Cyclin E - Cdk2 complexes control the transition from G1 into S-phase. In this case, the binding of p21Cip1/Waf1 or p27kip1 is inhibitory. Important substrates for Cyclin E - Cdk2 complexes include proteins involved in the initiation of DNA replication. The two Cyclin E proteins are subjected to ubiquitin-dependent proteolysis, under the control of an E3 ubiquitin ligase known as the SCF. Cyclin A - Cdk2 complexes, which are also regulated by p21Cip1/Waf1 and p27kip1, are likely to be important for continued DNA synthesis, and progression into G2. An additional level of control of Cdk2 is reversible phosphorylation of Threonine-14 (T14) and Tyrosine-15 (Y15), catalyzed by the Wee1 and Myt1 kinases, and dephosphorylation by the three Cdc25 phosphatases, Cdc25A, B and C.