TAK1 Regulation of TGF-beta and IL-1 signaling

描述(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微调应激反应和细胞发育过程中的命运决定很重要。转化生长因子β参与细胞的生长、分化、组织重塑、免疫反应和血管生成。白介素1(IL-1)途径在炎症反应的产生中起核心作用。我们发现，转化生长因子-β和白介素1都能激活转化生长因子-β激活的蛋白激酶1(TAK1)MAPKKK。活性形式的Tak1可促进转化生长因子-β和白介素2-L依赖的转录。作为对IL-1刺激的响应，TAK1激活转录因子AP-1和核因子-kappaB。虽然转化生长因子-6的刺激确实激活了TAK1，但TAK1在转化生长因子-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有关，SnoN是转化生长因子-β信号的负调控因子。TAK1可诱导SnoN的降解。我们推测，转化生长因子-β激活TAK1诱导SnoN的磷酸化，并靶向SnoN的蛋白酶体降解，从而上调转化生长因子-b的信号转导。此外，我们假设转化生长因子-β和IL-1通过特定的支架/调节蛋白以不同的方式激活TAK1，以诱导它们独特的细胞反应。因此，这项建议的总体目标是：描绘TAK1在转化生长因子-β信号转导中的途径和功能，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验证我们的假设，我们将：i)确定TAK1诱导的SnoN降解在转化生长因子-b信号通路中的机制和作用；ii)分离和鉴定与TAK1相关的分子；iii)产生皮肤特异的TAK1基因敲除，以表征TAK1在转化生长因子-β发挥重要作用的组织中的体内作用。这些研究将解决尚未解决的关于转化生长因子-β和IL-1家族信号转导机制的问题，并将有助于了解TAK-1在体内的生理功能。

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.