RIT1 oncoproteins escape LZTR1-mediated proteolysis
RIT1 oncoproteins escape LZTR1-mediated proteolysis
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DOI：
10.1126/science.aav1444
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发表时间：
2019-03-15
期刊：
影响因子：
56.9
通讯作者：
McCormick, Frank
中科院分区：
文献类型：
--
作者：
Castel, Pau;Cheng, Alice;McCormick, Frank
RIT 1癌蛋白已成为努南综合征和癌症的致病因素。尽管RIT1与Ras小鸟苷三磷酸酶（GTP酶）的其他成员相似，但在经典热点中未发现影响RIT1的突变，而是在蛋白质开关II结构域附近的区域中发现。我们使用同基因生殖系基因敲入小鼠模型来研究RIT 1突变在生物体水平上的影响，这导致了类似努南综合征的表型。通过质谱分析，我们检测到一个RIT1相互作用，亮氨酸拉链样转录调节因子1（LZTR1），作为蛋白质降解的接头。影响RIT 1或LZTR 1的致病性突变导致RIT 1的不完全降解。这导致RIT 1积累和生长因子信号传导反应失调。我们的研究结果强调了依赖于Ras GTCRIT1蛋白降解受损的发病机制。
RIT1 oncoproteins have emerged as an etiologic factor in Noonan syndrome and cancer. Despite the resemblance of RIT1 to other members of the Ras small guanosine triphosphatases (GTPases), mutations affecting RIT1 are not found in the classic hotspots but rather in a region near the switch II domain of the protein. We used an isogenic germline knock-in mouse model to study the effects of RIT1 mutation at the organismal level, which resulted in a phenotype resembling Noonan syndrome. By mass spectrometry, we detected a RIT1 interactor, leucine zipper-like transcription regulator 1 (LZTR1), that acts as an adaptor for protein degradation. Pathogenic mutations affecting either RIT1 or LZTR1 resulted in incomplete degradation of RIT1. This led to RIT1 accumulation and dysregulated growth factor signaling responses. Our results highlight a mechanism of pathogenesis that relies on impaired protein degradation of the Ras GTPase RIT1.