Regulation of c-Raf Stability through the CTLH Complex

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...

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Bibliographic Details
Published in:International journal of molecular sciences 2019-02, Vol.20 (4), p.934
Main Authors: McTavish, Christina J, Bérubé-Janzen, Wesley, Wang, Xu, Maitland, Matthew E R, Salemi, Louisa M, Hess, David A, Schild-Poulter, Caroline
Format: Article
Language:English
Subjects:
Activation
Animal models
Binding sites
c-Raf
C-Terminus
cancer
Cell adhesion
Cell adhesion & migration
Cell adhesion molecules
Cell growth
CRISPR
CTLH complex
Dephosphorylation
ERK pathway
Extracellular signal-regulated kinase
Gene expression
Heat shock proteins
Hsc70 protein
Hsp70 protein
Hsp90 protein
Kinases
Mutation
Phosphorylation
Proteasomes
Raf protein
Ran-binding protein
RanBPM
Regulation
RMND5A
Ron protein
Signal transduction
Stability
Transglutaminase 2
Tumorigenesis
Tumors
Ubiquitin
Ubiquitin-protein ligase
Ubiquitination
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms20040934