Abstract
Phosphorylation of wild-type BRAF on Ser729 by AMPK suppresses MEK/ERK signaling.
Major finding: Phosphorylation of wild-type BRAF on Ser729 by AMPK suppresses MEK/ERK signaling.
Mechanism: BRAF Ser729 phosphorylation disrupts binding to KSR1 and promotes binding to 14-3-3.
Impact: AMPK activators may prevent paradoxical ERK activation by BRAF inhibitors in BRAF–wild-type cells.
AMP-activated kinase (AMPK) is a critical regulator of energy homeostasis that is activated in response to low cellular energy levels. AMPK is thought to coordinate cellular energy status with cell growth and proliferation, but the underlying mechanisms are not completely clear. Shen and colleagues found that AMPK significantly attenuated MEK–ERK signaling in BRAF–wild-type cells by physically associating with BRAF and directly phosphorylating serine 729 (Ser729), which in turn led to decreased ERK activation. Phosphorylation of Ser729 had no effect on BRAF kinase catalytic activity, but blocked BRAF-mediated signaling by promoting an inhibitory interaction between BRAF and 14-3-3 proteins and disrupting the association between BRAF and the scaffolding protein KSR1, which facilitates phosphorylation of MEK by RAF. AMPK activation blocked cell cycle progression in keratinocytes expressing wild-type BRAF, whereas mutation of the Ser729 residue led to a significant increase in proliferation rates, further indicating that phosphorylation of Ser729 by AMPK negatively regulates BRAF-dependent mitogenic signaling. Given these findings, the authors hypothesized that AMPK activation might be a potential strategy to combat paradoxical MEK–ERK activation caused by BRAF inhibitors in BRAF–wild-type cells, a phenomenon that leads to the development of secondary cutaneous squamous cell carcinomas and keratoacanthomas in some patients with BRAF-mutant metastatic melanoma. Indeed, combined treatment with the AMPK activator phenformin and the BRAF inhibitor PLX4720 significantly reduced epidermal hyperplasia in mice in association with reduced ERK phosphorylation. The identification of AMPK as a BRAF Ser729 kinase provides a link between cellular energy status and proliferation and raises the possibility that combined use of AMPK activators with BRAF inhibitors may mitigate the paradoxical MEK–ERK activation that has been associated with secondary malignancies and drug resistance.
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