title: Lys63-linked polyubiquitination of BRAF at lysine 578 is required for BRAF-mediated signaling.
abstract: The RAF kinase family is essential in mediating signal transduction from RAS to ERK. BRAF constitutively active mutations correlate with human cancer development. However, the precise molecular regulation of BRAF activation is not fully understood. Here we report that BRAF is modified by Lys63-linked polyubiquitination at lysine 578 within its kinase domain once it is activated by gain of constitutively active mutation or epidermal growth factor (EGF) stimulation. Substitution of BRAF lysine 578 with arginine (K578R) inhibited BRAF-mediated ERK activation. Furthermore, ectopic expression of BRAF K578R mutant inhibited anchorage-independent colony formation of MCF7 breast cancer cell line. Our studies have identified a previously unrecognized regulatory role of Lys63-linked polyubiquitination in BRAF-mediated normal and oncogenic signalings.
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: An
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Ning
authors.initials: N
authors.lastname: Zou
authors.forename: Li
authors.initials: L
authors.lastname: Liang
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yihui
authors.initials: Y
authors.lastname: Fan
authors.forename: Jin
authors.initials: J
authors.lastname: Cheng
authors.forename: Zhongcheng
authors.initials: Z
authors.lastname: Shi
authors.forename: Gufeng
authors.initials: G
authors.lastname: Xu
authors.forename: Grace
authors.initials: G
authors.lastname: Li
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D061986:MCF-7 Cells; D025821:Polyubiquitin / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D025821:Polyubiquitin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D008239:Lysine
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