TAK1 Regulation of TGF-beta and IL-1 signaling

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对于发育过程中微调应激反应和细胞命运决定似乎是重要的。转化生长因子β（TGF-β）参与细胞生长、分化、组织重塑、免疫应答和血管生成。白细胞介素1（IL-1）通路在炎症反应的产生中起着核心作用。我们已经发现TGF-β和IL-1都激活TGF-β激活的激酶1（TAK 1）MAPKKK。TAK 1的活性形式可以增强TGF-β和IL-1依赖性转录。响应于IL-1刺激，TAK 1激活转录因子AP-1和NF-κ B。虽然TGF-6刺激确实激活了TAK 1，但TAK 1在TGF-β信号通路中的作用尚不清楚。最近，我们发现TAK 1与转录抑制因子SnoN相关，SnoN是TGF-β信号的负调节因子。TAK 1诱导SnoN的降解。我们假设TGF-β激活TAK 1诱导SnoN磷酸化，并靶向SnoN进行蛋白酶体降解，从而上调TGF-β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TAK 1，以诱导其独特的细胞反应。因此，本提案的总体目标是：描述TAK 1在TGF-β信号传导中的通路和功能作用，并阐明TAK 1调节信号通路特异性的机制。为了实现这些目标并测试我们的假设，我们将：i）确定TAK 1诱导的SnoN降解在TGF-β信号传导途径中的机制和作用; ii）分离并表征与TAK 1相关的分子;以及iii）产生皮肤特异性TAK 1敲除以表征TAK 1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。

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.