Cyclin-dependent kinase inhibitor 1B

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Reviewed, UniProtKB/Swiss-Prot P46414 (CDN1B_MOUSE)

Last modified November 4, 2008. Version 76. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    Cyclin-dependent kinase inhibitor 1B
Alternative name(s):
    Cyclin-dependent kinase inhibitor p27
    p27Kip1

Gene names

Name:

Cdkn1b

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

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Protein attributes

Sequence length	197 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	Important regulator of cell cycle progression. Involved in G1 arrest. Potent inhibitor of cyclin E- and cyclin A-CDK2 complexes. Positive regulator of cyclin D-dependent kinases such as CDK4. Regulated by phosphorylation and degradation events.
Subunit structure	Interacts with NUP50; the interaction leads to nuclear import and degradation of phosphorylated p27kip1. Interacts with COPS5, subunit of the COP9 signalosome complex; the interaction leads to p27KIP degradation. Interacts with SPDYA in the SPDYA/CDK2/p27kip1 complex. 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, LYN and UHMK1; the interactions lead to cytoplasmic mislocation, phosphorylation of p27kip1 and inhibition of cell cycle arrest. Interacts (unphosphorylated form) with CDK2. Interacts (phosphorylated on Tyr-88 and Tyr-89) with CDK4; the interaction induces nuclear translocation. Interacts with GRB2 By similarity.
Subcellular location	Nucleus. Cytoplasm. 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.
Domain	A peptide sequence containing only AA 28-79 retains substantial Kip1 cyclin A/CDK2 inhibitory activity By similarity.
Post-translational modification	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)-G(1) 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-197 is required for interaction with 14-3-3 proteins. Phosphorylation on Thr-187, by 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. Ubiquitinated; in the cytoplasm by the KPC1/KPC2 complex and, in the nucleus, by SCF/SKP2. The latter requires prior phosphorylation on Thr-187 By similarity.
Sequence similarities	Belongs to the CDI family.

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Ontologies

Keywords
Biological process	Cell cycle
Cellular component	Cytoplasm Nucleus
Molecular function	Protein kinase inhibitor
PTM	Phosphoprotein Ubl conjugation
Gene Ontology (GO)
Biological process	cell cycle arrest Ref.1 Inferred from direct assay. Source: MGI inner ear development Inferred from mutant phenotype. Source: MGI negative regulation of cell motion Inferred from direct assay. Source: MGI negative regulation of cyclin-dependent protein kinase activity Inferred from direct assay. Source: MGI negative regulation of epithelial cell proliferation Inferred from mutant phenotype. Source: MGI positive regulation of cell proliferation Inferred from mutant phenotype. Source: MGI positive regulation of microtubule polymerization Inferred from genetic interaction. Source: MGI potassium ion transport Inferred from genetic interaction. Source: MGI sensory perception of sound Inferred from mutant phenotype. Source: MGI
Cellular component	cytosol Inferred from direct assay. Source: MGI nucleus Inferred from direct assay. Source: MGI
Molecular function	cyclin-dependent protein kinase inhibitor activity Ref.1 Inferred from direct assay. Source: MGI protein binding Ref.1 Inferred from physical interaction. Source: IntAct
Complete GO annotation...

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Binary interactions

With	Entry	#Exp.	IntAct	Notes
Stmn1	P54227	2	EBI-1005742,EBI-1006438

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 197

197

Cyclin-dependent kinase inhibitor 1B

PRO_0000190085

Regions

Motif

153 – 169

Nuclear localization signal Potential

Sites

Site

Required for interaction with NUP50

Amino acid modifications

Modified residue

Phosphoserine; by UHMK1

Modified residue

Phosphotyrosine; by SRC By similarity

Modified residue

Phosphotyrosine; by ABL, LYN and SRC By similarity

Modified residue

Phosphotyrosine By similarity

Modified residue

187

Phosphothreonine; by PKB/AKT1 and CDK2

Modified residue

197

Phosphothreonine; by PKB/AKT1; RPS6KA4 and RPS6KA5 By similarity

Experimental info

Mutagenesis

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

Mutagenesis

R → G: Loss of interaction with NUP50. No cyclin E-mediated degradation of phosphorylated p27KIP1

Mutagenesis

187

T → E: Loss of cMyc-induced CDK2-mediated phosphorylation. Rapid dissociation from the cyclin E/CDK2 complex after induction by c-Myc

Mutagenesis

187

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

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Sequences

Sequence

Length

Mass (Da)

Tools

P46414-1 [UniParc].

Last modified November 1, 1995. Version 1.
Checksum: 2D19A6CFE6EA650D
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FASTA

197

22,210

        10         20         30         40         50         60 
MSNVRVSNGS PSLERMDARQ ADHPKPSACR NLFGPVNHEE LTRDLEKHCR DMEEASQRKW 

        70         80         90        100        110        120 
NFDFQNHKPL EGRYEWQEVE RGSLPEFYYR PPRPPKSACK VLAQESQDVS GSRQAVPLIG 

       130        140        150        160        170        180 
SQANSEDRHL VDQMPDSSDN QAGLAEQCPG MRKRPAAEDS SSQNKRANRT EENVSDGSPN 

       190 
AGTVEQTPKK PGLRRQT

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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: 8033213] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"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: 8033212] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Embryo.
[3]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: FVB/N. Tissue: Salivary gland.
[4]	"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: 9399644] [Abstract] Cited for: PHOSPHORYLATION AT THR-187, INTERACTION WITH CCNE1 IN CCNE1/ CDK2/P27KIP COMPLEX, FUNCTION, MUTAGENESIS OF SER-10 AND THR-187.
[5]	"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: 10086358] [Abstract] Cited for: INTERACTION WITH COPS5.
[6]	"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: 10811608] [Abstract] Cited for: INTERACTION WITH NUP50, MUTAGENESIS OF ARG-90. Strain: BALB/c.
[7]	"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: 12093740] [Abstract] Cited for: INTERACTION WITH UHMK1, FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-10.
[8]	"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: 12972555] [Abstract] Cited for: INTERACTION WITH SPDYA.
[9]	"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: 15528185] [Abstract] Cited for: PHOSPHORYLATION AT SER-10, FUNCTION, MUTAGENESIS OF SER-10.
+	Additional computationally mapped references.

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Cross-references

Sequence databases
	U10440 mRNA. Translation: AAA21149.1. U09968 mRNA. Translation: AAA20235.1. BC014296 mRNA. Translation: AAH14296.1.
PIR	I49064.
RefSeq	NP_034005.2.
UniGene	Mm.2958
3D structure databases
HSSP	HSSP built from PDB template 1JSU based on UniProtKB P46527.
SMR	P46414. Positions 25-93.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP:445N.
IntAct	P46414.
PTM databases
PhosphoSite	P46414.
Genome annotation databases
Ensembl	ENSMUSG00000003031. Mus musculus. [Contig view]
GeneID	12576.
KEGG	mmu:12576.
Organism-specific databases
MGI	MGI:104565. Cdkn1b.
Phylogenomic databases
HOGENOM	P46414.
HOVERGEN	P46414.
Gene expression databases
ArrayExpress	P46414.
CleanEx	MM_CDKN1B.
GermOnline	ENSMUSG00000003031. Mus musculus.
Family and domain databases
InterPro	IPR003175. CDI. [Graphical view]
PANTHER	PTHR10265. CDI. 1 hit.
Pfam	PF02234. CDI. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	281690.
SOURCE	Search...

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Entry information

Entry name

CDN1B_MOUSE

Accession

Primary (citable) accession number: P46414

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	November 1, 1995
Last modified:	November 4, 2008
This is version 76 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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Relevant documents

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot

SIMILARITY comments

Index of protein domains and families

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Keywords

Gene Ontology (GO)

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Experimental info

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Gene expression databases

Family and domain databases

Other Resources

Entry information

Relevant documents