Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell. 2012 May 25;149(5):1098-111. doi: 10.1016/j.cell.2012.02.065.
Akt kinase plays a central role in cell growth, metabolism, and tumorigenesis. The TRAF6 E3 ligase orchestrates IGF-1-mediated Akt ubiquitination and activation. Here, we show that Akt ubiquitination is also induced by activation of ErbB receptors; unexpectedly, and in contrast to IGF-1 induced activation, the Skp2 SCF complex, not TRAF6, is a critical E3 ligase for ErbB-receptor-mediated Akt ubiquitination and membrane recruitment in response to EGF. Skp2 deficiency impairs Akt activation, Glut1 expression, glucose uptake and glycolysis, and breast cancer progression in various tumor models. Moreover, Skp2 overexpression correlates with Akt activation and breast cancer metastasis and serves as a marker for poor prognosis in Her2-positive patients. Finally, Skp2 silencing sensitizes Her2-overexpressing tumors to Herceptin treatment. Our study suggests that distinct E3 ligases are utilized by diverse growth factors for Akt activation and that targeting glycolysis sensitizes Her2-positive tumors to Herceptin treatment.
Akt 激酶在细胞生长、代谢和肿瘤发生中起着核心作用。TRAF6 E3 连接酶协调 IGF-1 介导的 Akt 泛素化和激活。在这里，我们表明 Akt 泛素化也可被 ErbB 受体的激活所诱导；出乎意料的是，与 IGF-1 诱导的激活相反，Skp2 SCF 复合物而不是 TRAF6，是 ErbB 受体介导的 Akt 泛素化和膜募集的关键 E3 连接酶，以响应 EGF。Skp2 缺陷会损害 Akt 的激活、Glut1 的表达、葡萄糖摄取和糖酵解以及各种肿瘤模型中的乳腺癌进展。此外，Skp2 的过表达与 Akt 的激活和乳腺癌转移相关，并可作为 Her2 阳性患者预后不良的标志物。最后，Skp2 的沉默可使 Her2 过表达的肿瘤对赫赛汀治疗敏感。我们的研究表明，不同的生长因子利用不同的 E3 连接酶来激活 Akt，并且靶向糖酵解可使 Her2 阳性肿瘤对赫赛汀治疗敏感。
