Dual Function of UNC-51-like Kinase 3 (Ulk3) in the Sonic Hedgehog Signaling Pathway

The Sonic hedgehog (Shh) signaling pathway controls a variety of developmental processes and is implicated in tissue homeostasis maintenance and neurogenesis in adults. Recently, we identified Ulk3 as an active kinase able to positively regulate Gli proteins, mediators of the Shh signaling in mammals. Here, we provide several lines of evidence that Ulk3 participates in the transduction of the Shh signal also independently of its kinase activity. We demonstrate that Ulk3 through its kinase domain interacts with Suppressor of Fused (Sufu), a protein required for negative regulation of Gli proteins. Sufu blocks Ulk3 autophosphorylation and abolishes its ability to phosphorylate and positively regulate Gli proteins. We show that Shh signaling destabilizes the Sufu-Ulk3 complex and induces the release of Ulk3. We demonstrate that the Sufu-Ulk3 complex, when co-expressed with Gli2, promotes generation of the Gli2 repressor form, and that reduction of the Ulk3 mRNA level in Shh-responsive cells results in higher potency of the cells to transmit the Shh signal. Our data suggests a dual function of Ulk3 in the Shh signal transduction pathway and propose an additional way of regulating Gli proteins by Sufu, through binding to and suppression of Ulk3.     

胶质瘤相关癌基因蛋白在肿瘤发生中的作用

胶质瘤相关癌基因蛋白(glioma-associated oncogene1,Gli)是Hedgehog(Hh)信号通路的转录因子,定位于细胞核和细胞浆,将信号传送至核内。脊椎动物中已鉴定出3个成员,分别为Gli 1、Gli2和Gli3,该蛋白家族成员只有在维持全长时才具有转录激活子的功能,羧基端被蛋白酶体水解后,就形成了转录抑制子。近年来,Gli与肿瘤的关系日益受到人们的重视,以前普遍认为的Gli目的基因的调控和Gli蛋白的转录后修饰是通过Hh通路实现受到挑战,越来越多的研究证明有许多非经典机制可以不通过Hh通路来调节Gli目的基因的表达。Gli研究将有助于我们对肿瘤的认知和治疗。