TAK1 Regulation of TGF-beta and IL-1 signaling

TAK1 对 TGF-β 和 IL-1 信号传导的调节

• 批准号: 6779613
• 负责人: Jun Ninomiya-Tsuji
• 金额: $ 23.92万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6779613
• 关键词: biological signal transduction; cell differentiation; cell proliferation; genetic regulation; genetically modified animals; hair follicle; interleukin 1; keratinocyte; laboratory mouse; mass spectrometry; mitogen activated protein kinase; model design /development; proteasome; protooncogene; tissue /cell culture; transcription factor; transforming growth factors; ubiquitin

DESCRIPTION (provided by applicant): Cytokines play important roles in human development and disease. Specificity and cross-talk of cytokine signaling pathways appear to be important for fine-tuning stress responses and cell fate decision during development. Transforming growth factor beta (TGF-beta) is involved in cell growth, differentiation, tissue remodeling, immune response and angiogenesis. Interleukin 1 (IL-1) pathway plays a central role in the generation of inflammatory responses. We have found that both TGF-beta and IL-1 activate TGF-beta activated kinase 1 (TAK1) MAPKKK. Active form of TAK1 can enhance both TGF-beta- and IL-l-dependent transcription. In response to IL-1 stimulation, TAK1 activates transcription factors AP-1 and NF-KappaB. While TGF-6 stimulation does activate TAK1, the role of TAK1 in TGF-beta signaling pathway is not known. Recently, we found that TAK1 associates with a transcriptional repressor SnoN, a negative regulator of TGF-beta signaling. TAK1 induces degradation of SnoN. We hypothesize that TGF-beta activates TAK1 to induce phosphorylation of SnoN and targets SnoN for proteasomal degradation, thereby up-regulating TGF-b signal transduction. In addition, we hypothesize that TGF-beta and IL-1 activate TAK1 in distinct manner via specific scaffold/regulatory proteins to induce their unique cellular responses. Thus, the overall objectives of this proposal are; to delineate the pathway and functional role of TAK1 in TGF-beta signaling and to elucidate the mechanisms through which TAK1 regulates signal pathway specificity. To accomplish these objectives and to test our hypotheses we will: i) determine the mechanism and role of TAK1-induced SnoN degradation in TGF-b signaling pathway; ii) isolate and characterize molecules associated with TAK1 and iii) generate a skin specific knockout of TAK1 to characterize the in vivo role of TAK1 in a tissue in which TGF-beta play important roles. These studies will address unsolved questions regarding the mechanisms of TGF-beta and IL-1 family signaling and will provide an understanding of the physiological function of TAK 1 in vivo.

描述（由申请人提供）：细胞因子在人类发育和疾病中发挥重要作用。细胞因子信号通路的特异性和串扰似乎对于发育过程中应激反应和细胞命运决定的微调很重要。转化生长因子β (TGF-β) 参与细胞生长、分化、组织重塑、免疫反应和血管生成。白介素 1 (IL-1) 通路在炎症反应的产生中发挥着核心作用。我们发现 TGF-β 和 IL-1 都会激活 TGF-β 激活激酶 1 (TAK1) MAPKKK。 TAK1 的活性形式可以增强 TGF-β 和 IL-1 依赖性转录。为了响应 IL-1 刺激，TAK1 激活转录因子 AP-1 和 NF-KappaB。虽然 TGF-6 刺激确实会激活 TAK1，但 TAK1 在 TGF-β 信号通路中的作用尚不清楚。最近，我们发现 TAK1 与转录抑制因子 SnoN 相关，SnoN 是 TGF-β 信号传导的负调节因子。 TAK1 诱导 SnoN 降解。我们假设 TGF-β 激活 TAK1 诱导 SnoN 磷酸化，并靶向 SnoN 进行蛋白酶体降解，从而上调 TGF-b 信号转导。此外，我们假设 TGF-β 和 IL-1 通过特定的支架/调节蛋白以不同的方式激活 TAK1，从而诱导其独特的细胞反应。因此，该提案的总体目标是：描述 TAK1 在 TGF-β 信号传导中的通路和功能作用，并阐明 TAK1 调节信号通路特异性的机制。为了实现这些目标并检验我们的假设，我们将： i) 确定 TAK1 诱导的 SnoN 降解在 TGF-b 信号通路中的机制和作用； ii) 分离并表征与 TAK1 相关的分子，以及 iii) 产生 TAK1 的皮肤特异性敲除，以表征 TAK1 在 TGF-β 发挥重要作用的组织中的体内作用。这些研究将解决有关 TGF-β 和 IL-1 家族信号传导机制的未解决问题，并将提供对 TAK 1 体内生理功能的理解。