PathwayStep4524 PathwayStep4525 PathwayStep4522 PathwayStep4523 PathwayStep4526 PathwayStep4521 PathwayStep4520 PathwayStep4516 PathwayStep4517 PathwayStep4518 PathwayStep4519 Formation of Cyclin D:Cdk4/6 complexes Ubiquitination of p130 (RBL2) by SCF (Skp2) Cyclin D:Cdk4/6 mediated phosphorylation of Rb and dissociation of phospho-Rb from the E2F1/2/3:DP-1 complexes Phosphorylation of Cyclin D:Cdk4/6 complexes Cyclin D:CDK4/6 mediated phosphorylation of p107 (RBL1) and dissociation of phosphorylated p107 (p-RBL1) from DP1:E2F4 complex Association of INK4A with Cdk4/6 Cyclin D:Cdk4/6 mediated phosphorylation of p130 (RBL2) and dissociation of phosphorylated p130 (RBL2) from DP1:E2F4/5 complex Dephosphorylation of p107 by PP2A Phosphorylated p130 (RBL2) binds SCF(Skp2):Cks1 complex Dephosphorylation of p107 by PP2A Translocation of Cyclin D:Cdk4/6 complexes from the cytoplasm to the nucleus Cyclin D associated events in G1 Reactome Database ID Release 4369231 Reactome, http://www.reactome.org ReactomeREACT_821 Three D-type cyclins are essential for progression from G1 to S-phase. These D cyclins bind to and activate both CDK4 and CDK6. The formation of all possible complexes between the D-type cyclins and CDK4/6 is promoted by the proteins, p21(CIP1/WAF1) and p27(KIP1). The cyclin-dependent kinases are then activated due to phosphorylation by CAK. The cyclin dependent kinases phosphorylate the RB1 protein and RB1-related proteins p107 (RBL1) and p130 (RBL2). Phosphorylation of RB1 leads to release of activating E2F transcription factors (E2F1, E2F2 and E2F3). After repressor E2Fs (E2F4 and E2F5) dissociate from phosphorylated RBL1 and RBL2, activating E2Fs bind to E2F promoter sites, stimulating transcription of cell cycle genes, which then results in proper G1/S transition. The binding and sequestration of p27Kip may also contribute to the activation of CDK2 cyclin E/CDK2 cyclin A complexes at the G1/S transition (Yew et al., 2001).