蛋白激酶Wts/Lats的稳定性调控

Balancing cell proliferation and cell death is a critical mechanism for maintaining homeostasis of organisms, and its dysregulation is a common property of cancer development. The Hippo tumor suppressor signaling pathway coordinated regulates cell growth, proliferation and apoptosis and plays a crucial role in growth control and organ development. Central to this pathway, kinase Wts/Lats is a core component and its activity is regulated by multiple cues. Using genetic screen, three E3 ubiquitin ligases, Su(wts)1/2/3, were identified as novel regulators to modulate the activity of Wts/lats. Here we are planning to elucidate the molecular mechanism by which how these regulators control Wts/Lats turnover and its function in physiology or pathophysiology. Also, we are going to investigate the roles of Su(wts)1/2/3 in reducing Wts level by RNA interference of fat, an upstream modulator of Hippo signaling.

细胞增殖与细胞凋亡的平衡是机体维持稳态的重要机制。研究表明，几乎所有的肿瘤都存在细胞周期调控机制紊乱而导致细胞生长增殖失控、分化受阻、凋亡异常。Hippo肿瘤抑制信号通路能够协同调控细胞生长、增殖与凋亡，在生长控制和特定器官大小发育中发挥重要作用。肿瘤抑制基因Wts/Lats是Hippo通路核心组分之一，其活性受到内外环境的精密调节。通过遗传学筛选筛选，申请人实验室鉴定了3个新的调节Wts/Lats活性的E3泛素连接酶Su(wts)1、2和3。本申请项目将综合利用细胞生物学、遗传学和生化与分子生物学等手段着重研究Su(wts)1/2/3调控Wts蛋白稳定性的分子机制及其在动物发育过程中的生理意义。另外，我们也将探讨Su(wts)1/2/3在fat调节Wts活性中的作用。

Hippo肿瘤抑制信号通路能够协同调控细胞生长、增殖与凋亡，在生长控制和特定器官大小发育中发挥重要作用。肿瘤抑制基因Wts/Lats是Hippo通路核心组分之一，其活性受到内外环境的精密调节。本项目在遗传学筛选筛选的基础上，研究了E3泛素连接酶SIAH2/Sina、dSmurf和NEDD4调控Wts/Lats稳定性的分子机制。研究结果表明，三种E3泛素连接酶均可以调节Wts/Lats的泛素化修饰进而影响Hippo信号通路活性与功能；其中通过SIAH2对Lats稳定性的调节研究，首次建立了hypoxia-SIAH2-Lats轴性调节机制，对阐明Hippo信号通路在低氧条件参与动物正常发育和乳腺癌等实体瘤发生发展的生理病理意义具有重要意义。