The RAS pathway is among the most frequently activated signaling nodes in cancer. However, the mechanisms that alter RAS activity in human pathologies are not entirely understood. The most prevalent post-translational modification within the GTPase core domain of NRAS and KRAS is ubiquitination at lysine 128 (K128), which is significantly decreased in cancer samples compared to normal tissue. Here, we found that K128 ubiquitination creates an additional binding interface for RAS GTPase-activating proteins (GAPs), NF1 and RASA1, thus increasing RAS binding to GAP proteins and promoting GAP-mediated GTP hydrolysis. Stimulation of cultured cancer cells with growth factors or cytokines transiently induces K128 ubiquitination and restricts the extent of wild-type RAS activation in a GAP-dependent manner. In KRAS mutant cells, K128 ubiquitination limits tumor growth by restricting RAL/ TBK1 signaling and negatively regulating the autocrine circuit induced by mutant KRAS. Reduction of K128 ubiquitination activates both wild-type and mutant RAS signaling and elicits a senescence-associated secretory phenotype, promoting RAS-driven pancreatic tumorigenesis.

中文翻译：

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K128 泛素化通过扩展其与 GAP 蛋白的结合界面来限制 RAS 活性。


RAS 通路是癌症中最常激活的信号传导节点之一。然而，改变人类病理学中 RAS 活性的机制尚不完全清楚。 NRAS 和 KRAS 的 GTPase 核心结构域内最常见的翻译后修饰是赖氨酸 128 (K128) 处的泛素化，与正常组织相比，癌症样本中的泛素化显着减少。在这里，我们发现 K128 泛素化为 RAS GTP 酶激活蛋白 (GAP)、NF1 和 RASA1 创建了一个额外的结合界面，从而增加了 RAS 与 GAP 蛋白的结合并促进 GAP 介导的 GTP 水解。用生长因子或细胞因子刺激培养的癌细胞会短暂诱导 K128 泛素化，并以 GAP 依赖性方式限制野生型 RAS 激活的程度。在 KRAS 突变细胞中，K128 泛素化通过限制 RAL/TBK1 信号传导和负向调节突变 KRAS 诱导的自分泌回路来限制肿瘤生长。 K128 泛素化的减少会激活野生型和突变型 RAS 信号传导，并引发衰老相关的分泌表型，促进 RAS 驱动的胰腺肿瘤发生。