K27-linked ubiquitination of BRAF by ITCH engages cytokine response to maintain MEK-ERK signaling

Qing Yin, Tao Han, Bin Fang, Guolin Zhang, Chao Zhang, Evan R. Roberts, Victoria Izumi, Mengmeng Zheng, Shulong Jiang, Xiu Yin, Minjung Kim, Jianfeng Cai, Eric B. Haura, John M. Koomen, Keiran S. M. Smalley and Lixin Wan ()
Additional contact information
Qing Yin: H. Lee Moffitt Cancer Center and Research Institute
Tao Han: H. Lee Moffitt Cancer Center and Research Institute
Bin Fang: H. Lee Moffitt Cancer Center and Research Institute
Guolin Zhang: H. Lee Moffitt Cancer Center and Research Institute
Chao Zhang: H. Lee Moffitt Cancer Center and Research Institute
Evan R. Roberts: H. Lee Moffitt Cancer Center and Research Institute
Victoria Izumi: H. Lee Moffitt Cancer Center and Research Institute
Mengmeng Zheng: University of South Florida
Shulong Jiang: H. Lee Moffitt Cancer Center and Research Institute
Xiu Yin: H. Lee Moffitt Cancer Center and Research Institute
Minjung Kim: H. Lee Moffitt Cancer Center and Research Institute
Jianfeng Cai: University of South Florida
Eric B. Haura: H. Lee Moffitt Cancer Center and Research Institute
John M. Koomen: H. Lee Moffitt Cancer Center and Research Institute
Keiran S. M. Smalley: H. Lee Moffitt Cancer Center and Research Institute
Lixin Wan: H. Lee Moffitt Cancer Center and Research Institute

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract BRAF plays an indispensable role in activating the MEK/ERK pathway to drive tumorigenesis. Receptor tyrosine kinase and RAS-mediated BRAF activation have been extensively characterized, however, it remains undefined how BRAF function is fine-tuned by stimuli other than growth factors. Here, we report that in response to proinflammatory cytokines, BRAF is subjected to lysine 27-linked poly-ubiquitination in melanoma cells by the ITCH ubiquitin E3 ligase. Lysine 27-linked ubiquitination of BRAF recruits PP2A to antagonize the S365 phosphorylation and disrupts the inhibitory interaction with 14–3–3, leading to sustained BRAF activation and subsequent elevation of the MEK/ERK signaling. Physiologically, proinflammatory cytokines activate ITCH to maintain BRAF activity and to promote proliferation and invasion of melanoma cells, whereas the ubiquitination-deficient BRAF mutant displays compromised kinase activity and reduced tumorigenicity. Collectively, our study reveals a pivotal role for ITCH-mediated BRAF ubiquitination in coordinating the signals between cytokines and the MAPK pathway activation in melanoma cells.

Date: 2019
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DOI: 10.1038/s41467-019-09844-0

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