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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
PubMed

Insights

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.
Keywords:
CTLH complexERK pathwayRMND5ARanBPMc-Rafcancerubiquitination

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