Login / Signup

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

Qing YinTao HanBin FangGuolin ZhangChao ZhangEvan R RobertsVictoria IzumiMengmeng ZhengShulong JiangXiu YinMinjung KimJianfeng CaiEric B HauraJohn M KoomenKeiran S M SmalleyLixin Wan
Published in: Nature communications (2019)
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.
Keyphrases
  • wild type
  • metastatic colorectal cancer
  • signaling pathway
  • tyrosine kinase
  • pi k akt
  • cell proliferation
  • oxidative stress
  • epidermal growth factor receptor
  • multidrug resistant
  • air pollution
  • protein kinase