RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy.
RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy.
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DOI：
10.1126/sciadv.adf4766
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发表时间：
2023-07-14
期刊：
影响因子：
13.6
通讯作者：
Castel, Pau
中科院分区：
文献类型：
--
作者：
Cuevas-Navarro, Antonio;Wagner, Morgan;Van, Richard;Swain, Monalisa;Mo, Stephanie;Columbus, John;Allison, Madeline R.;Cheng, Alice;Messing, Simon;Turbyville, Thomas J.;Simanshu, Dhirendra K.;Sale, Matthew J.;McCormick, Frank;Stephen, Andrew G.;Castel, Pau
RIT1是一种Ras鸟苷三磷酸酶(GTPase)，调节信号转导的不同方面，在肺癌、白血病和Noonan综合征患者的胚系中发生突变。致病的RIT1蛋白促进丝裂原活化蛋白激酶(MAPK)的过度激活；然而，这一机制尚不清楚。在这里，我们证明RAF激酶是MAPK激活所必需的膜结合突变体RIT1的直接效应器。我们确定了RIT1中促进与膜脂相互作用的关键残基，并表明这些残基对于与RAF激酶和MAPK激活是必要的。虽然突变体RIT1直接与RAF蛋白结合，但在缺乏经典RAS蛋白的情况下，它不能激活MAPK信号。与异常的RAF/MAPK激活是疾病的驱动因素一致，我们证明了通路抑制可以减轻RIT1突变Noonan综合征小鼠模型的心肌肥厚。这些数据阐明了致病RIT1的功能，并确定了治疗干预的途径。静电质膜结合促进RIT1介导的RAF激活以促进致病的MAPK信号转导。
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 RIT1 mutant Noonan syndrome. These data shed light on the function of pathogenic RIT1 and identify avenues for therapeutic intervention. Electrostatic plasma membrane binding facilitates RIT1-mediated RAS-dependent RAF activation to promote pathogenic MAPK signaling.
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影响因子：
56.9
作者：
Joneson, T;White, MA;BarSagi, D
通讯作者：
BarSagi, D
影响因子：
4.6
作者：
Figueira TN;Freire JM;Cunha-Santos C;Heras M;Gonçalves J;Moscona A;Porotto M;Salomé Veiga A;Castanho MA
通讯作者：
Castanho MA
DOI：
10.1016/j.cub.2021.06.030
发表时间：
2021-09-13
期刊：
Current biology : CB
影响因子：
--
作者：
Cuevas-Navarro A;Van R;Cheng A;Urisman A;Castel P;McCormick F
通讯作者：
McCormick F
影响因子：
3.5
作者：
Koenighofer M;Hung CY;McCauley JL;Dallman J;Back EJ;Mihalek I;Gripp KW;Sol-Church K;Rusconi P;Zhang Z;Shi GX;Andres DA;Bodamer OA
通讯作者：
Bodamer OA
影响因子：
5.3
作者：
FEIG, LA;COOPER, GM
通讯作者：
COOPER, GM