TGF beta Receptors and Cell Proliferation

描述（由申请人提供）：转化生长因子β (TGF-B)生物学中的一个中心悖论是相同的生长因子如何诱导生长刺激（即间充质细胞）和生长抑制（即上皮细胞）等不同的反应。考虑到TGF-B在正常生长控制和各种增殖性疾病中的关键作用，如果我们希望制定具体的干预策略，解决这个问题是至关重要的。为此，在之前的资助周期中，我们已经确定p21活化的激酶2 （PAK2）代表了TGF-B刺激的一种新的细胞类型特异性信号通路。PAKs首先被确定为Rho GTPases的效应器，并被认为是肌动蛋白重组、细胞运动、细胞凋亡、基因转录和肿瘤发生的调节因子。在这一竞争性更新中，我们希望扩展这些发现并验证PAK2激活定义了区分间充质细胞和上皮细胞对TGF-B反应的关键分支点的一般假设。这一假设将通过各种生化、生物学和遗传学方法来解决。首先，我们将确定Ras和Rho家族成员在tgf - b刺激的PAK2激活中的作用。其次，定义PI3K的功能及其与Ras和Rho GTPases在PAK2信号传导中的时空关系。最后，我们将描述tgf - b刺激的PAK2活性调节MAPK激活的下游介质。因为这些研究代表了(i) TGF-B的一个新的不依赖于smad的信号通路；（ii）细胞类型特异性TGF-B信号的首次演示，如果要阐明控制TGF-B各种生物反应的机制，这些问题的答案是至关重要的。

DESCRIPTION (provided by applicant): A central paradox in transforming growth factor beta (TGF-B) biology is how the same growth factor can induce such divergent responses as growth stimulation (i.e., mesenchymal cells) and growth inhibition (i.e., epithelial cells). Considering the pivotal role TGF-B has in both normal growth control and various proliferative disorders, addressing that issue is fundamental if we hope to develop specific intervention strategies. To that end, during the previous funding cycle we have determined that p21-activated kinase 2 (PAK2) represents a new cell type specific signaling pathway stimulated by TGF-B. PAKs were first identified as effectors of Rho GTPases and have been implicated as regulators of actin reorganization, cell motility, apoptosis, gene transcription, and oncogenesis. In this competing renewal we wish to extend these findings and test the general hypothesis that PAK2 activation defines a critical branchpoint(s) in distinguishing mesenchymal from epithelial cell responses to TGF-B. This hypothesis will be addressed through a variety of biochemical, biological, and genetic approaches. First, we will determine the role of Ras and Rho family members in TGF-B-stimulated PAK2 activation. Second, the function of PI3K and its spatiotemporal relation to Ras and Rho GTPases in PAK2 signaling will be defined. Finally, we will characterize the downstream mediators through which TGF-B-stimulated PAK2 activity regulates MAPK activation. As these studies represent (i) a new Smad-independent signaling pathway for TGF-B; and (ii) the first demonstration of cell type specific TGF-B signaling, answers to these questions are critical if the mechanisms controlling the various biological responses to TGF-B are to be elucidated.