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Updated: Feb 16, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization

Amandine Verlande1,2, Michaela Krafčíková3, David Potěšil3

  • 1International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.

EMBO Reports
|December 22, 2017
PubMed

Insights

Metabolic stressors activate the ERK pathway in NRAS-mutant melanoma but downregulate it in BRAF-mutant melanoma, both causing cell cycle arrest. Specific metabolic targeting is crucial for effective melanoma therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Altered cell metabolism is a key feature of cancer.
  • Targeting metabolic pathways is a promising cancer therapy strategy.
  • The ERK pathway is frequently deregulated in melanoma.

Purpose of the Study:

  • To investigate the impact of metabolic stressors on the ERK pathway in NRAS- and BRAF-mutant melanoma.
  • To understand the differential responses of melanoma subtypes to metabolic stress.
  • To identify potential therapeutic strategies targeting melanoma metabolism.

Main Methods:

  • Culturing melanoma cell lines with NRAS or BRAF mutations.
  • Inducing metabolic stress using specific agents.
  • Analyzing ERK pathway activation and dimerization of KSR/CRAF/BRAF proteins.
  • Investigating the role of AMPK in pathway regulation.

Main Results:

  • Metabolic stressors promote KSR dimerization, enhancing ERK activation in both NRAS- and BRAF-mutant melanoma.
  • Higher metabolic stress stimulates ERK in NRAS-mutant cells but downregulates it in BRAF-mutant cells.
  • BRAF dissociation from KSR, mediated by AMPK, causes ERK downregulation in BRAF-mutant cells.
  • Both ERK regulation patterns result in cell cycle arrest.

Conclusions:

  • Melanoma subtypes with NRAS and BRAF mutations exhibit distinct ERK pathway responses to metabolic stress.
  • AMPK activation plays a critical role in the differential regulation of the ERK pathway.
  • Tailored metabolic targeting strategies are necessary for effective treatment of both melanoma subtypes.
Keywords:
RAF‐ERK signalingcell cycle arrestcell survivalmelanomametabolic stress

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