Non-Smad Mechanisms of TGFBeta Signaling

TGFBeta 信号转导的非 Smad 机制

• 批准号: 7827981
• 负责人: RIK M DERYNCK
• 金额: $ 31.66万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7827981
• 关键词: Address; Adult; Adverse effects; Affect; Binding; Biochemical; Biological Assay; Bronchopulmonary Dysplasia; C-terminal; Carcinoma; Cell Line; Cell Nucleus; Cell surface; Cells; Chemicals; Complex; Cytoplasmic Tail; Development; Differentiation and Growth; Dominant-Negative Mutation; Epithelial; Epithelial Cells; Family; Family member; Fibrosis; Gene Expression; Genes; Genetic Transcription; Individual; Inflammation; Injury; Ligands; Link; Lung; Lung diseases; MAPK8 gene; Malignant - descriptor; Mediating; Mesenchymal Differentiation; Microarray Analysis; Mitogen-Activated Protein Kinases; Modeling; Modification; Molecular; Monomeric GTP-Binding Proteins; Morphogenesis; Mutate; Neonatal; Nuclear Translocation; Organ; Pathology; Pathway interactions; Phenocopy; Phenotype; Phosphorylation; Phosphotransferases; Play; Proteins; RNA; Receptor Activation; Receptor Serine/Threonine Kinase; Reporter; Research; Research Proposals; Role; Signal Pathway; Signal Transduction; Signaling Protein; Smad Proteins; Smad protein; Tissue Differentiation; Tissues; Transcriptional Activation; Transcriptional Regulation; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Tyrosine Phosphorylation; Work; base; fetal; inhibitor/antagonist; injury and repair; insight; interest; interstitial; lung basal segment; lung development; member; mitogen-activated protein kinase p38; mutant; neoplastic cell; postnatal; programs; prototype; receptor; research study; response; response to injury; transcription factor

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.

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，TGF-β超家族的成员起关键作用。TGF-β和相关蛋白质也发挥作用， TGF-β在正常肺发育中起关键作用，而TGF-β本身在对损伤的反应中起重要作用。 TGF-β的表达和信号传导也有助于某些肺部疾病和癌症的病理生物学 发展和进步。因此，TGF-β信号传导的机制已经引起了人们的极大兴趣， 无论是正常发育还是病理学。TGF-β和相关蛋白通过异聚体细胞表面信号传导 两种类型的跨膜丝氨酸-苏氨酸激酶受体的复合物，其依次通过 磷酸化，Smads。Smad蛋白作为TGF-β信号的细胞内效应物， 激活和异聚化，易位到细胞核中，在那里它们阐述配体诱导的转录 许多基因的反应。TGF-β诱导的Smad信号通路现在已被广泛接受，其模型 激活和作用机制已得到充分发展。然而，越来越多的证据指出，TGF-β 受体复合物的激活也启动其它非Smad信号通路。其中一些意见 现在已经被认识到，但对这些非Smad信号传导机制知之甚少，它们如何与 受体及其在TGF-β诱导的细胞反应中的作用。其中一些平行途径可能 直接调节Smad信号，而其他可能影响无关的反应。这项研究计划从 假设这些TGF-β诱导的非Smad信号通路极大地促进了细胞内 对TGF-β及相关因素的反应。我们提议启动一项研究计划， TGF-β诱导的非Smad信号通路，从而特异性地集中于Erk MAP激酶的激活， p38 MAP激酶、JNK和RhoA信号转导对TGF-β的响应。本提案的四个目标将研究如何 这些通路的激活在生物化学和机械上与TGF-β的激活相关， 受体以及它们如何在Smad激活和基因水平上影响细胞对TGF-β的反应 表情总之，这些研究应该提供深入了解TGF-β和相关的作用机制， 正常发育和非病理生物学因素。