{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Zhu G"],"funding":["NCI NIH HHS","NIAMS NIH HHS","U.S. Department of Health & Human Services | National Institutes of Health"],"pagination":["978-991"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8440396"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["23(9)"],"pubmed_abstract":["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."],"journal":["Nature cell biology"],"pubmed_title":["TRIM15 and CYLD regulate ERK activation via lysine-63-linked polyubiquitination."],"pmcid":["PMC8440396"],"funding_grant_id":["R01 CA243520","R01CA235760","R01CA184867","R01 CA184867","P30 CA010815","R01 CA182675","R01CA243520","P30 AR069589","R01 CA235760"],"pubmed_authors":["Yang X","Herlyn M","Zhu G"],"additional_accession":[]},"is_claimable":false,"name":"TRIM15 and CYLD regulate ERK activation via lysine-63-linked polyubiquitination.","description":"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.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Sep","modification":"2026-05-31T07:06:08.975Z","creation":"2025-04-05T09:49:45.201Z"},"accession":"S-EPMC8440396","cross_references":{"pubmed":["34497368"],"doi":["10.1038/s41556-021-00732-8"]}}