Related Experiment Video

Updated: May 7, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation

Che-Hung Shen1, Ping Yuan, Rolando Perez-Lorenzo

  • 1Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA; Department of Dermatology, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.

Molecular Cell
|October 8, 2013
PubMed

Insights

AMP-activated protein kinase (AMPK) phosphorylates BRAF, reducing MEK-ERK signaling and keratinocyte proliferation. This discovery offers a strategy to prevent BRAF inhibitor-induced skin cancers.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Signaling

Background:

  • BRAF oncogenic protein kinase drives cell growth via the MEK-ERK pathway.
  • BRAF inhibitors are effective melanoma treatments but can cause cutaneous squamous cell carcinomas (cSCCs).

Purpose of the Study:

  • To investigate the regulatory mechanism of BRAF signaling by AMP-activated protein kinase (AMPK).
  • To explore a potential strategy for preventing BRAF inhibitor-associated cSCCs.

Main Methods:

  • Investigated BRAF phosphorylation at Ser729 by AMPK.
  • Analyzed BRAF interactions with 14-3-3 proteins and KSR1 scaffolding protein.
  • Assessed the impact of AMPK activation on keratinocyte proliferation and MEK-ERK signaling in vitro and in mouse models.

Main Results:

  • AMPK phosphorylates BRAF at Ser729, disrupting BRAF-KSR1 interaction and attenuating MEK-ERK signaling.
  • AMPK-mediated BRAF phosphorylation inhibits keratinocyte proliferation and cell-cycle progression.
  • AMPK activation reduces BRAF inhibitor-induced ERK hyperactivation and epidermal hyperplasia in mouse skin.

Conclusions:

  • AMPK acts as a negative regulator of BRAF signaling through direct phosphorylation.
  • This mechanism links cellular energy status to BRAF pathway activity.
  • Targeting AMPK may prevent cSCC development during BRAF-targeted cancer therapy.

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