Non-Smad Mechanisms of TGFBeta Signaling

发育和组织分化由分泌的生长和分化因子决定。其中， 众所周知，转化生长因子-β超家族的成员扮演着关键角色。转化生长因子-β及其相关蛋白也发挥了作用 在正常的肺发育中起关键作用，而转化生长因子-β本身在对损伤的反应中发挥重要作用。 转化生长因子-β的表达和信号转导也与某些肺部疾病和癌症的病理生物学有关。 发展和进步。因此，转化生长因子-β信号转导机制引起了人们极大的兴趣。 无论是在正常发育还是在病理上。转化生长因子-β及其相关蛋白通过异构体、细胞表面传递信号 两种类型的跨膜丝氨酸-苏氨酸激酶受体的复合体，进而通过 磷酸化，Smads。Smad蛋白作为转化生长因子-β信号的细胞内效应器， 激活和异构化，转位到细胞核，在那里它们阐述了配体诱导的转录 许多基因的反应。转化生长因子-β诱导的Smad信号通路目前已被广泛接受，其模型 激活作用和作用机制都很发达。然而，越来越多的证据表明，转化生长因子-β 受体复合体的激活也启动了其他非Smad信号通路。其中一些观察到的 现已被认识到，但对这些非Smad信令机制、它们如何链接到 受体及其在转化生长因子-β诱导的细胞反应中所起的作用。这些平行路径中的一些可能 直接调节Smad信号，而其他信号可能影响无关的反应。这项研究计划是从 假设这些转化生长因子-β诱导的非Smad信号通路对细胞 对转化生长因子-β的反应及相关因素。我们建议启动一项研究计划，旨在定义几个 转化生长因子-β诱导的非Smad信号通路，从而特异性地集中在Erk MAP激酶的激活上， P38 MAP激酶、JNK和RhoA信号对转化生长因子-β的反应。这项提案的四个目标将研究如何 这些通路的激活在生化和机械上与转化生长因子-β的激活有关。 受体及其在Smad激活和基因水平上如何影响细胞对转化生长因子-β的反应 表情。总之，这些研究应该有助于深入了解转化生长因子-β及其相关的作用机制。 正常发育和病程生物学的因素。

Development and tissue differentiation isdictated by secreted growth and differentiation factors. Among these, members of the TGF-beta superfamily are well known to play key roles. TGF-beta and related proteins also play key roles in normal lung development, while TGF-beta itself plays an important role in the response to injury. TGF-beta expression and signaling also contributes to pathobiology of some lung diseases and to carcinoma development and progression. Consequently the mechanisms of TGF-beta signaling have been of great interest in both normal development and in pathology. TGF-beta and related proteins signal through heteromeric, cell surface complexes of two types of transmembrane serine-threonine kinase receptors, which in turn activate, through phosphorylation, the Smads. Smad proteins act as intracellular effectors of TGF-beta signals that, following activation and heteromerization, translocate into the nucleus where they elaborate the ligand-induced transcription responses of many genes. The TGF-beta-induced Smad signaling pathway is now well accepted and its model of activation and mechanism of action are well developed. Increasing evidence, however, points out that the TGF-beta activation of the receptor complex also initiates other, non-Smad signaling pathways. Some of these observations are now being recognize, but very little is known about these non-Smad signaling mechanisms, how they link to receptors and what role they play inthe TGF-beta induced cellular response. Some of these parallel pathways may directlyregulate Smad signaling,while others may effect unrelated responses. This research proposal works from the hypothesis that these TGF-beta-induced non-Smad signaling pathways greatly contributeto the cellular response to TGF-beta and related factors. We propose to initiatea research program aimed at defining several TGF-beta-induced non-Smad signaling pathways, thereby specifically focusing on the activation of Erk MAP kinase, p38 MAP kinase, JNK and RhoA signaling in response to TGF-beta. The four Aims of this proposal will study how the activtion of these pathways is biochemically and mechanistically linked to the activation of the TGF-beta receptors and how they affect the cellular response to TGF-beta at the level of Smad activation and gene expression. Together, these studies should provide insight into the mechanisms of action of TGF-beta and related factors in normal development and inpathobiology.