Regulation of c-Raf Stability through the CTLH Complex

International Journal of Molecular Sciences
Christina J McTavishCaroline Schild-Poulter

Abstract

c-Raf is a central component of the extracellular signal-regulated kinase (ERK) pathway which is implicated in the development of many cancer types. RanBPM (Ran-Binding Protein M) was previously shown to inhibit c-Raf expression, but how this is achieved remains unclear. RanBPM is part of a recently identified E3 ubiquitin ligase complex, the CTLH (C-terminal to LisH) complex. Here, we show that the CTLH complex regulates c-Raf expression through a control of its degradation. Several domains of RanBPM were found necessary to regulate c-Raf levels, but only the C-terminal CRA (CT11-RanBPM) domain showed direct interaction with c-Raf. c-Raf ubiquitination and degradation is promoted by the CTLH complex. Furthermore, A-Raf and B-Raf protein levels are also regulated by the CTLH complex, indicating a common regulation of Raf family members. Finally, depletion of CTLH subunits RMND5A (required for meiotic nuclear division 5A) and RanBPM resulted in enhanced proliferation and loss of RanBPM promoted tumour growth in a mouse model. This study uncovers a new mode of control of c-Raf expression through regulation of its degradation by the CTLH complex. These findings also uncover a novel target of the CTLH complex, and suggest that the ...Continue Reading

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Citations

Jun 10, 2020·Proceedings of the National Academy of Sciences of the United States of America·Cheng DongJinrong Min
Dec 31, 2019·Journal of Oncology·Nickelas HuffmanVincenzo Coppola
Jan 3, 2020·Biochemistry·Shun-Jia ChenAlexander Varshavsky
May 17, 2021·Seminars in Cancer Biology·Rahim UllahLixin Wan
Aug 13, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Matthew E R MaitlandCaroline Schild-Poulter

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Methods Mentioned

BETA
ubiquitination
xenograft
co-immunoprecipitation
pull-down
Assay
pull down
CTLH
PCR
transfection
proximity ligation assay

Software Mentioned

RAPTORX
Pro Plus
Image Lab
Image

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