FZR1 (also known as CDH1 or Fizzy-related protein homolog or CDC20-like protein 1 or Cdh1/Hct1 homolog), a substrate-specific adapter for the anaphase promoting complex/cyclosome (APC/C), which is an E3 ubiquitin-protein ligase, was found to bind to CCNA2 specifically in G2 as compared with S phase (Pagliuca et al. 2011) and was reproducibly identified as a substrate of CCNA:CDK1 (Mitra et al. 2006, Dumitru et al. 2017). CCNA:CDK2 and CCNA:CDK1-mediated phosphorylation of FZR1 inhibits premature activation of the APC/C complex during S and G2 phases, respectively (Mitra et al. 2006). As functional studies involved CCNA2, the CCNA1:CDK1 complex is annotated as a candidate.
In developing Drosophila epidermis, where Cyclin A is only required for terminal mitosis (mitosis 16), it was shown that in the absence of Cyclin A:Cdk1-mediated inhibitory phosphorylation of Fzr1, Cyclin B, Cyclin B3, and Cdc25 phosphatases get prematurely degraded, which impairs the entry into terminal mitoses (Dienemann and Sprenger 2004, Reber et al. 2006).
The residue of FZR1 phosphorylated by CCNA:CDK1 has not been identified, but serine 151 (S151) is the only residue that satisfies the criteria of CDK consensus site and evolutionary conservation between human, mouse, and Drosophila (by Reactome curator evaluation), is part of the human mitotic phosphoproteome (Dephoure et al. 2008), and has been reported to be phosphorylated by CCND:CDK4/6 complexes to inhibit theAPC/C function during G1/S transition (The et al. 2015).
CDC20, also a component of the APC/C complex, was reported to be reproducibly phosphorylated by CCNA2:CDK1 complex in a high-throughput study (Dumitru et al. 2017) and was previously reported to be phosphorylated in vitro by the CCNA2:CDK2 (Ohtoshi et al. 2000).
