Sidebar A. Cdc25 at a glance

Cdc25 is a dual specific phosphatase, which targets phosphorylated serine, threonine and tyrosine. It is a monomeric enzyme expressed in all eukaryotes, comprising several isoforms depending on species (from one in fungi to four in Caenorhabditis elegans and Xenopus, three in humans). Cdc25 proteins can be divided in two regions. The N-terminal regions are highly divergent in sequence, contain numerous sites for phosphorylation and ubiquitination, which are involved in regulating phosphatase activity, protein levels, association with other proteins and intracellular localization thanks to nuclear import–export signals. The C-terminal regions are more homologous and contain a small catalytic domain with the signature motif HCX5R of the Tyrosine-phosphatases but with a surprising lack of any apparent substrate recognition site. The active site face of the Cdc25s is astonishingly flat and the active site pocket is extremely shallow, well-suited for allowing access to both pT- and pY-containing substrates. Cdc25 phosphatases exhibit high specificity for pTpY-Cdk-Cyclin substrates, acting in a stepwise mechanism, wherein the enzyme dissociates after dephosphorylation of pT and must re-associate for dephosphorylation of pY [39].