The E3 ubiquitin ligase HERC1 controls the ERK signaling pathway targeting C-RAF for degradation

Oncotarget
Taiane SchneiderJose Luis Rosa

Abstract

The RAF/MEK/ERK cascade is a conserved intracellular signaling pathway that controls fundamental cellular processes including growth, proliferation, differentiation, survival and migration. Aberrant regulation of this signaling pathway has long been associated with human cancers. A major point of regulation of this pathway occurs at the level of the serine/threonine protein kinase C-RAF. Here, we show how the E3 ubiquitin ligase HERC1 regulates ERK signaling. HERC1 knockdown induced cellular proliferation, which is associated with an increase in ERK phosphorylation and in C-RAF protein levels. We demonstrate that overexpression of wild-type C-RAF is sufficient to increase ERK phosphorylation. Experiments with pharmacological inhibitors of RAF activity, or with interference RNA, show that the regulation of ERK phosphorylation by HERC1 is RAF-dependent. Immunoprecipitation, pull-down and confocal fluorescence microscopy experiments demonstrate an interaction between HERC1 and C-RAF proteins. Mechanistically, HERC1 controls C-RAF stability by regulating its polyubiquitylation in a lysine 48-linked chain. In vitro ubiquitylation assays indicate that C-RAF is a substrate of the E3 ubiquitin ligase HERC1. Altogether, we show how HERC...Continue Reading

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Citations

Aug 6, 2020·Cell Cycle·Kristina Riegel, Krishnaraj Rajalingam
Aug 27, 2019·Frontiers in Physiology·Jesús García-CanoJose Luis Rosa
Jun 26, 2020·Cancers·Joan Sala-GastonJose Luis Rosa
Jul 6, 2019·Frontiers in Oncology·Taiane SchneiderJose Luis Rosa
Jan 31, 2020·Science Translational Medicine·Mushtaq AhmedShabaana A Khader
Jul 23, 2020·Scientific Reports·Mª Angeles Montes-FernándezJosé A Armengol
Feb 24, 2019·International Journal of Molecular Sciences·Christina J McTavishCaroline Schild-Poulter
Dec 18, 2020·Frontiers in Neuroanatomy·Eva M Pérez-VillegasJosé A Armengol
Aug 18, 2020·Journal of Pharmacological and Toxicological Methods·A F SantosK B Felipe
May 17, 2021·Seminars in Cancer Biology·Rahim UllahLixin Wan

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Methods Mentioned

BETA
nucleotide
GTPase
transfection
immunoprecipitation
pull-down
confocal microscopy
pull-downs
PCR
electrophoresis

Software Mentioned

ImageJ
GraphPad Prism

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