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.
journal_name
Mol Celljournal_title
Molecular cellauthors
Shen CH,Yuan P,Perez-Lorenzo R,Zhang Y,Lee SX,Ou Y,Asara JM,Cantley LC,Zheng Bdoi
10.1016/j.molcel.2013.08.044subject
Has Abstractpub_date
2013-10-24 00:00:00pages
161-72issue
2eissn
1097-2765issn
1097-4164pii
S1097-2765(13)00644-8journal_volume
52pub_type
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