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

TitleThe APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function.
Publication TypeJournal Article
Year of Publication2017
AuthorsWan L, Chen M, Cao J, Dai X, Yin Q, Zhang J, Song S-J, Lu Y, Liu J, Inuzuka H, Katon JM, Berry K, Fung J, Ng C, Liu P, Song MSup, Xue L, Bronson RT, Kirschner MW, Cui R, Pandolfi PPaolo, Wei W
JournalCancer Discov
Volume7
Issue4
Pagination424-441
Date Published2017 Apr
ISSN2159-8290
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 APC(FZR1), APC(FZR1) 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 APC(FZR1), leading to elevation of a cohort of oncogenic APC(FZR1) substrates to facilitate melanomagenesis. Importantly, CDK4 and/or BRAF/MEK inhibitors restore APC(FZR1) 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 APC(FZR1) 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.

DOI10.1158/2159-8290.CD-16-0647
Alternate JournalCancer Discov
PubMed ID28174173
PubMed Central IDPMC5380472
Grant ListR00 CA183914 / CA / NCI NIH HHS / United States
R01 CA200651 / CA / NCI NIH HHS / United States
R01 GM094777 / GM / NIGMS NIH HHS / United States
K01 AG041218 / AG / NIA NIH HHS / United States
K99 CA183914 / CA / NCI NIH HHS / United States
R01 CA200573 / CA / NCI NIH HHS / United States
R01 CA177910 / CA / NCI NIH HHS / United States
R01 GM089763 / GM / NIGMS NIH HHS / United States
P50 CA168536 / CA / NCI NIH HHS / United States
R01 GM039023 / GM / NIGMS NIH HHS / United States