4.7 Article

USP7 regulates the ERK1/2 signaling pathway through deubiquitinating Raf-1 in lung adenocarcinoma

Journal

CELL DEATH & DISEASE
Volume 13, Issue 8, Pages -

Publisher

SPRINGERNATURE
DOI: 10.1038/s41419-022-05136-6

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Funding

  1. Basic Research Program through the National Research Foundation of Korea (NRF) - ministry of Education [2019R1A6A1A03032888, 2020R1I1A207500311]

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This study analyzed the potential substrate proteins of USP7 using bioinformatics tools and confirmed Raf-1 as one of its substrates. By removing ubiquitin from Raf-1, USP7 inhibits the activation of the ERK1/2 signaling pathway, resulting in the suppression of lung adenocarcinoma cell proliferation.
Ubiquitin-specific protease 7 (USP7) is one of the deubiquitinating enzymes (DUBs) in the ubiquitin-specific protease (USP) family. It is a key regulator of numerous cellular functions including immune response, cell cycle, DNA damage and repair, epigenetics, and several signaling pathways. USP7 acts by removing ubiquitin from the substrate proteins. USP7 also binds to a specific binding motif of substrate proteins having the [P/A/E]-X-X-S or K-X-X-X-K protein sequences. To date, numerous substrate proteins of USP7 have been identified, but no studies have been conducted using the binding motif that USP7 binds. In the current study, we analyzed putative substrate proteins of USP7 through the [P/A/E]-X-X-S and K-X-X-X-K binding motifs using bioinformatics tools, and confirmed that Raf-1 is one of the substrates for USP7. USP7 binds to the Pro-Val-Asp-Ser (PVDS) motif of the conserved region 2 (CR2) which contains phosphorylation sites of Raf-1 and decreased M1-, K6-, K11-, K27-, K33-, and K48-linked polyubiquitination of Raf-1. We further identified that the DUB activity of USP7 decreases the threonine phosphorylation level of Raf-1 and inhibits signaling transduction through Raf activation. This regulatory mechanism inhibits the activation of the ERK1/2 signaling pathway, thereby inhibiting the G2/M transition and the cell proliferation of lung adenocarcinoma cells. In summary, our results indicate that USP7 deubiquitinates Raf-1 and is a new regulator of the ERK1/2 signaling pathway in lung adenocarcinoma.

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