TRIM15 and CYLD regulate ERK activation via lysine 63-linked polyubiquitination

The extracellular signal-regulated kinases ERK1 and ERK2 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 Lys63-linked polyubiquitin chains. We identify the tripartite motif-containing protein TRIM15 as a ubiquitin ligase, and the tumor suppressor CYLD as a deubiquitinase, for ERKs. TRIM15 and CYLD regulate ERK ubiquitination at defined lysine residues via mutually exclusive interactions as well as opposing activities. K63-linked polyubiquitination enhances ERK interaction with and activation by MEK. Down-regulation of TRIM15 inhibits growth of both drug-responsive and -resistant melanomas. Moreover, high TRIM15 expression and low CYLD expression are associated with poor prognosis of melanoma patients. These findings define a role of Lys63-linked polyubiquitination in the ERK signaling pathway and suggest a potential target for cancer therapy.