Reactome | Translocation of CDK4/6:CCND complexes from the cytoplasm to the nucleus

Translocation of CDK4/6:CCND complexes from the cytoplasm to the nucleus

Stable Identifier

R-HSA-8942803

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

nuclear envelope

ReviewStatus

5/5

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Translocation of CDK4/6:CCND complexes from the cytoplasm to the nucleus

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Cyclin D:CDK4/6 complexes translocate to the nucleus from the cytoplasm at G1/S transition (Wang et al. 2008). This nuclear accumulation requires the binding to the Cip/Kip cyclin-dependent kinase (CDK) inhibitors CDKN1A (p21Cip), CDKN1B (p27Kip1) and probably also CDKN1C (p57Kip2), and the C-terminal NLS sequence of Cip/Kip proteins (LaBaer et al. 1997, Reynisdottir and Massagué 1997). Phosphorylations close to the NLS (at T145 in CDKN1A and T157 in CDKN1B) impede the nuclear localization of Cip/Kip proteins (Zhou et al. 2001, Shin et al. 2005) and potentially of CDK4/6:CCND complexes. One study suggested that tyrosine phosphorylation of p27 (CDKN1B) could facilitate the nuclear import of p27-bound CDK4 (Kardinal et al. 2006). However, others observed that endogenous Y88-phosphorylated p27Kip1, as well as overexpressed p27Kip1 phosphorylated by JAK2 was predominantly cytoplasmic (Jäkel et al. 2011). Effects of tyrosine phosphorylation of CDKN1A and CDKN1C on their localization have not been investigated.
In the absence of Cip/Kip proteins, a small number of CDK4/6:CCND complexes enter the nucleus through an unknown mechanism and phosphorylate target proteins (Bagui et al. 2003).

Literature References

PubMed ID	Title	Journal	Year
15579463	Phosphorylation of p27Kip1 at Thr-157 interferes with its association with importin alpha during G1 and prevents nuclear re-entry Rotty, J, Arteaga, CL, Shin, I, Wu, FY	J. Biol. Chem.	2005
14517297	P27Kip1 and p21Cip1 are not required for the formation of active D cyclin-cdk4 complexes Pledger, WJ, Mohapatra, S, Bagui, TK, Haura, E	Mol. Cell. Biol.	2003
21423214	Phosphorylation of p27Kip1 by JAK2 directly links cytokine receptor signaling to cell cycle control Hengst, L, Jäkel, H, Weinl, C	Oncogene	2011
16195327	Tyrosine phosphorylation modulates binding preference to cyclin-dependent kinases and subcellular localization of p27Kip1 in the acute promyelocytic leukemia cell line NB4 Koch, A, Welte, K, Kardinal, C, Brandt, DT, Dangers, M, Kardinal, A, Tamura, T	Blood	2006
18827403	Migratory localization of cyclin D2-Cdk4 complex suggests a spatial regulation of the G1-S transition Zhang, L, An, X, Wang, T, Xie, Y, Meng, A, Wang, Z, Zhang, H	Cell Struct. Funct.	2008
11231573	Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells Xia, W, Liao, Y, Hung, MC, Zhou, BP, Lee, MH, Spohn, B	Nat. Cell Biol.	2001
9106657	New functional activities for the p21 family of CDK inhibitors. LaBaer, J, Garrett, MD, Fattaey, A, Harlow, E, Sandhu, C, Chou, HS, Stevenson, LF, Slingerland, JM	Genes Dev	1997
9042862	The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2 Reynisdóttir, I, Massagué, J	Genes Dev.	1997