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Protein

Cyclin-dependent kinase inhibitor 1B

Gene

CDKN1B

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

Functioni

Important regulator of cell cycle progression. Inhibits the kinase activity of CDK2 bound to cyclin A, but has little inhibitory activity on CDK2 bound to SPDYA (PubMed:28666995). 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.6 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

GO - Biological processi

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-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

Protein family/group databases

MoonDBiP46527 Predicted

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent kinase inhibitor 1B
Alternative name(s):
Cyclin-dependent kinase inhibitor p271 Publication
p27Kip11 Publication
Gene namesi
Name:CDKN1B
Synonyms:KIP1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000111276.10
HGNCiHGNC:1785 CDKN1B
MIMi600778 gene
neXtProtiNX_P46527

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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
ProteomicsDBi55741
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 Expressed in 243 organ(s), highest expression level in pigmented layer of retina
CleanExiHS_CDKN1B
ExpressionAtlasiP46527 baseline and differential
GenevisibleiP46527 HS

Organism-specific databases

HPAiCAB003691
CAB021888
HPA059086

Interactioni

Subunit structurei

Forms a ternary complex composed of CCNE1, CDK2 and 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 (PubMed:14504289). Interacts with AKT1 and LYN; the interactions lead to cytoplasmic mislocation, phosphorylation of CDKN1B and inhibition of cell cycle arrest (PubMed:12042314, PubMed:12244301, PubMed:17254966). 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 complex with CDK2 and SPDYA, but does not directly interact with SPDYA (PubMed:12972555, PubMed:28666995). Forms a ternary complex composed of cyclin D, CDK4 and CDKN1B. Interacts (phosphorylated on Tyr-88 and Tyr-89) with CDK4; the interaction is required for cyclin D and CDK4 complex assembly, induces nuclear translocation and activates the CDK4 kinase activity. Interacts with GRB2 (PubMed:16195327). Interacts with PIM1 (PubMed:18593906). Identified in a complex with SKP1, SKP2 and CKS1B (PubMed:16209941). Interacts with UHMK1; the interaction leads to cytoplasmic mislocation, phosphorylation of CDKN1B and inhibition of cell cycle arrest (PubMed:12093740). Interacts also with CDK1 (PubMed:16007079). Dephosphorylated on Thr-187 by PPM1H, leading to CDKN1B stability (PubMed:22586611).By similarity15 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi107461, 88 interactors
CORUMiP46527
DIPiDIP-33341N
IntActiP46527, 68 interactors
MINTiP46527
STRINGi9606.ENSP00000228872

Structurei

Secondary structure

1198
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

DisProtiDP00018
ProteinModelPortaliP46527
SMRiP46527
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP46527

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni51 – 91Interaction with CDK21 PublicationAdd BLAST41

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:SF9 PTHR10265:SF9, 1 hit
PfamiView protein in Pfam
PF02234 CDI, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 2 potential isoforms that are computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
E7ES52E7ES52_HUMAN
Cyclin-dependent kinase inhibitor 1...
CDKN1B
205Annotation score:
H7C2T1H7C2T1_HUMAN
Cyclin-dependent kinase inhibitor 1...
CDKN1B
104Annotation score:

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:rs2066828EnsemblClinVar.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:rs777354267EnsemblClinVar.1
Natural variantiVAR_011872109V → G3 PublicationsCorresponds to variant dbSNP:rs2066827EnsemblClinVar.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

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology
NIEHS-SNPs

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

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[»]
5UQ3X-ray3.60C1-198[»]
DisProtiDP00018
ProteinModelPortaliP46527
SMRiP46527
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107461, 88 interactors
CORUMiP46527
DIPiDIP-33341N
IntActiP46527, 68 interactors
MINTiP46527
STRINGi9606.ENSP00000228872

Protein family/group databases

MoonDBiP46527 Predicted

PTM databases

iPTMnetiP46527
PhosphoSitePlusiP46527

Polymorphism and mutation databases

BioMutaiCDKN1B

2D gel databases

SWISS-2DPAGEiP46527

Proteomic databases

EPDiP46527
PaxDbiP46527
PeptideAtlasiP46527
PRIDEiP46527
ProteomicsDBi55741
TopDownProteomicsiP46527

Protocols and materials databases

DNASUi1027
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000228872; ENSP00000228872; ENSG00000111276
GeneIDi1027
KEGGihsa:1027

Organism-specific databases

CTDi1027
DisGeNETi1027
EuPathDBiHostDB:ENSG00000111276.10
GeneCardsiCDKN1B
HGNCiHGNC:1785 CDKN1B
HPAiCAB003691
CAB021888
HPA059086
MalaCardsiCDKN1B
MIMi600778 gene
610755 phenotype
neXtProtiNX_P46527
OpenTargetsiENSG00000111276
Orphaneti652 Multiple endocrine neoplasia type 1
276152 Multiple endocrine neoplasia type 4
PharmGKBiPA105
GenAtlasiSearch...

Phylogenomic databases

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

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-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

Miscellaneous databases

ChiTaRSiCDKN1B human
EvolutionaryTraceiP46527
GeneWikiiCDKN1B
GenomeRNAii1027
PMAP-CutDBiP46527
PROiPR:P46527
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000111276 Expressed in 243 organ(s), highest expression level in pigmented layer of retina
CleanExiHS_CDKN1B
ExpressionAtlasiP46527 baseline and differential
GenevisibleiP46527 HS

Family and domain databases

InterProiView protein in InterPro
IPR003175 CDI
IPR029843 CDKN1B
PANTHERiPTHR10265 PTHR10265, 1 hit
PTHR10265:SF9 PTHR10265:SF9, 1 hit
PfamiView protein in Pfam
PF02234 CDI, 1 hit
ProtoNetiSearch...

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: September 12, 2018
This is version 203 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 entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  2. SIMILARITY comments
    Index of protein domains and families
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  5. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  6. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
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