Lys63-linked polyubiquitination of BRAF at lysine 578 is required for BRAF-mediated signaling

Lei An; Wei Jia; Yang Yu; Ning Zou; Li Liang; Yanling Zhao; Yihui Fan; Jin Cheng; Zhongcheng Shi; Gufeng Xu; Grace Li; Jianhua Yang; Hong Zhang

doi:10.1038/srep02344

Lys63-linked polyubiquitination of BRAF at lysine 578 is required for BRAF-mediated signaling

Lei An, Wei Jia, Yang Yu, Ning Zou, Li Liang, Yanling Zhao, Yihui Fan, Jin Cheng, Zhongcheng Shi, Gufeng Xu, Grace Li, Jianhua Yang, Hong Zhang

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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.

Original language	English (US)
Article number	2344
Journal	Scientific reports
Volume	3
DOIs	https://doi.org/10.1038/srep02344
State	Published - 2013

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@article{0845c7665cea4a188bac12c1be68f60d,

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.",

author = "Lei An and Wei Jia and Yang Yu and Ning Zou and Li Liang and Yanling Zhao and Yihui Fan and Jin Cheng and Zhongcheng Shi and Gufeng Xu and Grace Li and Jianhua Yang and Hong Zhang",

note = "Funding Information: We thank Kristine Yang for editing our manuscript. This work was supported in part by the grants from the Fleming-Davenport Award from Texas Medical Center (H.Z.), Start-up funding support from the University of Texas MD Anderson Cancer Center (H.Z.), the University Cancer Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center (H.Z.), and from NIH/NINDS 1R01NS072420 (J.Y.). Wei Jia and Jin Cheng are the recipients of China Scholarship Council training grants.",

year = "2013",

doi = "10.1038/srep02344",

language = "English (US)",

volume = "3",

journal = "Scientific reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Lys63-linked polyubiquitination of BRAF at lysine 578 is required for BRAF-mediated signaling

AU - An, Lei

AU - Jia, Wei

AU - Yu, Yang

AU - Zou, Ning

AU - Liang, Li

AU - Zhao, Yanling

AU - Fan, Yihui

AU - Cheng, Jin

AU - Shi, Zhongcheng

AU - Xu, Gufeng

AU - Li, Grace

AU - Yang, Jianhua

AU - Zhang, Hong

N1 - Funding Information: We thank Kristine Yang for editing our manuscript. This work was supported in part by the grants from the Fleming-Davenport Award from Texas Medical Center (H.Z.), Start-up funding support from the University of Texas MD Anderson Cancer Center (H.Z.), the University Cancer Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center (H.Z.), and from NIH/NINDS 1R01NS072420 (J.Y.). Wei Jia and Jin Cheng are the recipients of China Scholarship Council training grants.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

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U2 - 10.1038/srep02344

DO - 10.1038/srep02344

M3 - Article

C2 - 23907581

AN - SCOPUS:84881326734

SN - 2045-2322

VL - 3

JO - Scientific reports

JF - Scientific reports

M1 - 2344

ER -

Lys63-linked polyubiquitination of BRAF at lysine 578 is required for BRAF-mediated signaling

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