Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France.
ART Group, Inserm U830, Paris, France.
Elife. 2018 Oct 15;7:e40474. doi: 10.7554/eLife.40474.
The two Ral GTPases, RalA and RalB, have crucial roles downstream Ras oncoproteins in human cancers; in particular, RalB is involved in invasion and metastasis. However, therapies targeting Ral signalling are not available yet. By a novel optogenetic approach, we found that light-controlled activation of Ral at plasma-membrane promotes the recruitment of the Wave Regulatory Complex (WRC) via its effector exocyst, with consequent induction of protrusions and invasion. We show that active Ras signals to RalB via two RalGEFs (Guanine nucleotide Exchange Factors), RGL1 and RGL2, to foster invasiveness; RalB contribution appears to be more important than that of MAPK and PI3K pathways. Moreover, on the clinical side, we uncovered a potential role of RalB in human breast cancers by determining that RalB expression at protein level increases in a manner consistent with progression toward metastasis. This work highlights the Ras-RGL1/2-RalB-exocyst-WRC axis as appealing target for novel anticancer strategies.
两种 Ral GTPases，RalA 和 RalB，在人类癌症中的 Ras 癌蛋白下游发挥关键作用；特别是，RalB 参与了侵袭和转移。然而，针对 Ral 信号的治疗方法尚未出现。通过一种新的光遗传学方法，我们发现通过其效应物胞吐作用，光控激活质膜上的 Ral 会促进波状调控复合物（WRC）的募集，从而导致突起和侵袭的诱导。我们表明，活性 Ras 通过两种 RalGEFs（鸟嘌呤核苷酸交换因子）RGL1 和 RGL2 向 RalB 发出信号，以促进侵袭性；RalB 的贡献似乎比 MAPK 和 PI3K 途径更为重要。此外，在临床方面，我们通过确定 RalB 在蛋白质水平上的表达随着向转移进展的方式增加，揭示了 RalB 在人类乳腺癌中的潜在作用。这项工作强调了 Ras-RGL1/2-RalB-胞吐-WRC 轴作为新型抗癌策略的有吸引力的靶标。
