Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.
Sci Adv. 2023 Jul 14;9(28):eadf4766. doi: 10.1126/sciadv.adf4766.
RIT1 is a RAS guanosine triphosphatase (GTPase) that regulates different aspects of signal transduction and is mutated in lung cancer, leukemia, and in the germline of individuals with Noonan syndrome. Pathogenic RIT1 proteins promote mitogen-activated protein kinase (MAPK) hyperactivation; however, this mechanism remains poorly understood. Here, we show that RAF kinases are direct effectors of membrane-bound mutant RIT1 necessary for MAPK activation. We identify critical residues in RIT1 that facilitate interaction with membrane lipids and show that these are necessary for association with RAF kinases and MAPK activation. Although mutant RIT1 binds to RAF kinases directly, it fails to activate MAPK signaling in the absence of classical RAS proteins. Consistent with aberrant RAF/MAPK activation as a driver of disease, we show that pathway inhibition alleviates cardiac hypertrophy in a mouse model of mutant Noonan syndrome. These data shed light on the function of pathogenic RIT1 and identify avenues for therapeutic intervention.
RIT1 是一种 RAS 鸟嘌呤三磷酸酶（GTPase），可调节信号转导的不同方面，并且在肺癌、白血病以及 Noonan 综合征个体的种系中发生突变。致病性 RIT1 蛋白可促进丝裂原活化蛋白激酶（MAPK）过度激活；然而，这种机制仍知之甚少。在这里，我们表明 RAF 激酶是膜结合突变 RIT1 的直接效应物，对于 MAPK 激活是必需的。我们确定了 RIT1 中有助于与膜脂相互作用的关键残基，并表明这些残基对于与 RAF 激酶的关联和 MAPK 激活是必需的。尽管突变 RIT1 可直接与 RAF 激酶结合，但在没有经典 RAS 蛋白的情况下，它无法激活 MAPK 信号转导。与异常 RAF/MAPK 激活作为疾病驱动因素一致，我们表明，在突变型 Noonan 综合征的小鼠模型中，通路抑制可缓解心脏肥大。这些数据阐明了致病性 RIT1 的功能，并确定了治疗干预的途径。
Zotero 插件
