Hierarchical order of phosphorylation events commits Cdc25A to betaTrCP-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(betaTrCP) activity. Based on sequence homology of known betaTrCP substrates, we found that Cdc25A contains a conserved motif (DSG), phosphorylation of which is required for interaction with betaTrCP.1 Here, we show that phosphorylation at Ser 82 within the DSG motif anchors Cdc25A to betaTrCP and that Chk1-dependent phosphorylation at Ser 76 affects this interaction as well as betaTrCP-dependent degradation. We propose that a hierarchical order of phosphorylation events commits Cdc25A to betaTrCP-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 betaTrCP and subsequent betaTrCP-dependent degradation.
Donzelli
Maddalena
M
European Institute of Oncology, Milan, Italy. maddalena.donzelli@ieo-research.it
Busino
Luca
L
Chiesa
Massimo
M
Ganoth
Dvora
D
Hershko
Avram
A
Draetta
Giulio F
GF
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D004249:DNA Damage; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D014176:Protein Biosynthesis; D016196:S Phase; D012694:Serine / Q000737:chemistry; D025801:Ubiquitin / Q000378:metabolism; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000378:metabolism*
D010455:Peptides; D025801:Ubiquitin; D044844:beta-Transducin Repeat-Containing Proteins; D012694:Serine; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases