚一种生长因子如何与同一种受体结合，从而引发如此不同的表型。tgf - β在调节许多生物活性中起着关键作用，因此确定tgf - β作用被调节的潜在靶标至关重要。在之前的资助周期中，我们已经确定了间充质细胞系和上皮细胞系中受体内吞活性的差异调节，tgf - β受体（tgf - β ar）内化和信号传导的主要决定因素分别是II型受体激酶和I型受体中的一个新元件。我们希望扩展这些发现，并验证细胞对tgf - β的反应是由内吞和信号机制的综合活动控制的一般假设。这一假设将通过各种方法来解决。首先，我们将描述调节TGF- β - ar寡聚初始膜反应的细胞蛋白。接下来，我们将确定I型TGF-betaR中一个先前未定义的元件在控制下游受体信号传导中的作用。最后，我们将利用酵母的遗传分析鉴定哺乳动物tgf - β信号中介。考虑到TGF- β在各种增生性疾病中的重要性，如果我们希望开发特定的（和新颖的）干预策略，那么回答这些类型的问题是至关重要的。

Cellular proliferation is controlled by the integrated action of stimulatory and inhibitory growth factors. Transforming growth factor beta (TGF-beta) is unique in that regard since depending upon the cellular context it can either stimulate or inhibit cell growth. In general, mesenchymal-derived cells are growth stimulated while most other cell types are inhibited. It is presently unknown how 1 growth factor, binding to the same receptor species, can elicit such distinct phenotypes. The pivotal role which TGF-beta plays in modulating a number of biological activities makes it critical to identify potential targets through which TGF-beta actions are regulated. During the previous funding cycle we have determined that receptor endocytic activity is differentially modulated in mesenchymal and epithelial cell lines and that major determinants of TGF-beta receptor (TGF-betaR) internalization and signaling are the type II receptor kinase and a novel element in the type I receptor, respectively. We wish to extend these findings and test the general hypothesis that the cellular response to TGF-beta is controlled by the integrated activities of the endocytic and signaling machinery. This hypothesis will be addressed through a variety of approaches. First, we will characterize cellular proteins which regulate the initial membrane response to TGF- betaR oligomerization. Next, we will determine the function of a previously undefined element in the type I TGF-betaR in controlling downstream receptor signaling. Finally, we will identify mammalian TGF-beta signaling intermediaries using genetic analysis of yeast. Considering the importance of TGF- beta in various proliferative disorders, answers to these type of questions are critical if we hope to develop specific (and novel) intervention strategies.