CDK2 tyrosine phosphorylation

Arrest in Gx phase can now be achieved in at least two ways, depending on the substrates of the Chkl and Chk2 enzymes. In one rapid way, the dual specificity phosphatase Cdc25C is phosphorylated on Ser 123 and is thereby targeted for ubiquitina-tion and degradation in the proteasome pathway. The lack of this enzyme locks the CDK2 kinase in the inactive form phosphorylated on threonine 14 and tyrosine 15.The cyclin E-CDK2 complex that is required for entry into S phase is inhibited, and the cell cycle arrests at Gj/S. It should be noted that the scheme in Fig. 13.19 is only a minimal scheme that does not address the participation of numerous other proteins that function as adaptors or structural proteins in these processes. 

The Inhibitory tyrosine residue (Y15) in the 5. pombe CDK is in the region of the protein that binds the ATP phosphates. Vertebrate CDK2 proteins contain a second inhibitory residue, threonine-14 (T14), that is located in the same region of the protein. Phosphorylation of Y15 and T14 in these proteins prevents binding of ATP because of electrostatic repulsion between the phosphates linked to the protein and the phosphates of ATP. Thus these phosphorylations inhibit protein kinase activity even when the CDK protein is bound by a cyclin and the activating residue is phosphoryiated. 

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