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

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

nucleoplasm

ReviewStatus

4/5

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

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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
10499802	Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1 Dean, DC, Dei Santi, A, Postigo, AA, Harbour, JW, Luo, RX	Cell	1999
30711375	A Code of Mono-phosphorylation Modulates the Function of RB Boukhali, M, Haas, W, Tai, EC, Rumde, PH, Lawrence, MS, Dyson, NJ, Sanidas, I, Ting, DT, Fella, KA, Morris, R	Mol. Cell	2019
9447971	Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes Weinberg, RA, Lundberg, AS	Mol. Cell. Biol.	1998
10207050	Cumulative effect of phosphorylation of pRB on regulation of E2F activity Gallie, BL, Brown, VD, Phillips, RA	Mol. Cell. Biol.	1999
31543423	Transient Hysteresis in CDK4/6 Activity Underlies Passage of the Restriction Point in G1 Meyer, T, Köberlin, MS, Yang, HW, Liu, C, Cappell, SD, Chung, M	Mol. Cell	2019
9190208	Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation Connell-Crowley, L, Goodrich, DW, Harper, JW	Mol Biol Cell	1997
24876129	Cyclin D activates the Rb tumor suppressor by mono-phosphorylation Choi, YJ, Kaulich, M, Sicinski, P, Shapiro, GS, Dowdy, SF, Narasimha, AM	Elife	2014
11032757	Downregulation of cyclin D1 alters cdk 4- and cdk 2-specific phosphorylation of retinoblastoma protein Wadler, S, Albanese, C, Pestell, RG, Lane, ME, Yu, B	Mol. Cell Biol. Res. Commun.	2000
11416152	Differential regulation of retinoblastoma tumor suppressor protein by G(1) cyclin-dependent kinase complexes in vivo Becker-Hapak, M, Davis, PK, Ezhevsky, SA, Ho, A, Dowdy, SF	Mol. Cell. Biol.	2001

Participants

Input

Output

Participates

as an event of

Cyclin D associated events in G1 (Homo sapiens)

Catalyst Activity

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]

Physical Entity

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] (Homo sapiens)

Activity

cyclin-dependent protein serine/threonine kinase activity (GO:0004693)

This event is regulated

Negatively by

Regulator

p-T172-CDK4:CCND:CDK4 inhibitors [nucleoplasm] (Homo sapiens)

Active Unit

CDK4 inhibitors [nucleoplasm]

Regulator

p-T177-CDK6:CCND:CDK6 inhibitors [nucleoplasm] (Homo sapiens)