P46414 (CDN1B_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified April 16, 2014. Version 115. History...
Names and origin
|Protein names||Recommended name:|
Cyclin-dependent kinase inhibitor 1B
Cyclin-dependent kinase inhibitor p27
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||197 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Important regulator of cell cycle progression. Involved in G1 arrest. Potent inhibitor of cyclin E- and cyclin A-CDK2 complexes. Forms a complex with cyclin type D-CDK4 complexes and is involved in the assembly, stability, and modulation of cyclin D-CDK4 complex activation. Acts either as an inhibitor or an activator of cyclin type D-CDK4 complexes depending on its phosphorylation state and/or stoichometry. Ref.7 Ref.10 Ref.12 Ref.15
Interacts (Thr-197-phosphorylated form) with 14-3-3 proteins, binds strongly YWHAQ, weakly YWHAE and YWHAH, but not YWHAB nor YWHAZ; the interaction with YWHAQ results in translocation to the cytoplasm. Interacts with AKT1 and LYN; the interactions lead to cytoplasmic mislocation, phosphorylation of CDKN1B and inhibition of cell cycle arrest. Interacts (unphosphorylated form) with CDK2. Forms a ternary complex, cyclin D/CDK4/CDKN1B. Interacts (phosphorylated on Tyr-88 and Tyr-89) with CDK4; the interaction is required for cyclin D/CDK4 complex assembly, induces nuclear translocation and activates the CDK4 kinase activity. Interacts with GRB2. Interacts with PIM1. Identified in a complex with SKP1, SKP2 and CKS1B. Interacts also with CDK1 By similarity. Interacts with NUP50; the interaction leads to nuclear import and degradation of phosphorylated CDKN1B. Interacts with COPS5, subunit of the COP9 signalosome complex; the interaction leads to CDKN1B degradation. Interacts with SPDYA in the SPDYA/CDK2/CDKN1B complex. Interacts with UHMK1; the interaction leads to cytoplasmic mislocation, phosphorylation of CDKN1B and inhibition of cell cycle arrest. Forms a ternary complex with CCNE1/CDK2/CDKN1B. Interacts directly with CCNE1; the interaction is inhibited by CDK2-dependent phosphorylation on Thr-187. Interacts with CCND1 and SNX6. Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.14 Ref.15
Nucleus. Cytoplasm. Endosome. Note: Nuclear and cytoplasmic in quiescent cells. AKT- or RSK-mediated phosphorylation on Thr-197, binds 14-3-3, translocates to the cytoplasm and promotes cell cycle progression. Mitogen-activated UHMK1 phosphorylation on Ser-10 also results in translocation to the cytoplasm and cell cycle progression. Phosphorylation on Ser-10 facilitates nuclear export. Translocates to the nucleus on phosphorylation of Tyr-88 and Tyr-89 By similarity. Colocalizes at the endosome with SNX6; this leads to lysosomal degradation. Ref.10 Ref.15
A peptide sequence containing only AA 28-79 retains substantial Kip1 cyclin A/CDK2 inhibitory activity By similarity.
Phosphorylated; phosphorylation occurs on serine, threonine and tyrosine residues. Phosphorylation on Ser-10 is the major site of phosphorylation in resting cells, takes place at the G(0)-G1 phase and leads to protein stability. Phosphorylation on other sites is greatly enhanced by mitogens, growth factors, MYC and in certain cancer cell lines. The phosphorylated form found in the cytoplasm is inactivate. Phosphorylation on Thr-197 is required for interaction with 14-3-3 proteins. Phosphorylation on Thr-187, by CDK1 and CDK2 leads to protein ubiquitination and proteasomal degradation. Tyrosine phosphorylation promotes this process. Phosphorylation by PKB/AKT1 can be suppressed by LY294002, an inhibitor of the catalytic subunit of PI3K. Phosphorylation on Tyr-88 and Tyr-89 has no effect on binding CDK2, but is required for binding CDK4. Dephosphorylated on tyrosine residues by G-CSF By similarity. Ref.7 Ref.10 Ref.12 Ref.16
Ubiquitinated; in the cytoplasm by the KPC complex (composed of RNF123/KPC1 and UBAC1/KPC2) and, in the nucleus, by SCF(SKP2). The latter requires prior phosphorylation on Thr-187. Ubiquitinated; by a TRIM21-containing SCF(SKP2)-like complex; leads to its degradation By similarity. Ref.15
Subject to degradation in the lysosome. Interaction with SNX6 promotes lysosomal degradation.
Belongs to the CDI family.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 197||197||Cyclin-dependent kinase inhibitor 1B||PRO_0000190085|
|Motif||153 – 169||17||Nuclear localization signal Potential|
|Site||90||1||Required for interaction with NUP50|
Amino acid modifications
|Modified residue||10||1||Phosphoserine; by UHMK1 Ref.10 Ref.12 Ref.13|
|Modified residue||74||1||Phosphotyrosine; by SRC By similarity|
|Modified residue||88||1||Phosphotyrosine; by ABL, LYN, SRC and JAK2 By similarity|
|Modified residue||89||1||Phosphotyrosine By similarity|
|Modified residue||170||1||Phosphothreonine; by CaMK1 Ref.16|
|Modified residue||187||1||Phosphothreonine; by PKB/AKT1, CDK1 and CDK2 Ref.7|
|Modified residue||197||1||Phosphothreonine; by CaMK1, PKB/AKT1, RPS6KA1, RPS6KA3 and PIM1 By similarity|
|Mutagenesis||10||1||S → A: Loss of phosphorylation in G(0) phase. No change in cMYC-induced CDK2-mediated phosphorylation. Rapid dissociation from the cyclin E/CDK2 complex after induction by cMYC. Loss of protein stability in G(0) phase. No change in protein stability at S-phase. Ref.7 Ref.12|
|Mutagenesis||90||1||R → G: Loss of interaction with NUP50. No cyclin E-mediated degradation of phosphorylated p27KIP1. Ref.9|
|Mutagenesis||187||1||T → E: Loss of cMyc-induced CDK2-mediated phosphorylation. Rapid dissociation from the cyclin E/CDK2 complex after induction by c-Myc. Ref.7|
|Mutagenesis||187||1||T → V: Loss of cMYC-induced CDK2-mediated phosphorylation Dissociates very slowly from the cyclin E/CDK2 complex after induction by cMYC. Cell cycle arrest. Ref.7|
|Sequence conflict||22||1||E → D in AAA21149. Ref.1|
|Sequence conflict||22||1||E → D in AAA20235. Ref.2|
|Sequence conflict||22||1||E → D in AAH14296. Ref.5|
|Sequence conflict||141||1||P → Q in AAA21149. Ref.1|
|Sequence conflict||141||1||P → Q in AAA20235. Ref.2|
|Sequence conflict||141||1||P → Q in AAH14296. Ref.5|
|||"p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21."|
Toyoshima H., Hunter T.
Cell 78:67-74(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||"Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals."|
Polyak K., Lee M.-H., Erdjument-Bromage H., Koff A., Roberts J.M., Tempst P., Massague J.
Cell 78:59-66(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||"The transcriptional landscape of the mammalian genome."|
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Adipose tissue, Corpus striatum and Liver.
|||"Lineage-specific biology revealed by a finished genome assembly of the mouse."|
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."|
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Salivary gland.
|||"Redistribution of the CDK inhibitor p27 between different cyclin.CDK complexes in the mouse fibroblast cell cycle and in cells arrested with lovastatin or ultraviolet irradiation."|
Poon R.Y., Toyoshima H., Hunter T.
Mol. Biol. Cell 6:1197-1213(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CCND1 IN THE CCND1-CDK4-CDKN1B COMPLEX.
|||"Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from cyclin E/cdk2 complexes."|
Mueller D., Bouchard C., Rudolph B., Steiner P., Stuckmann I., Saffrich R., Ansorge W., Huttner W., Eilers M.
Oncogene 15:2561-2576(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-187, INTERACTION WITH CCNE1 IN CCNE1/ CDK2/CDKN1B COMPLEX, FUNCTION, MUTAGENESIS OF SER-10 AND THR-187.
|||"Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1."|
Tomoda K., Kubota Y., Kato J.-Y.
Nature 398:160-165(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH COPS5.
|||"Cyclin E-mediated elimination of p27 requires its interaction with the nuclear pore-associated protein mNPAP60."|
Mueller D., Thieke K., Buergin A., Dickmanns A., Eilers M.
EMBO J. 19:2168-2180(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NUP50, MUTAGENESIS OF ARG-90.
|||"A growth factor-dependent nuclear kinase phosphorylates p27(Kip1) and regulates cell cycle progression."|
Boehm M., Yoshimoto T., Crook M.F., Nallamshetty S., True A., Nabel G.J., Nabel E.G.
EMBO J. 21:3390-3401(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH UHMK1, FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-10.
|||"Spy1 interacts with p27Kip1 to allow G1/S progression."|
Porter L.A., Kong-Beltran M., Donoghue D.J.
Mol. Biol. Cell 14:3664-3674(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SPDYA.
|||"Role of serine 10 phosphorylation in p27 stabilization revealed by analysis of p27 knock-in mice harboring a serine 10 mutation."|
Kotake Y., Nakayama K., Ishida N., Nakayama K.I.
J. Biol. Chem. 280:1095-1102(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-10, FUNCTION, MUTAGENESIS OF SER-10.
|||"Large-scale phosphorylation analysis of mouse liver."|
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-10, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
|||"Lysine 269 is essential for cyclin D1 ubiquitylation by the SCF(Fbx4/alphaB-crystallin) ligase and subsequent proteasome-dependent degradation."|
Barbash O., Egan E., Pontano L.L., Kosak J., Diehl J.A.
Oncogene 28:4317-4325(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CCND1.
|||"Tumor suppressor p27(Kip1) undergoes endolysosomal degradation through its interaction with sorting nexin 6."|
Fuster J.J., Gonzalez J.M., Edo M.D., Viana R., Boya P., Cervera J., Verges M., Rivera J., Andres V.
FASEB J. 24:2998-3009(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, DEGRADATION IN THE LYSOSOME, INTERACTION WITH SNX6.
|||"Fbxl12 triggers G1 arrest by mediating degradation of calmodulin kinase I."|
Mallampalli R.K., Kaercher L., Snavely C., Pulijala R., Chen B.B., Coon T., Zhao J., Agassandian M.
Cell. Signal. 25:2047-2059(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-170 AND THR-197 BY CAMK1.
|+||Additional computationally mapped references.|
|U10440 mRNA. Translation: AAA21149.1.|
U09968 mRNA. Translation: AAA20235.1.
AK046676 mRNA. Translation: BAC32833.1.
AK047669 mRNA. Translation: BAC33119.1.
AK050240 mRNA. Translation: BAC34141.1.
AC122193 Genomic DNA. No translation available.
BC014296 mRNA. Translation: AAH14296.1.
|RefSeq||NP_034005.2. NM_009875.4. |
3D structure databases
|SMR||P46414. Positions 25-93. |
Protein-protein interaction databases
|BioGrid||198652. 24 interactions.|
|IntAct||P46414. 7 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000003115; ENSMUSP00000003115; ENSMUSG00000003031. |
ENSMUST00000067327; ENSMUSP00000065832; ENSMUSG00000003031.
|UCSC||uc009ela.2. mouse. |
|MGI||MGI:104565. Cdkn1b. |
Gene expression databases
Family and domain databases
|InterPro||IPR003175. CDI. |
|PANTHER||PTHR10265. PTHR10265. 1 hit. |
|Pfam||PF02234. CDI. 1 hit. |
|ChiTaRS||CDKN1B. mouse. |
|Accession||Primary (citable) accession number: P46414|
Secondary accession number(s): Q8BG74
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|