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Regulation of c-Raf Stability through the CTLH Complex

1
Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON N6A 5B7, Canada
2
Department of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON N6A 5C1, Canada
3
Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON N6A 5C1, Canada
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(4), 934; https://doi.org/10.3390/ijms20040934
Received: 1 February 2019 / Accepted: 14 February 2019 / Published: 21 February 2019
(This article belongs to the Section Molecular Biology)
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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 CTLH complex has activities that suppress cell transformation and tumour formation. View Full-Text
Keywords: c-Raf; CTLH complex; RanBPM; RMND5A; ubiquitination; cancer; ERK pathway c-Raf; CTLH complex; RanBPM; RMND5A; ubiquitination; cancer; ERK pathway
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McTavish, C.J.; Bérubé-Janzen, W.; Wang, X.; Maitland, M.E.R.; Salemi, L.M.; Hess, D.A.; Schild-Poulter, C. Regulation of c-Raf Stability through the CTLH Complex. Int. J. Mol. Sci. 2019, 20, 934.

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