瑞典科学家近日研究发现了一种细胞生长因子的全新信号通道,这种生长因子对于癌细胞的存活和生长至关重要。这一发现为某些癌症的研究开启了全新的图景。相关论文8月31日在线发表于《自然—细胞生物学》(Nature Cell Biology)上。
人体细胞“理解”来自多种生长因子的信号的能力,对于正常的胎儿发育极为重要。癌细胞的入侵性和存活能力同样由许多生长因子控制,其中转化生长因子b(TGF-b)发挥着显著作用。
在最新的研究中,瑞典乌普萨拉大学遗传学与病理学系的Marene Landstr?m和同事发现了一个全新的由TGF-b调控的信号通道。Landstr?m说:“这一发现具有重大的价值,它可以帮助我们鉴别TGF-b使用何种信号通道来抑制细胞生长,以及刺激癌细胞存活和转移的能力。”
TGF-b通过绑定在细胞膜上的受体将信号传入细胞内,与大多数动物中的方式类似。大约十年前,科学家发现了所谓的Smad蛋白,它是活跃TGF-b信号的独特信使。当磷酸盐绑定于其上时,这些蛋白会被激活,激活的方式依赖于TGF-b受体内酶(丝氨酸-苏氨酸激酶)的活性。
而新发现的信号通道完全不依赖于丝氨酸-苏氨酸激酶活性。研究显示,另外一种酶——TRAF6被激活,它绑定在受体联合体上。TRAF6是一个泛素连接酶(ubiquitin-ligase),当它被激活的时候,会在自身和其它蛋白上产生短小蛋白链。因此TRAF6作为一个开关,能够决定在细胞内开启何种信号。TGF-利用TRAF6特定地激活激酶TAK1,TAK1随后激活其它的应激活化激酶,导致细胞死亡。
研究人员表示,“发现TGF-利用TRAF6激活细胞内信号通道,为未来的研究开启了全新的图景。这使得开发新的治疗策略来对抗一些依赖TGF-的晚期癌症成为可能,如乳腺癌和前列腺癌。”(生物谷Bioon.com)
生物谷推荐原始出处:
Nature Cell Biology,doi:10.1038/ncb1780,Alessandro Sorrentino,Maréne Landstr?m
The type I TGF- receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner
Alessandro Sorrentino1,3, Noopur Thakur1,2,3, Susanne Grimsby1,3, Anders Marcusson1,2, Verena von Bulow1, Norbert Schuster1, Shouting Zhang1, Carl-Henrik Heldin1 & Maréne Landström1,2
Transforming growth factor- (TGF-) is a multifunctional cytokine that regulates embryonic development and tissue homeostasis; however, aberrations of its activity occur in cancer1, 2. TGF- signals through its Type II and Type I receptors (TRII and TRI) causing phosphorylation of Smad proteins3, 4. TGF--associated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, was originally identified as an effector of TGF--induced p38 activation5. However, the molecular mechanisms for its activation are unknown. Here we report that the ubiquitin ligase (E3) TRAF6 interacts with a consensus motif present in TRI. The TRI–TRAF6 interaction is required for TGF--induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1–p38/JNK pathway, which leads to apoptosis. TRI kinase activity is required for activation of the canonical Smad pathway, whereas E3 activity of TRAF6 regulates the activation of TAK1 in a receptor kinase-independent manner. Intriguingly, TGF--induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF- specifically activates TAK1 through interaction of TRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6.