The extracellular-signal-regulated kinases ERK1 and ERK2 (hereafter ERK1/2) represent the foremost mitogenic pathway in mammalian cells, and their dysregulation drives tumorigenesis and confers therapeutic resistance. ERK1/2 are known to be activated by MAPK/ERK kinase (MEK)-mediated phosphorylation. Here, we show that ERK1/2 are also modified by lysine-63 (K63)-linked polyubiquitin chains. We identify the tripartite motif–containing protein TRIM15 as a ubiquitin ligase and the tumour suppressor CYLD as a deubiquitinase of ERK1/2. TRIM15 and CYLD regulate ERK ubiquitination at defined lysine residues through mutually exclusive interactions as well as opposing activities. K63-linked polyubiquitination enhances ERK interaction with and activation by MEK. Downregulation of TRIM15 inhibits the growth of both drug-responsive and drug-resistant melanomas. Moreover, high TRIM15 expression and low CYLD expression are associated with poor prognosis of patients with melanoma. These findings define a role of K63-linked polyubiquitination in the ERK signalling pathway and suggest a potential target for cancer therapy.

细胞外信号调节激酶 ERK1 和 ERK2（以下简称 ERK1/2）代表哺乳动物细胞中最重要的有丝分裂途径，它们的失调驱动肿瘤发生并赋予治疗抗性。已知 ERK1/2 被 MAPK/ERK 激酶 (MEK) 介导的磷酸化激活。在这里，我们显示 ERK1/2 也被 lysine-63 (K63)-连接的多泛素链修饰。我们将含有三部分基序的蛋白 TRIM15 鉴定为泛素连接酶，将肿瘤抑制因子 CYLD 鉴定为 ERK1/2 的去泛素酶。TRIM15 和 CYLD 通过相互排斥的相互作用和相反的活动在确定的赖氨酸残基处调节 ERK 泛素化。K63 连接的多泛素化增强了 ERK 与 MEK 的相互作用和激活。TRIM15 的下调抑制药物反应性和耐药性黑色素瘤的生长。此外，高TRIM15表达和 CYLD 低表达与黑色素瘤患者预后不良有关。这些发现定义了 K63 连接的多泛素化在 ERK 信号通路中的作用，并提出了癌症治疗的潜在靶点。