The NF2 tumor suppressor merlin interacts with Ras and RasGAP, which may modulate Ras signaling
The NF2 tumor suppressor merlin interacts with Ras and RasGAP, which may modulate Ras signaling
复制标题
DOI：
10.1038/s41388-019-0883-6
复制
发表时间：
2019-09-05
期刊：
影响因子：
8
通讯作者：
Morrison, Helen
中科院分区：
文献类型：
--
作者：
Cui, Yan;Groth, Susann;Morrison, Helen
肿瘤抑制因子NF 2/merlin的失活是2型神经纤维瘤病（NF 2）和一些散发性肿瘤的基础。先前的研究已经确定，梅林介导的接触抑制增殖，然而，确切的机制仍然不清楚，多个途径已经牵连。我们以前曾报道过，梅林抑制Ras和Rac的活性在接触抑制，但梅林如何调节Ras活性仍然难以捉摸。在这里，我们证明了梅林可以直接与Ras和p120 RasGAP（也称为RasGAP）相互作用。虽然merlin不增加RasGAP的催化活性，但与Ras和RasGAP的相互作用可以微调Ras信号传导。在体内，在雪旺细胞中的RasGAP的损失，不像梅林的损失，未能促进原位模型中的致瘤性生长。因此，通过RasGAP调节Ras信号可能有助于但不足以解释merlin的肿瘤抑制活性。我们的研究为merlin依赖的Ras调节机制提供了新的见解，并可能对merlin依赖的其他小GTP酶的调节产生额外的影响。
Inactivation of the tumor suppressor NF2/merlin underlies neurofibromatosis type 2 (NF2) and some sporadic tumors. Previous studies have established that merlin mediates contact inhibition of proliferation; however, the exact mechanisms remain obscure and multiple pathways have been implicated. We have previously reported that merlin inhibits Ras and Rac activity during contact inhibition, but how merlin regulates Ras activity has remained elusive. Here we demonstrate that merlin can directly interact with both Ras and p120RasGAP (also named RasGAP). While merlin does not increase the catalytic activity of RasGAP, the interactions with Ras and RasGAP may fine-tune Ras signaling. In vivo, loss of RasGAP in Schwann cells, unlike the loss of merlin, failed to promote tumorigenic growth in an orthotopic model. Therefore, modulation of Ras signaling through RasGAP likely contributes to, but is not sufficient to account for, merlin's tumor suppressor activity. Our study provides new insight into the mechanisms of merlin-dependent Ras regulation and may have additional implications for merlin-dependent regulation of other small GTPases.