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

Stable Identifier
Reaction [BlackBoxEvent]
Homo sapiens
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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
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