The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function.
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 articleSubject
Cell Line, TumorHela 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
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https://hdl.handle.net/10161/20379Published Version (Please cite this version)
10.1158/2159-8290.CD-16-0647Publication 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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Show full item recordScholars@Duke
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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