Hierarchical order of phosphorylation events commits Cdc25A to βTrCP-dependent degradation

We have recently demonstrated that regulation of Cdc25A protein abundance during S phase and in response to DNA damage is mediated by SCF ^βTrCP activity. Based on sequence homology of known βTrCP substrates, we found that Cdc25A contains a conserved motif (DSG), phosphorylation of which is required for interaction with βTrCP. Here, we show that phosphorylation at Ser 82 within the DSG motif anchors Cdc25A to βTrCP and that Chk1-dependent phosphorylation at Ser 76 affects this interaction as well as βTrCP-dependent degradation. We propose that a hierarchical order of phosphorylation events commits Cdc25A to βTrCP-dependent degradation. According to our model, phosphorylation at Ser 76 is a "priming" step required for Ser 82 phosphorylation, which in turn allows recruitment of Cdc25A by βTrCP and subsequent βTrCP-dependent degradation.