Meta-Biol

• Pathways

CDK4 and CDK6, in complex with D type cyclins (CCND1, CCND2 or CCND3) monophosphorylate RB1 (Narasimha et al. 2014). In G1, any serine or threonine residue on RB1 can be monophosphorylated by CDK4/CDK6 in complex with cyclin D. Studies have implicated progressive phosphorylation of RB1 by CDK2. CDK4/CDK6-mediated monophosphorylation is a pre-requisite for hyperphosphorylation of RB1 mediated by the complex of CDK2 and E type cyclins (CCNE1 or CCNE2) (Connell-Crowley et al. 1997, Lundberg and Weinberg 1998, Brown et al. 1999, Harbour et al. 1999, Yu et al. 2000, Ezhevsky et al. 2001). Some studies imply that CDK4/CDK6 activity results in RB1 hyperphosphorylation in late G1 phase, while the CDK2:CCNE complex takes over the role of RB1 hyperphosphorylation at S phase entry (Chung et al. 2019). Several studies have shown that the complex of CDK4/CDK6 and cyclin D monophosphorylates RB1 on any of the fourteen in vivo phosphorylated RB1 residues (out of sixteen predicted CDK-target sites). Monophosphorylation at different residues has different consequences on RB1 protein-protein interactions (Narasimha et al. 2014, Sanidas et al. 2019).