Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation

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Updated: Jun 26, 2026

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
06:09

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

Published on: June 7, 2019

Bin Zheng1, Joseph H Jeong, John M Asara

  • 1Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA. bzheng@bidmc.harvard.edu

Molecular Cell
|February 4, 2009
PubMed

Insights

Melanoma cells with BRAF V600E mutations suppress the LKB1-AMPK energy pathway. Phosphorylation of LKB1 by ERK/RSK inhibits AMPK, promoting tumor growth, but a mutant LKB1 blocks this effect.

Area of Science:

  • Cellular signaling
  • Cancer biology
  • Metabolic regulation

Background:

  • The LKB1-AMPK pathway is crucial for energy balance, controlling cell growth and survival.
  • Tumor cells often suppress this pathway for growth advantages during energy stress.
  • Mechanisms of LKB1-AMPK suppression in cancer remain largely unknown.

Purpose of the Study:

  • To investigate how melanoma cells suppress the LKB1-AMPK signaling pathway.
  • To identify the molecular link between BRAF signaling and AMPK activity in melanoma.
  • To explore therapeutic strategies targeting this pathway.

Main Methods:

  • Analysis of AMPK activation in melanoma cells with BRAF V600E mutations.
  • Investigating the phosphorylation status of LKB1 in response to BRAF signaling.
  • Utilizing phosphorylation-deficient LKB1 mutants to assess AMPK activation and cell proliferation.

Main Results:

  • AMPK activation is suppressed in melanoma cells harboring the BRAF V600E mutation.
  • BRAF signaling leads to LKB1 phosphorylation by ERK and RSK, inhibiting LKB1-AMPK binding.
  • Expression of a phosphorylation-deficient LKB1 mutant reactivates AMPK and inhibits melanoma cell proliferation.

Conclusions:

  • BRAF V600E signaling suppresses LKB1 function through ERK/RSK-mediated phosphorylation, inhibiting AMPK.
  • This suppression of LKB1-AMPK signaling plays a significant role in BRAF V600E-driven melanoma tumorigenesis.
  • Targeting LKB1 phosphorylation offers a potential therapeutic strategy for melanoma.

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