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- W3148765469 endingPage "108928" @default.
- W3148765469 startingPage "108928" @default.
- W3148765469 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." @default.
- W3148765469 created "2021-04-13" @default.
- W3148765469 creator A5009978411 @default.
- W3148765469 creator A5024591656 @default.
- W3148765469 creator A5071941800 @default.
- W3148765469 creator A5073953160 @default.
- W3148765469 date "2021-03-01" @default.
- W3148765469 modified "2023-10-15" @default.
- W3148765469 title "PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK" @default.
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