TGF beta Receptors and Cell Proliferation

描述(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不同的反应，如生长刺激(即，间充质细胞)和生长抑制(即，上皮细胞)。考虑到转化生长因子-β在正常生长控制和各种增生性疾病中的关键作用，如果我们希望制定具体的干预策略，解决这个问题是根本的。为此，在之前的资金周期中，我们已经确定p21激活的激酶2(PAK2)代表了一种由转化生长因子-B刺激的新的细胞类型特异性信号通路。PAK首先被鉴定为Rho GTP酶的效应因子，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。在这一竞争更新中，我们希望扩展这些发现，并检验PAK2激活在区分间质和上皮细胞对转化生长因子-B的反应中定义了一个关键分支点(S)这一普遍假设。这一假说将通过各种生化、生物学和遗传学方法加以解决。首先，我们将确定Ras和Rho家族成员在转化生长因子-B刺激的PAK2激活中的作用。其次，将定义PI3K的功能及其与RAS和Rho GTP酶在PAK2信号中的时空关系。最后，我们将描述转化生长因子-B刺激的PAK2活性调节MAPK激活的下游介体。由于这些研究代表了(I)一条新的Smad非依赖性的转化生长因子-β信号通路；(Ii)首次证实了细胞类型特异的转化生长因子-β信号转导途径，如果要阐明控制转化生长因子-β的各种生物学反应的机制，对这些问题的回答是至关重要的。

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.