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).
Rotty, J, Arteaga, CL, Shin, I, Wu, FY
Pledger, WJ, Mohapatra, S, Bagui, TK, Haura, E
Hengst, L, Jäkel, H, Weinl, C
Koch, A, Welte, K, Kardinal, C, Brandt, DT, Dangers, M, Kardinal, A, Tamura, T
Zhang, L, An, X, Wang, T, Xie, Y, Meng, A, Wang, Z, Zhang, H
Xia, W, Liao, Y, Hung, MC, Zhou, BP, Lee, MH, Spohn, B
LaBaer, J, Garrett, MD, Fattaey, A, Harlow, E, Sandhu, C, Chou, HS, Stevenson, LF, Slingerland, JM
Reynisdóttir, I, Massagué, J
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