PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK

• Published in: Cell reports (Cambridge) 2021-03, Vol.34 (13), p.108928-108928, Article 108928
• Main Authors: Cho, Eunice, Lou, Hua Jane, Kuruvilla, Leena, Calderwood, David A., Turk, Benjamin E.
• Format: Article
• Language: English
• Subjects: cancer cell signaling; Carcinogenesis - pathology; Cell Line, Tumor; HEK293 Cells; Humans; kinase inhibitor resistance; MAP kinase signaling; MAP Kinase Signaling System; melanoma; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Phosphoprotein Phosphatases - genetics; Phosphoprotein Phosphatases - metabolism; Phosphorylation; protein phosphatases; RNA, Small Interfering - metabolism; Substrate Specificity
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.108928

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. [Display omitted] •The phosphatase PPP6C promotes sensitivity of melanoma cells to MEK inhibitors•PPP6C loss causes ERK pathway hyperactivation in cells harboring BRAF and RAS mutations•PP6 regulatory subunits recruit MEK for dephosphorylation by PPP6C•Recurrent melanoma-associated PPP6C mutants lead to elevated MEK and ERK activity Through an shRNA screen, Cho et al. identify PPP6C as a phosphatase that inactivates the kinase MEK, sensitizing tumor cells to clinical MEK inhibitors. This study suggests that cancer-associated loss-of-function PPP6C mutations prevalent in melanoma serve to activate the core oncogenic RAF-MEK-ERK pathway that drives the disease.