Kashatus David F, Counter Christopher M
Department of Pharmacology and Cancer Biology; Department of Radiation Oncology; Duke University Medical Center; Durham, NC USA.
Small GTPases. 2011 Nov 1;2(6):329-333. doi: 10.4161/sgtp.18284.
The small GTPases RalA and RalB are activated downstream of oncogenic Ras. While activation of RalA is critically important for tumor initiation and growth of Ras-driven cancers, the highly similar small GTPase RalB is implicated in cell survival and metastasis. This difference in function between these two related proteins maps to the C-terminus, a 30 amino acid region that regulates subcellular localization and contains several potential phosphorylation sites. Here we discuss our recent evidence that phosphorylation by the mitotic kinase Aurora A promotes RalA relocalization to mitochondrial membranes, where it recruits the effector RalBP1 and the large dynamin-related GTPase Drp1 to promote mitochondrial fission. As upregulation of both RalA and Aurora A have been observed in human tumors, and phosphorylation of RalA at the site targeted by Aurora A promotes tumorigenesis, it is possible that regulation of mitochondrial fission is one mechanism by which RalA promotes cancer.
小GTP酶RalA和RalB在致癌性Ras的下游被激活。虽然RalA的激活对于Ras驱动的癌症的肿瘤起始和生长至关重要，但高度相似的小GTP酶RalB与细胞存活和转移有关。这两种相关蛋白在功能上的差异定位于C末端，这是一个由30个氨基酸组成的区域，可调节亚细胞定位并包含几个潜在的磷酸化位点。在此，我们讨论我们最近的证据，即有丝分裂激酶Aurora A的磷酸化促进RalA重新定位到线粒体膜，在那里它招募效应器RalBP1和大型动力蛋白相关GTP酶Drp1以促进线粒体分裂。由于在人类肿瘤中已观察到RalA和Aurora A均上调，并且Aurora A靶向位点的RalA磷酸化促进肿瘤发生，因此线粒体分裂的调节可能是RalA促进癌症的一种机制。
