BOTH P16 AND P21 FAMILIES OF CYCLIN-DEPENDENT KINASE (CDK) INHIBITORS BLOCK THE PHOSPHORYLATION OF CYCLIN-DEPENDENT KINASES BY THE CDK-ACTIVATING KINASE

Phosphorylation of cyclin-dependent kinases (CDKs) by the CDK-activating kinase is required for the activation of CDK enzymes, Members of two families of CDK inhibitors, p16/p18 and p21/p27, become physically associated with and inhibit the activity of CDKs in response to a variety of growth-modulating signals, Here, we show that the representative members of both families of CDK inhibitors, p21(waf1,cip1), p27(kip1), and p18, can prevent the phosphorylation of their CDK partners, CDK2 and CDK6, by CDK-activating kinase. No direct interaction between CDK-activating kinase and the CDK inhibitors could be detected, suggesting that binding of these CDK inhibitors to CDK subunits renders CDK inaccessible to the CDK-activating kinase phosphorylation. These findings suggest that a general mechanism of CDK inhibitor function is to block the phosphorylation of CDK enzymes by CDK-activating kinase.