The study investigates the role of CDK inhibitors (CKIs) p21CIP, p27KIP, and p57KIP2 in promoting the assembly of cyclin-dependent kinase (CDK)4 with D-type cyclins. The researchers found that these CKIs specifically enhance the association of CDK4 with D-type cyclins, both in vivo and in vitro, without affecting other CDKs or cyclin partners. This effect is dose-dependent and requires both the cdk and cyclin-binding domains of the CKIs. Kinetic studies show that p21 and p27 increase the affinity of CDK4 and cyclin D1 by 35-fold and 80-fold, respectively. In addition, p21 promotes the formation of active kinase complexes, while at higher concentrations, it inhibits kinase activity. The study also demonstrates that p21, p27, and p57 target CDK4 and cyclin D1 to the nucleus, and that most of the active cyclin D1-associated kinase activity is associated with p21. These findings suggest that the CIP/KIP family of proteins, initially identified as inhibitors, may also function as adaptor proteins that assemble and program kinase complexes for specific functions.The study investigates the role of CDK inhibitors (CKIs) p21CIP, p27KIP, and p57KIP2 in promoting the assembly of cyclin-dependent kinase (CDK)4 with D-type cyclins. The researchers found that these CKIs specifically enhance the association of CDK4 with D-type cyclins, both in vivo and in vitro, without affecting other CDKs or cyclin partners. This effect is dose-dependent and requires both the cdk and cyclin-binding domains of the CKIs. Kinetic studies show that p21 and p27 increase the affinity of CDK4 and cyclin D1 by 35-fold and 80-fold, respectively. In addition, p21 promotes the formation of active kinase complexes, while at higher concentrations, it inhibits kinase activity. The study also demonstrates that p21, p27, and p57 target CDK4 and cyclin D1 to the nucleus, and that most of the active cyclin D1-associated kinase activity is associated with p21. These findings suggest that the CIP/KIP family of proteins, initially identified as inhibitors, may also function as adaptor proteins that assemble and program kinase complexes for specific functions.