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The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function.

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Date
2017-04
Authors
Wan, Lixin
Chen, Ming
Cao, Juxiang
Dai, Xiangpeng
Yin, Qing
Zhang, Jinfang
Song, Su-Jung
Lu, Ying
Liu, Jing
Inuzuka, Hiroyuki
Katon, Jesse M
Berry, Kelsey
Fung, Jacqueline
Ng, Christopher
Liu, Pengda
Song, Min Sup
Xue, Lian
Bronson, Roderick T
Kirschner, Marc W
Cui, Rutao
Pandolfi, Pier Paolo
Wei, Wenyi
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Abstract
BRAF drives tumorigenesis by coordinating the activation of the RAS/RAF/MEK/ERK oncogenic signaling cascade. However, upstream pathways governing BRAF kinase activity and protein stability remain undefined. Here, we report that in primary cells with active APCFZR1, APCFZR1 earmarks BRAF for ubiquitination-mediated proteolysis, whereas in cancer cells with APC-free FZR1, FZR1 suppresses BRAF through disrupting BRAF dimerization. Moreover, we identified FZR1 as a direct target of ERK and CYCLIN D1/CDK4 kinases. Phosphorylation of FZR1 inhibits APCFZR1, leading to elevation of a cohort of oncogenic APCFZR1 substrates to facilitate melanomagenesis. Importantly, CDK4 and/or BRAF/MEK inhibitors restore APCFZR1 E3 ligase activity, which might be critical for their clinical effects. Furthermore, FZR1 depletion cooperates with AKT hyperactivation to transform primary melanocytes, whereas genetic ablation of Fzr1 synergizes with Pten loss, leading to aberrant coactivation of BRAF/ERK and AKT signaling in mice. Our findings therefore reveal a reciprocal suppression mechanism between FZR1 and BRAF in controlling tumorigenesis.Significance: FZR1 inhibits BRAF oncogenic functions via both APC-dependent proteolysis and APC-independent disruption of BRAF dimers, whereas hyperactivated ERK and CDK4 reciprocally suppress APCFZR1 E3 ligase activity. Aberrancies in this newly defined signaling network might account for BRAF hyperactivation in human cancers, suggesting that targeting CYCLIN D1/CDK4, alone or in combination with BRAF/MEK inhibition, can be an effective anti-melanoma therapy. Cancer Discov; 7(4); 424-41. ©2017 AACR.See related commentary by Zhang and Bollag, p. 356This article is highlighted in the In This Issue feature, p. 339.
Type
Journal article
Subject
Cell Line, Tumor
Hela Cells
Melanocytes
Animals
Humans
Mice
Melanoma
Multiprotein Complexes
Ubiquitin-Protein Ligases
Proto-Oncogene Proteins B-raf
Cyclin D1
Adenomatous Polyposis Coli Protein
Protein Kinase Inhibitors
Xenograft Model Antitumor Assays
Signal Transduction
Dimerization
Phosphorylation
Carcinogenesis
Cdh1 Proteins
Permalink
https://hdl.handle.net/10161/20379
Published Version (Please cite this version)
10.1158/2159-8290.CD-16-0647
Publication Info
Wan, Lixin; Chen, Ming; Cao, Juxiang; Dai, Xiangpeng; Yin, Qing; Zhang, Jinfang; ... Wei, Wenyi (2017). The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function. Cancer discovery, 7(4). pp. 424-441. 10.1158/2159-8290.CD-16-0647. Retrieved from https://hdl.handle.net/10161/20379.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Chen

Ming Chen

Associate Professor in Pathology
Our laboratory is interested in understanding the molecular and genetic events underlying cancer progression and metastasis. The focus of our work is a series of genetically engineered mouse models that faithfully recapitulate human disease. Using a combination of mouse genetics, omics technologies, cross-species analyses and in vitro approaches, we aim to identify cancer cell–intrinsic and –extrinsic mechanisms driving metastatic cancer progression, with a long
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