From the Molecular Targets Group, James Graham Brown Cancer Center, Departments of Biochemistry and Molecular Biology.
Medicine, and.
J Biol Chem. 2014 Nov 7;289(45):31102-10. doi: 10.1074/jbc.M114.594283. Epub 2014 Sep 12.
Ras is the most frequently activated oncogene found in human cancer, but its mechanisms of action remain only partially understood. Ras activates multiple signaling pathways to promote transformation. However, Ras can also exhibit a potent ability to induce growth arrest and death. NORE1A (RASSF5) is a direct Ras effector that acts as a tumor suppressor by promoting apoptosis and cell cycle arrest. Expression of NORE1A is frequently lost in human tumors, and its mechanism of action remains unclear. Here we show that NORE1A forms a direct, Ras-regulated complex with β-TrCP, the substrate recognition component of the SCF(β-TrCP) ubiquitin ligase complex. This interaction allows Ras to stimulate the ubiquitin ligase activity of SCF(β-TrCP) toward its target β-catenin, resulting in degradation of β-catenin by the 26 S proteasome. However, the action of Ras/NORE1A/β-TrCP is substrate-specific because IκB, another substrate of SCF(β-TrCP), is not sensitive to NORE1A-promoted degradation. We identify a completely new signaling mechanism for Ras that allows for the specific regulation of SCF(β-TrCP) targets. We show that the NORE1A levels in a cell may dictate the effects of Ras on the Wnt/β-catenin pathway. Moreover, because NORE1A expression is frequently impaired in tumors, we provide an explanation for the observation that β-TrCP can act as a tumor suppressor or an oncogene in different cell systems.
Ras 是人类癌症中最常被激活的致癌基因，但它的作用机制仍不完全了解。Ras 激活多种信号通路以促进转化。然而，Ras 也具有很强的诱导生长停滞和死亡的能力。NORE1A（RASSF5）是 Ras 的直接效应物，通过促进细胞凋亡和细胞周期停滞而发挥肿瘤抑制作用。NORE1A 的表达在人类肿瘤中经常丢失，其作用机制尚不清楚。在这里，我们表明 NORE1A 与β-TrCP 形成直接的 Ras 调节复合物，β-TrCP 是 SCF（β-TrCP）泛素连接酶复合物的底物识别成分。这种相互作用使 Ras 能够刺激 SCF（β-TrCP）对其靶标β-catenin 的泛素连接酶活性，导致 26S 蛋白酶体降解β-catenin。然而，Ras/NORE1A/β-TrCP 的作用是底物特异性的，因为 SCF（β-TrCP）的另一个底物 IκB 不受 NORE1A 促进的降解的影响。我们为 Ras 确定了一种全新的信号机制，允许对 SCF（β-TrCP）的靶标进行特异性调节。我们表明，细胞中的 NORE1A 水平可能决定 Ras 对 Wnt/β-catenin 途径的影响。此外，由于肿瘤中经常存在 NORE1A 表达受损的情况，我们为观察到β-TrCP 在不同细胞系统中可以作为肿瘤抑制因子或癌基因的情况提供了一种解释。
