Cyclin D:CDK4/6 phosphorylates RB1 and prevents RB1 binding to E2F1/2/3:DP1/2 complexes

Stable Identifier
R-HSA-69227
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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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).

Literature References
PubMed ID Title Journal Year
30711375 A Code of Mono-phosphorylation Modulates the Function of RB

Sanidas, I, Morris, R, Fella, KA, Rumde, PH, Boukhali, M, Tai, EC, Ting, DT, Lawrence, MS, Haas, W, Dyson, NJ

Mol. Cell 2019
10499802 Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1

Harbour, JW, Luo, RX, Dei Santi, A, Postigo, AA, Dean, DC

Cell 1999
9447971 Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes

Lundberg, AS, Weinberg, RA

Mol. Cell. Biol. 1998
10207050 Cumulative effect of phosphorylation of pRB on regulation of E2F activity

Brown, VD, Phillips, RA, Gallie, BL

Mol. Cell. Biol. 1999
31543423 Transient Hysteresis in CDK4/6 Activity Underlies Passage of the Restriction Point in G1

Chung, M, Liu, C, Yang, HW, Köberlin, MS, Cappell, SD, Meyer, T

Mol. Cell 2019
9190208 Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation

Connell-Crowley, L, Harper, JW, Goodrich, DW

Mol Biol Cell 1997
24876129 Cyclin D activates the Rb tumor suppressor by mono-phosphorylation

Narasimha, AM, Kaulich, M, Shapiro, GS, Choi, YJ, Sicinski, P, Dowdy, SF

Elife 2014
11032757 Downregulation of cyclin D1 alters cdk 4- and cdk 2-specific phosphorylation of retinoblastoma protein

Yu, B, Lane, ME, Pestell, RG, Albanese, C, Wadler, S

Mol. Cell Biol. Res. Commun. 2000
11416152 Differential regulation of retinoblastoma tumor suppressor protein by G(1) cyclin-dependent kinase complexes in vivo

Ezhevsky, SA, Ho, A, Becker-Hapak, M, Davis, PK, Dowdy, SF

Mol. Cell. Biol. 2001
Participants
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Catalyst Activity
Title
cyclin-dependent protein serine/threonine kinase activity of p-T172-CDK4,p-T177-CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C); p-T172-CDK4,p-T177-CDK6:CCND; (p-T172-CDK4,p-T177-CDK6:CCND:p-Y88-CDKN1B) [nucleoplasm]
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