Fas接头蛋白调节TGF-β II 型受体(TβRII)的机理和在恶性肿瘤转移中的功能

TGF-β signaling plays critical roles in embryonic development and the maintenance of tissue homeostasis in all metazoans. Deregulation of TGF-β activity results in cancer development. TGF-β type II receptor (TβRII) is the original site of TGF-β signal transduction on the plasma membrane. The cell surface level of TβRII determine the signal intensity and duration. However, the mechanism by which TβRII protein is regulated remains elusive. In previous study, we found TβRII interacted with Fas-associated factor1 (FAF1). Knockdown of FAF1 leads to the accumulation of TβRII on the cell membrane. Furthermore, FAF1 was found to associate with VCP/E3 ligase complex and contain several AKT consensus phosphorylation motifs. We hypothesized that FAF1, by recruiting VCP/E3 ligase complex, promotes membrane-associated TβRII degradation via ubiquitination. While in malignant tumors, highly activated oncogenic PI3K-AKT signal phosphorylates and inactivates FAF1, leading to the accumulation of TβRII on the cell membrane. Thus, in this study, we aim to identity the mechanism explaining how membrane-associated TβRII protein level is regulated and figure out the reason why TβRII accumulated on the membrane in malignant tumor. Upon successful conclusion of this work, we will have discovered the detailed mechanism of TβRII regulation and provide reference for TGF-β receptor anti-cancer therapy.

TGF-β超家族信号通路在多细胞生物胚胎发育和维持组织内稳态方面发挥着重要的作用，该通路的失调会导致癌症的发生。TGF-β II 型受体(TβRII)是细胞膜上TGF-β信号转导的起始点，其在细胞膜上的蛋白水平决定着TGF-β信号的强弱和持续时间。但其在细胞膜上的代谢机制并不清楚。我们前期的研究发现，在正常或早期肿瘤细胞中，TβRII能与FAF1结合，并且FAF1可能通过招募VCP/E3 ligase复合物使TβRII进入溶酶体进行泛素化降解，而在肿瘤恶化过程中，原癌信号如PI3K-AKT等可能通过磷酸化FAF1使其失活，从而导致TβRII在细胞膜上的积累，在恶性肿瘤当中加速了TGF-β的促肿瘤转移作用。本项目旨在阐明细胞膜上TβRII蛋白水平的调控机制及其调控紊乱对肿瘤转移的影响，为针对TGF-β受体的抗癌疗法提供新的思路。

TGF-β对晚期乳腺癌细胞具有促转移作用。尽管有最新进展，但对TGF-βII型受体的调节仍不确定。在这里我们报告说，FAF1通过募集VCP/E3连接酶复合物使细胞表面的TβRII不稳定，从而限制了过量的TGF-β信号激活。重要的是，活化的AKT直接在Ser582处使FAF1磷酸化，从而破坏FAF1-VCP复合物并还原质膜上的FAF1。后者导致细胞表面TβRII的增加，从而促进TGF-β诱导的SMAD和非SMAD信号传导。我们通过利用FAF1基因敲除小鼠研究上皮到间充质转化和肿瘤转移；利用多种体外和体内模型，包括MMTV-PyMT转基因小鼠乳腺肿瘤进展和临床乳腺癌样本的分析，揭示了FAF1的转移抑制作用。这些发现描述了以前未知的机制，通过该机制可以严格控制TβRII。这些结论揭示了SMAD和AKT途径如何相互作用以赋予对TGF-β的促癌作用。