TRIM15 and CYLD regulate ERK activation via lysine-63-linked polyubiquitination
- Nat Cell Biol. 2021 Sep;23(9):978-991. doi: 10.1038/s41556-021-00732-8.
- 1. Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- 2. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- 3. Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
- 4. Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
- 5. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
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.