ArticleCell reports2021
PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK.
Article in Cell reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 32 citations in OpenAlex.
- AARS1 promotes diabetic kidney disease through rewiring Akt and NF-κB signaling to suppress autophagy and sustain inflammation.Cellular & molecular biology letters · 2026Article
- ERKed by too much signaling: from oncogenic driver to therapeutic vulnerability.Cellular and molecular life sciences : CMLS · 2026Review
- Integrative neuroimmunology reveals leukocyte-expressing PAX6 as a critical predictor of major depressive disorder.Translational psychiatry · 2025Article
- The protein phosphatase 6 subunit SAPS3 modulates lifespan by regulating metabolism.Science advances · 2025Article
- Functional Role of Protein Phosphatase-6 (Current medicinal chemistry · 2025Review
- Melanoma genomics - will we go beyond BRAF in clinics?Journal of cancer research and clinical oncology · 2024Review
- SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers.Nature communications · 2024Article
- The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis.BMC biology · 2024Article
- Protein phosphatase 6 activates NF-κB to confer sensitivity to MAPK pathway inhibitors inScience signaling · 2024Article
- Oncogenic K-RasFEBS open bio · 2024Article
- Drug dependence in cancer is exploitable by optimally constructed treatment holidays.Nature ecology & evolution · 2024Article
- Protein phosphatase 6 regulates trametinib sensitivity, a mitogen-activated protein kinase kinase (MEK) inhibitor, by regulating MEK1/2-ERK1/2 signaling in canine melanoma cells.The Journal of veterinary medical science · 2023Article
- Molecular Modeling Unveils the Effective Interaction of B-RAF Inhibitors with Rare B-RAF Insertion Variants.International journal of molecular sciences · 2023Article
- Tackling FGFR3-driven bladder cancer with a promising synergistic FGFR/HDAC targeted therapy.NPJ precision oncology · 2023Article
- Inducible protein degradation as a strategy to identify Phosphoprotein Phosphatase 6 substrates in RAS-mutant colorectal cancer cells.bioRxiv : the preprint server for biology · 2023Article
- A Comprehensive Analysis of Cutaneous Melanoma Patients in Greece Based on Multi-Omic Data.Cancers · 2023Article
- Elaiophylin triggers paraptosis and preferentially kills ovarian cancer drug-resistant cells by inducing MAPK hyperactivation.Signal transduction and targeted therapy · 2022Article
- Rab40c regulates focal adhesions and PP6 activity by controlling ANKRD28 ubiquitylation.Life science alliance · 2022Article
- PP6 deficiency in mice with KRAS mutation and Trp53 loss promotes early death by PDAC with cachexia-like features.Cancer science · 2022Article
- PPP6C, a serine-threonine phosphatase, regulates melanocyte differentiation and contributes to melanoma tumorigenesis through modulation of MITF activity.Scientific reports · 2022Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Flux through the RAF-MEK-ERK protein kinase cascade is shaped by phosphatases acting on the core components of the pathway. Despite being an established drug target and a hub for crosstalk regulation, little is known about dephosphorylation of MEK, the central kinase within the cascade. Here, we identify PPP6C, a phosphatase frequently mutated or downregulated in melanoma, as a major MEK phosphatase in cells exhibiting oncogenic ERK pathway activation. Recruitment of MEK to PPP6C occurs through an interaction with its associated regulatory subunits. Loss of PPP6C causes hyperphosphorylation of MEK at activating and crosstalk phosphorylation sites, promoting signaling through the ERK pathway and decreasing sensitivity to MEK inhibitors. Recurrent melanoma-associated PPP6C mutations cause MEK hyperphosphorylation, suggesting that they promote disease at least in part by activating the core oncogenic pathway driving melanoma. Collectively, our studies identify a key negative regulator of ERK signaling that may influence susceptibility to targeted cancer therapies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.