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

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.
Mesh Terms:
14-3-3 Proteins, Animals, Cell Line, Tumor, Cell Survival, Cell Transformation, Neoplastic, Cytokines, HEK293 Cells, Humans, Inflammation Mediators, JNK Mitogen-Activated Protein Kinases, Lysine, MAP Kinase Signaling System, Male, Melanoma, Mice, Mice, Nude, Phosphorylation, Proto-Oncogene Proteins B-raf, Repressor Proteins, Skin Neoplasms, Ubiquitin-Protein Ligases, Ubiquitination, Xenograft Model Antitumor Assays
Nat Commun
Date: Dec. 23, 2018
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