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UniProtKB - P46527 (CDN1B_HUMAN)

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Protein

Cyclin-dependent kinase inhibitor 1B

Gene

CDKN1B

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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 CCND1-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.5 Publications

Miscellaneous

Decreased levels of p27Kip1, mainly due to proteasomal degradation, are found in various epithelial tumors originating from lung, breast, colon, ovary, esophagus, thyroid and prostate.

GO - Molecular functioni

  • chaperone binding Source: Ensembl
  • cyclin binding Source: CAFA
  • cyclin-dependent protein serine/threonine kinase activity Source: Reactome
  • cyclin-dependent protein serine/threonine kinase inhibitor activity Source: Reactome
  • Hsp70 protein binding Source: Ensembl
  • protein complex binding Source: CAFA
  • protein kinase binding Source: CAFA
  • protein kinase inhibitor activity Source: CAFA
  • protein phosphatase binding Source: BHF-UCL
  • transforming growth factor beta receptor, cytoplasmic mediator activity Source: ProtInc
Complete GO annotation...

GO - Biological processi

Complete GO annotation...

Keywordsi

Molecular functionProtein kinase inhibitor
Biological processCell cycle

Enzyme and pathway databases

ReactomeiR-HSA-187577. SCF(Skp2)-mediated degradation of p27/p21.
R-HSA-198323. AKT phosphorylates targets in the cytosol.
R-HSA-2559582. Senescence-Associated Secretory Phenotype (SASP).
R-HSA-2559586. DNA Damage/Telomere Stress Induced Senescence.
R-HSA-5625900. RHO GTPases activate CIT.
R-HSA-5674400. Constitutive Signaling by AKT1 E17K in Cancer.
R-HSA-6804116. TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest.
R-HSA-68949. Orc1 removal from chromatin.
R-HSA-69202. Cyclin E associated events during G1/S transition.
R-HSA-69231. Cyclin D associated events in G1.
R-HSA-69563. p53-Dependent G1 DNA Damage Response.
R-HSA-69656. Cyclin A:Cdk2-associated events at S phase entry.
R-HSA-8849470. PTK6 Regulates Cell Cycle.
SIGNORiP46527.

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent kinase inhibitor 1B
Alternative name(s):
Cyclin-dependent kinase inhibitor p27
p27Kip1
Gene namesi
Name:CDKN1B
Synonyms:KIP1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

HGNCiHGNC:1785. CDKN1B.

Subcellular locationi

  • Nucleus
  • Cytoplasm
  • Endosome By similarity

    • Note: Nuclear and cytoplasmic in quiescent cells. AKT- or RSK-mediated phosphorylation on Thr-198, 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. Colocalizes at the endosome with SNX6; this leads to lysosomal degradation (By similarity).By similarity

GO - Cellular componenti

  • Cul4A-RING E3 ubiquitin ligase complex Source: MGI
  • cytoplasm Source: HGNC
  • cytosol Source: Reactome
  • endosome Source: UniProtKB-SubCell
  • intracellular membrane-bounded organelle Source: HPA
  • nucleoplasm Source: Reactome
  • nucleus Source: BHF-UCL
  • protein complex Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Endosome, Nucleus

Pathology & Biotechi

Involvement in diseasei

Multiple endocrine neoplasia 4 (MEN4)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionMultiple endocrine neoplasia (MEN) syndromes are inherited cancer syndromes of the thyroid. MEN4 is a MEN-like syndrome with a phenotypic overlap of both MEN1 and MEN2.
See also OMIM:610755

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi10S → A: Loss of phosphorylation by UHMK1. No translocation to the cytoplasm. Greater cell cycle arrest. 3 Publications1
Mutagenesisi10S → D: Exported to the cytoplasm. Inhibits cell cycle arrest. 3 Publications1
Mutagenesisi10S → E: Increased stability in vivo and in vitro. 3 Publications1
Mutagenesisi74Y → F: No change in binding CDK4 and no inhibition of CDK4 activity. Translocates to nucleus. No effect on in vitro phosphorylation of CDK4 by CCNH-CDK7. 2 Publications1
Mutagenesisi88Y → F: Abolishes LYN-mediated phosphorylation, reduces CDK2-mediated phosphorylation on T-187, has greater cell cycle arrest into S-phase, no effect on binding CDK2 complexes, reduced CDK4 binding and inhibits CDK4 enzyme activity. No nuclear translocation. No effect on in vitro phosphorylation of CDK4 by CCNH-CDK7. Completely abolishes CDK4 binding; when associated with F-89. 3 Publications1
Mutagenesisi89Y → F: No effect on binding CDK2 complexes, reduced CDK4 binding and greatly inhibits CDK4 enzyme activity. No nuclear translocation. Inhibits in vitro phosphorylation of CDK4 by CCNH-CDK7. Completely abolishes CDK4 binding; when associated with F-88. 3 Publications1
Mutagenesisi157T → A: Greatly reduced PKB/AKT1-mediated phosphorylation. Nuclear location. Inhibits cyclin E/CDK2 cell cycle progression. No effect on binding AKT1. Completely abolishes PKB/AKT1-mediated phosphorylation and no cytoplasmic translocation; when associated with A-198. 5 Publications1
Mutagenesisi161S → A: No change in PKB/AKT1-mediated phosphorylation. 1 Publication1
Mutagenesisi162T → A: No change in PKB/AKT1-mediated phosphorylation. 1 Publication1
Mutagenesisi185E → A, D or Q: Strongly reduced ubiquitination by a TRIM21-containing SCF(SKP2) complex. 1 Publication1
Mutagenesisi187T → A or D: No change in PKB/AKT1- nor UHMK1-mediated phosphorylation. 5 Publications1
Mutagenesisi187T → A: Abolishes phosphorylation-dependent ubiquitination. 5 Publications1
Mutagenesisi198T → A or D: Abolishes PKB/AKT1-mediated phosphorylation. 46% cytoplasmic location. Greatly reduced binding to YWHAQ. Equally reduced binding; when associated with A-10 and A-187. No nuclear import; when associated with A-157. Completely abolishes PKB/AKT1-mediated phosphorylation and no cytoplasmic translocation; when associated with A-157. 3 Publications1

Keywords - Diseasei

Tumor suppressor

Organism-specific databases

DisGeNETi1027.
MalaCardsiCDKN1B.
MIMi610755. phenotype.
OpenTargetsiENSG00000111276.
Orphaneti652. Multiple endocrine neoplasia type 1.
276152. Multiple endocrine neoplasia type 4.
PharmGKBiPA105.

Polymorphism and mutation databases

BioMutaiCDKN1B.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001900841 – 198Cyclin-dependent kinase inhibitor 1BAdd BLAST198

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei10Phosphoserine; by UHMK1Combined sources4 Publications1
Modified residuei74Phosphotyrosine; by SRC1 Publication1
Modified residuei88Phosphotyrosine; by ABL, LYN, SRC and JAK24 Publications1
Modified residuei89Phosphotyrosine1 Publication1
Modified residuei157Phosphothreonine; by CaMK1, PKB/AKT1 and PIM14 Publications1
Modified residuei170PhosphothreonineBy similarity1
Modified residuei187Phosphothreonine; by PKB/AKT1, CDK1 and CDK24 Publications1
Modified residuei198Phosphothreonine; by CaMK1, PKB/AKT1, RPS6KA1, RPS6KA3 and PIM15 Publications1

Post-translational modificationi

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 G0-G1 phase and leads to protein stability. Phosphorylation on other sites is greatly enhanced by mitogens, growth factors, cMYC and in certain cancer cell lines. The phosphorylated form found in the cytoplasm is inactivate. Phosphorylation on Thr-198 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.14 Publications
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.4 Publications
Subject to degradation in the lysosome. Interaction with SNX6 promotes lysosomal degradation (By similarity).By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP46527.
PaxDbiP46527.
PeptideAtlasiP46527.
PRIDEiP46527.
TopDownProteomicsiP46527.

2D gel databases

SWISS-2DPAGEiP46527.

PTM databases

iPTMnetiP46527.
PhosphoSitePlusiP46527.

Miscellaneous databases

PMAP-CutDBiP46527.

Expressioni

Tissue specificityi

Expressed in all tissues tested. Highest levels in skeletal muscle, lowest in liver and kidney.

Inductioni

Maximal levels in quiescence cells and early G1. Levels decrease after mitogen stimulation as cells progress toward S-phase.1 Publication

Gene expression databases

BgeeiENSG00000111276.
CleanExiHS_CDKN1B.
ExpressionAtlasiP46527. baseline and differential.
GenevisibleiP46527. HS.

Organism-specific databases

HPAiCAB003691.
CAB021888.
HPA059086.

Interactioni

Subunit structurei

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 COPS5, subunit of the COP9 signalosome complex; the interaction leads to CDKN1B degradation. Interacts with NUP50; the interaction leads to nuclear import and degradation of phosphorylated CDKN1B. Interacts with CCND1 and SNX6 (By similarity). Interacts (Thr-198-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. Forms a ternary complex with CCNA2 and CDK2; CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements. 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 with UHMK1; the interaction leads to cytoplasmic mislocation, phosphorylation of CDKN1B and inhibition of cell cycle arrest. Interacts also with CDK1. Dephosphorylated on Thr-187 by PPM1H, leading to CDKN1B stability (PubMed:22586611).By similarity14 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • chaperone binding Source: Ensembl
  • cyclin binding Source: CAFA
  • Hsp70 protein binding Source: Ensembl
  • protein complex binding Source: CAFA
  • protein kinase binding Source: CAFA
  • protein phosphatase binding Source: BHF-UCL
Complete GO annotation...

Protein-protein interaction databases

BioGridi107461. 85 interactors.
DIPiDIP-33341N.
IntActiP46527. 61 interactors.
MINTiMINT-239177.
STRINGi9606.ENSP00000228872.

Structurei

Secondary structure

1198
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi38 – 49Combined sources12
Turni50 – 53Combined sources4
Helixi54 – 60Combined sources7
Turni64 – 67Combined sources4
Beta strandi71 – 74Combined sources4
Beta strandi77 – 80Combined sources4
Helixi86 – 89Combined sources4

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1H27X-ray2.20E25-35[»]
1JSUX-ray2.30C23-106[»]
2ASTX-ray2.30D181-190[»]
DisProtiDP00018.
ProteinModelPortaliP46527.
SMRiP46527.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP46527.

Family & Domainsi

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi153 – 169Nuclear localization signalSequence analysisAdd BLAST17

Domaini

A peptide sequence containing only AA 28-79 retains substantial Kip1 cyclin A/CDK2 inhibitory activity.

Sequence similaritiesi

Belongs to the CDI family.Curated

Phylogenomic databases

eggNOGiKOG4743. Eukaryota.
ENOG410XXN5. LUCA.
GeneTreeiENSGT00530000063588.
HOGENOMiHOG000294081.
HOVERGENiHBG073988.
InParanoidiP46527.
KOiK06624.
OMAiYPKPSAC.
PhylomeDBiP46527.
TreeFamiTF101038.

Family and domain databases

InterProiView protein in InterPro
IPR003175. CDI.
IPR029843. CDKN1B.
PANTHERiPTHR10265. PTHR10265. 1 hit.
PTHR10265:SF38. PTHR10265:SF38. 1 hit.
PfamiView protein in Pfam
PF02234. CDI. 1 hit.

Sequencei

Sequence statusi: Complete.

P46527-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSNVRVSNGS PSLERMDARQ AEHPKPSACR NLFGPVDHEE LTRDLEKHCR 
        60         70         80         90        100
DMEEASQRKW NFDFQNHKPL EGKYEWQEVE KGSLPEFYYR PPRPPKGACK 
       110        120        130        140        150
VPAQESQDVS GSRPAAPLIG APANSEDTHL VDPKTDPSDS QTGLAEQCAG 
       160        170        180        190 
IRKRPATDDS STQNKRANRT EENVSDGSPN AGSVEQTPKK PGLRRRQT
Length:198
Mass (Da):22,073
Last modified:November 1, 1995 - v1
Checksum:i1118D58901CDF3FC
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti22E → D in AAD14244 (PubMed:7882309).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01187115R → W1 PublicationCorresponds to variant dbSNP:rs2066828Ensembl.1
Natural variantiVAR_06442969P → L Found in a patient with multiple endocrine tumors; germline mutation; reduced expression levels; shows impaired binding to CDK2. 1 PublicationCorresponds to variant dbSNP:rs777354267Ensembl.1
Natural variantiVAR_011872109V → G3 PublicationsCorresponds to variant dbSNP:rs2066827Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U10906 mRNA. Translation: AAA20240.1.
S76988, S76986 Genomic DNA. Translation: AAD14244.1.
BT019553 mRNA. Translation: AAV38360.1.
BT019554 mRNA. Translation: AAV38361.1.
AF480891 Genomic DNA. Translation: AAL78041.1.
BC001971 mRNA. Translation: AAH01971.1.
CCDSiCCDS8653.1.
RefSeqiNP_004055.1. NM_004064.4.
UniGeneiHs.238990.

Genome annotation databases

EnsembliENST00000228872; ENSP00000228872; ENSG00000111276.
GeneIDi1027.
KEGGihsa:1027.

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiCDN1B_HUMAN
AccessioniPrimary (citable) accession number: P46527
Secondary accession number(s): Q16307, Q5U0H2, Q9BUS6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: November 1, 1995
Last modified: July 5, 2017
This is version 191 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families