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 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

SUBMITTER: Wan L 

PROVIDER: S-EPMC5380472 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature