Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation Academic Article uri icon

Overview

MeSH Major

  • AMP-Activated Protein Kinases
  • Cell Proliferation
  • Protein Kinases
  • Proto-Oncogene Proteins B-raf

abstract

  • BRAF is an oncogenic protein kinase that drives cell growth and proliferation through the MEK-ERK signaling pathway. BRAF inhibitors have demonstrated antitumor efficacy in melanoma therapy but have also been found to be associated with the development of cutaneous squamous cell carcinomas (cSCCs) in certain patients. Here, we report that BRAF is phosphorylated at Ser729 by AMP-activated protein kinase (AMPK), a critical energy sensor. This phosphorylation promotes the association of BRAF with 14-3-3 proteins and disrupts its interaction with the KSR1 scaffolding protein, leading to attenuation of the MEK-ERK signaling. We also show that phosphorylation of BRAF by AMPK impairs keratinocyte cell proliferation and cell-cycle progression. Furthermore, AMPK activation attenuates BRAF inhibitor-induced ERK hyperactivation in keratinocytes and epidermal hyperplasia in mouse skin. Our findings reveal a mechanism for regulating BRAF signaling in response to energy stress and suggest a strategy for preventing the development of cSCCs associated with BRAF-targeted therapy.

publication date

  • October 24, 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3892895

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2013.08.044

PubMed ID

  • 24095280

Additional Document Info

start page

  • 161

end page

  • 72

volume

  • 52

number

  • 2