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Protein

Cyclin-dependent kinase inhibitor 1B

Gene

Cdkn1b

Organism
Mus musculus (Mouse)
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 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.4 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei90Required for interaction with NUP501

GO - Molecular functioni

GO - Biological processi

  • activation of cysteine-type endopeptidase activity involved in apoptotic process Source: MGI
  • autophagic cell death Source: MGI
  • cell cycle arrest Source: MGI
  • cellular response to antibiotic Source: MGI
  • cellular response to lithium ion Source: MGI
  • cellular response to organic cyclic compound Source: MGI
  • G1/S transition of mitotic cell cycle Source: UniProtKB
  • inner ear development Source: MGI
  • mitotic cell cycle arrest Source: MGI
  • negative regulation of apoptotic process Source: MGI
  • negative regulation of cell growth Source: MGI
  • negative regulation of cell proliferation Source: MGI
  • negative regulation of cellular component movement Source: MGI
  • negative regulation of cyclin-dependent protein serine/threonine kinase activity Source: MGI
  • negative regulation of epithelial cell proliferation Source: MGI
  • negative regulation of epithelial cell proliferation involved in prostate gland development Source: MGI
  • negative regulation of kinase activity Source: MGI
  • negative regulation of mitotic cell cycle Source: MGI
  • negative regulation of phosphorylation Source: MGI
  • negative regulation of transcription, DNA-templated Source: MGI
  • negative regulation of vascular smooth muscle cell proliferation Source: MGI
  • Notch signaling pathway Source: MGI
  • placenta development Source: MGI
  • positive regulation of cell death Source: MGI
  • positive regulation of cell proliferation Source: MGI
  • positive regulation of cyclin-dependent protein serine/threonine kinase activity Source: Ensembl
  • positive regulation of microtubule polymerization Source: MGI
  • positive regulation of protein catabolic process Source: Ensembl
  • potassium ion transport Source: MGI
  • regulation of exit from mitosis Source: MGI
  • regulation of lens fiber cell differentiation Source: MGI
  • response to amino acid Source: Ensembl
  • response to cadmium ion Source: Ensembl
  • response to drug Source: Ensembl
  • response to estradiol Source: Ensembl
  • response to glucose Source: Ensembl
  • response to hypoxia Source: Ensembl
  • response to peptide hormone Source: Ensembl
  • sensory perception of sound Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Protein kinase inhibitor

Keywords - Biological processi

Cell cycle

Enzyme and pathway databases

ReactomeiR-MMU-176408. Regulation of APC/C activators between G1/S and early anaphase.
R-MMU-187577. SCF(Skp2)-mediated degradation of p27/p21.
R-MMU-198323. AKT phosphorylates targets in the cytosol.
R-MMU-2559582. Senescence-Associated Secretory Phenotype (SASP).
R-MMU-2559586. DNA Damage/Telomere Stress Induced Senescence.
R-MMU-5625900. RHO GTPases activate CIT.
R-MMU-6804116. TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest.
R-MMU-68949. Orc1 removal from chromatin.
R-MMU-69202. Cyclin E associated events during G1/S transition.
R-MMU-69231. Cyclin D associated events in G1.
R-MMU-69563. p53-Dependent G1 DNA Damage Response.
R-MMU-69656. Cyclin A:Cdk2-associated events at S phase entry.
R-MMU-8849470. PTK6 Regulates Cell Cycle.

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent kinase inhibitor 1B
Alternative name(s):
Cyclin-dependent kinase inhibitor p27
p27Kip1
Gene namesi
Name:Cdkn1b
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 6

Organism-specific databases

MGIiMGI:104565. Cdkn1b.

Subcellular locationi

  • 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.By similarity

GO - Cellular componenti

  • Cul4A-RING E3 ubiquitin ligase complex Source: Ensembl
  • cytoplasm Source: MGI
  • cytosol Source: MGI
  • endosome Source: UniProtKB-SubCell
  • nucleus Source: MGI
  • protein complex Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Endosome, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi10S → 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. 2 Publications1
Mutagenesisi90R → G: Loss of interaction with NUP50. No cyclin E-mediated degradation of phosphorylated p27KIP1. 1 Publication1
Mutagenesisi187T → E: Loss of cMyc-induced CDK2-mediated phosphorylation. Rapid dissociation from the cyclin E/CDK2 complex after induction by c-Myc. 1 Publication1
Mutagenesisi187T → V: Loss of cMYC-induced CDK2-mediated phosphorylation Dissociates very slowly from the cyclin E/CDK2 complex after induction by cMYC. Cell cycle arrest. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001900851 – 197Cyclin-dependent kinase inhibitor 1BAdd BLAST197

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei10Phosphoserine; by UHMK1Combined sources2 Publications1
Modified residuei74Phosphotyrosine; by SRCBy similarity1
Modified residuei88Phosphotyrosine; by ABL, LYN, SRC and JAK2By similarity1
Modified residuei89PhosphotyrosineBy similarity1
Modified residuei170Phosphothreonine; by CaMK11 Publication1
Modified residuei187Phosphothreonine; by PKB/AKT1, CDK1 and CDK21 Publication1
Modified residuei197Phosphothreonine; by CaMK1, PKB/AKT1, RPS6KA1, RPS6KA3 and PIM1By similarity1

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 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). Dephosphorylated on Thr-187 by PPM1H, leading to CDKN1B stability (By similarity).By similarity
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).By similarity
Subject to degradation in the lysosome. Interaction with SNX6 promotes lysosomal degradation.

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP46414.
PaxDbiP46414.
PeptideAtlasiP46414.
PRIDEiP46414.

PTM databases

iPTMnetiP46414.
PhosphoSitePlusiP46414.

Expressioni

Gene expression databases

BgeeiENSMUSG00000003031.
CleanExiMM_CDKN1B.
GenevisibleiP46414. MM.

Interactioni

Subunit structurei

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. Dephosphorylated on Thr-187 by PPM1H, leading to CDKN1B stability (By similarity).By similarity8 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Mcm7Q618812EBI-1005742,EBI-457180
Stmn1P542272EBI-1005742,EBI-1006438

GO - Molecular functioni

Protein-protein interaction databases

BioGridi198652. 23 interactors.
DIPiDIP-445N.
IntActiP46414. 7 interactors.
MINTiMINT-1780106.
STRINGi10090.ENSMUSP00000003115.

Structurei

3D structure databases

ProteinModelPortaliP46414.
SMRiP46414.
ModBaseiSearch...
MobiDBiSearch...

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.By similarity

Sequence similaritiesi

Belongs to the CDI family.Curated

Phylogenomic databases

eggNOGiKOG4743. Eukaryota.
ENOG410XXN5. LUCA.
GeneTreeiENSGT00530000063588.
HOGENOMiHOG000294081.
HOVERGENiHBG073988.
InParanoidiP46414.
KOiK06624.
OMAiYPKPSAC.
OrthoDBiEOG091G19PZ.
TreeFamiTF101038.

Family and domain databases

InterProiIPR003175. CDI.
IPR029843. CDKN1B.
[Graphical view]
PANTHERiPTHR10265. PTHR10265. 1 hit.
PTHR10265:SF9. PTHR10265:SF9. 1 hit.
PfamiPF02234. CDI. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P46414-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSNVRVSNGS PSLERMDARQ AEHPKPSACR NLFGPVNHEE LTRDLEKHCR
60 70 80 90 100
DMEEASQRKW NFDFQNHKPL EGRYEWQEVE RGSLPEFYYR PPRPPKSACK
110 120 130 140 150
VLAQESQDVS GSRQAVPLIG SQANSEDRHL VDQMPDSSDN PAGLAEQCPG
160 170 180 190
MRKRPAAEDS SSQNKRANRT EENVSDGSPN AGTVEQTPKK PGLRRQT
Length:197
Mass (Da):22,193
Last modified:October 3, 2012 - v2
Checksum:iBAC30D648B9BA3D6
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti22E → D in AAA21149 (PubMed:8033213).Curated1
Sequence conflicti22E → D in AAA20235 (PubMed:8033212).Curated1
Sequence conflicti22E → D in AAH14296 (PubMed:15489334).Curated1
Sequence conflicti141P → Q in AAA21149 (PubMed:8033213).Curated1
Sequence conflicti141P → Q in AAA20235 (PubMed:8033212).Curated1
Sequence conflicti141P → Q in AAH14296 (PubMed:15489334).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS20642.1.
PIRiI49064.
RefSeqiNP_034005.2. NM_009875.4.
UniGeneiMm.2958.

Genome annotation databases

EnsembliENSMUST00000003115; ENSMUSP00000003115; ENSMUSG00000003031.
ENSMUST00000067327; ENSMUSP00000065832; ENSMUSG00000003031.
ENSMUST00000204807; ENSMUSP00000145056; ENSMUSG00000003031.
GeneIDi12576.
KEGGimmu:12576.
UCSCiuc009ela.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS20642.1.
PIRiI49064.
RefSeqiNP_034005.2. NM_009875.4.
UniGeneiMm.2958.

3D structure databases

ProteinModelPortaliP46414.
SMRiP46414.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi198652. 23 interactors.
DIPiDIP-445N.
IntActiP46414. 7 interactors.
MINTiMINT-1780106.
STRINGi10090.ENSMUSP00000003115.

PTM databases

iPTMnetiP46414.
PhosphoSitePlusiP46414.

Proteomic databases

EPDiP46414.
PaxDbiP46414.
PeptideAtlasiP46414.
PRIDEiP46414.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000003115; ENSMUSP00000003115; ENSMUSG00000003031.
ENSMUST00000067327; ENSMUSP00000065832; ENSMUSG00000003031.
ENSMUST00000204807; ENSMUSP00000145056; ENSMUSG00000003031.
GeneIDi12576.
KEGGimmu:12576.
UCSCiuc009ela.2. mouse.

Organism-specific databases

CTDi1027.
MGIiMGI:104565. Cdkn1b.

Phylogenomic databases

eggNOGiKOG4743. Eukaryota.
ENOG410XXN5. LUCA.
GeneTreeiENSGT00530000063588.
HOGENOMiHOG000294081.
HOVERGENiHBG073988.
InParanoidiP46414.
KOiK06624.
OMAiYPKPSAC.
OrthoDBiEOG091G19PZ.
TreeFamiTF101038.

Enzyme and pathway databases

ReactomeiR-MMU-176408. Regulation of APC/C activators between G1/S and early anaphase.
R-MMU-187577. SCF(Skp2)-mediated degradation of p27/p21.
R-MMU-198323. AKT phosphorylates targets in the cytosol.
R-MMU-2559582. Senescence-Associated Secretory Phenotype (SASP).
R-MMU-2559586. DNA Damage/Telomere Stress Induced Senescence.
R-MMU-5625900. RHO GTPases activate CIT.
R-MMU-6804116. TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest.
R-MMU-68949. Orc1 removal from chromatin.
R-MMU-69202. Cyclin E associated events during G1/S transition.
R-MMU-69231. Cyclin D associated events in G1.
R-MMU-69563. p53-Dependent G1 DNA Damage Response.
R-MMU-69656. Cyclin A:Cdk2-associated events at S phase entry.
R-MMU-8849470. PTK6 Regulates Cell Cycle.

Miscellaneous databases

ChiTaRSiCdkn1b. mouse.
PROiP46414.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000003031.
CleanExiMM_CDKN1B.
GenevisibleiP46414. MM.

Family and domain databases

InterProiIPR003175. CDI.
IPR029843. CDKN1B.
[Graphical view]
PANTHERiPTHR10265. PTHR10265. 1 hit.
PTHR10265:SF9. PTHR10265:SF9. 1 hit.
PfamiPF02234. CDI. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCDN1B_MOUSE
AccessioniPrimary (citable) accession number: P46414
Secondary accession number(s): Q8BG74
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: October 3, 2012
Last modified: November 30, 2016
This is version 141 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

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.