The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function
Year: 2017
Type: article
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. 356. This article is highlighted in the In This Issue feature, p. 339
Source: Cancer Discovery
Authors: Lixin Wan, Ming Chen, Juxiang Cao, Xiangpeng Dai, Qing Yin, Jinfang Zhang, Su-Jung Song, Ying Lu, Jing Liu, Hiroyuki Inuzuka, Jesse M. Katon, Kelsey Berry, Jacqueline Fung, Christopher Ng, Pengda Liu, Min Sup Song, Lian Xue, Roderick T. Bronson, Marc W. Kirschner, Rutao Cui, Pier Paolo Pandolfi, Wenyi Wei
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1354459900, Modulation of lipid homeostasis in maintenance and directed differentiation of mesenchymal stem cells, G1971892388, G3084427372, G311021743, New insights into the role of the Fbw7 tumor suppressor in senescence and aging, Characterizing the signaling pathways that regulate Skp2 oncogenic function, A Novel Oncogenic Role for Cdc20 Implications in Adult T Cell Leukemia Treatment, Novel regulation of PI3K/Akt to direct targeted breast cancer therapies, Interplay between Cdh1 and major regulatory pathways in human cancer, Identification of proteolytic signaling pathways regulating reprogramming during iPS cell generation, Targeting the APC/Cdc20 E3 ubiquitin ligase for chemoradiation sensitization, Moffitt Skin Cancer SPORE, A Novel Oncogenic Role for Cdc20 Implications in Adult T Cell Leukemia Treatment
OpenAlex ID: W2586090195