Cutaneous 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.
Mol Cell. 2013 Oct 24;52(2):161-72. doi: 10.1016/j.molcel.2013.08.044. Epub 2013 Oct 3.
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.
BRAF 是一种致癌蛋白激酶，通过 MEK-ERK 信号通路驱动细胞生长和增殖。BRAF 抑制剂在黑色素瘤治疗中表现出抗肿瘤疗效，但也被发现与某些患者皮肤鳞状细胞癌 (cSCC) 的发展有关。在这里，我们报告 AMP 激活的蛋白激酶 (AMPK) 将 BRAF 磷酸化至丝氨酸 729 位，AMPK 是一种关键的能量传感器。这种磷酸化促进了 BRAF 与 14-3-3 蛋白的结合，并破坏了其与 KSR1 支架蛋白的相互作用，从而减弱了 MEK-ERK 信号。我们还表明，AMPK 对 BRAF 的磷酸化抑制了角质形成细胞的增殖和细胞周期进程。此外，AMPK 的激活减弱了 BRAF 抑制剂诱导的角质形成细胞中 ERK 的过度激活和小鼠皮肤中的表皮过度增生。我们的研究结果揭示了一种响应能量应激调节 BRAF 信号的机制，并提出了一种预防与 BRAF 靶向治疗相关的 cSCC 发展的策略。
