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Regulation of c-Raf Stability through the CTLH Complex
Christina J McTavish1,2, Wesley Bérubé-Janzen3,4, Xu Wang5
1Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON N6A 5B7, Canada. christina.mctavish@gmail.com.
International Journal of Molecular Sciences
|February 24, 2019
Summary
The CTLH complex, including RanBPM, targets c-Raf for degradation, controlling its expression. Depleting CTLH components enhances cell proliferation and tumor growth, revealing a new tumor suppressor mechanism.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- The extracellular signal-regulated kinase (ERK) pathway is crucial in cancer development.
- c-Raf is a key component of the ERK pathway.
- RanBPM's role in inhibiting c-Raf expression was previously observed but mechanistically unclear.
Purpose of the Study:
- To elucidate the mechanism by which RanBPM regulates c-Raf expression.
- To investigate the role of the C-terminal to LisH (CTLH) complex in c-Raf regulation.
- To determine the impact of CTLH complex activity on cell proliferation and tumor growth.
Main Methods:
- Investigated the interaction between RanBPM domains and c-Raf.
- Assessed the effect of the CTLH complex on c-Raf ubiquitination and degradation.
- Examined the regulation of other Raf family members (A-Raf, B-Raf) by the CTLH complex.
- Depleted CTLH subunits (RMND5A, RanBPM) in cellular and mouse models.
Main Results:
- The CTLH complex, particularly RanBPM, promotes c-Raf ubiquitination and degradation.
- The C-terminal CRA domain of RanBPM directly interacts with c-Raf.
- The CTLH complex also regulates A-Raf and B-Raf protein levels.
- Depletion of RMND5A and RanBPM led to increased cell proliferation and reduced tumor growth in mice.
Conclusions:
- The CTLH complex regulates c-Raf expression by controlling its degradation, representing a novel regulatory mechanism.
- The CTLH complex targets multiple Raf family members, suggesting a common regulatory pathway.
- The CTLH complex exhibits tumor-suppressive activities, inhibiting cell transformation and tumor formation.
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