Reviewed, UniProtKB/Swiss-Prot P46527 (CDN1B_HUMAN)

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
Synonyms:	KIP1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	198 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Important regulator of cell cycle progrssion. 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-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, 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.
Subcellular location	Nucleus. Cytoplasm. 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.
Tissue specificity	Expressed in all tissues tested. Highest levels in skeletal muscle, lowest in liver and kidney.
Induction	Maximal levels in quiescence cells and early G(1). Levels decrease after mitogen stimulation as cells progress toward S-phase.
Domain	A peptide sequence containing only AA 28-79 retains substantial Kip1 cyclin A/CDK2 inhibitory activity.
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-198 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. Ubiquitinated; in the cytoplasm by the KPC1/KPC2 complex and, in the nucleus, by SCF/SKP2. The latter requires prior phosphorylation on Thr-187.
Involvement in disease	Defects in CDKN1B are the cause of multiple endocrine neoplasia type 4 (MEN4) [MIM:610755]. Multiple 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.
Miscellaneous	Decreased levels of p27Kip1, mainly due to proteosomal degradation, are found in various epithelial tumors originating from lung, breast, colon, ovary, esophagus, thyroid and prostate.
Sequence similarities	Belongs to the CDI family.

Ontologies

Keywords
Biological process	Cell cycle
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Disease	Proto-oncogene
Molecular function	Protein kinase inhibitor
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	G1/S transition of mitotic cell cycle Inferred from direct assay. Source: UniProtKB autophagic cell death Inferred from direct assay. Source: UniProtKB cell cycle arrest Ref.7 Inferred from mutant phenotype. Source: HGNC induction of apoptosis Inferred from direct assay. Source: UniProtKB negative regulation of cell growth Inferred from direct assay. Source: UniProtKB negative regulation of cell proliferation Ref.1 Traceable author statement. Source: ProtInc negative regulation of phosphorylation Inferred from direct assay. Source: UniProtKB regulation of cyclin-dependent protein kinase activity Ref.1 Traceable author statement. Source: ProtInc
Cellular component	cytosol Ref.9 Inferred from Experiment. Source: Reactome nucleus Ref.7 Inferred from direct assay. Source: HGNC
Molecular function	cyclin-dependent protein kinase inhibitor activity Traceable author statement. Source: ProtInc protein binding Ref.7 Ref.19 Inferred from physical interaction. Source: IntAct transforming growth factor beta receptor, cytoplasmic mediator activity Ref.1 Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Abl1	P00520	1	EBI-519280,EBI-914519	From a different organism.
CCNA2	P20248	4	EBI-519280,EBI-457097
CCNB1	P14635	1	EBI-519280,EBI-495332
CCND1	P24385	2	EBI-519280,EBI-375001
CCNE1	P24864	2	EBI-519280,EBI-519526
CCNE2	O96020	1	EBI-519280,EBI-375033
CDK2	P24941	6	EBI-519280,EBI-375096
CDK4	P11802	2	EBI-519280,EBI-295644
CDK5	Q00535	2	EBI-519280,EBI-1041567
COPS5	Q92905	1	EBI-519280,EBI-594661
KPNA3	O00505	1	EBI-519280,EBI-358297
KPNA5	O15131	3	EBI-519280,EBI-540602
LYN	P07948	2	EBI-519280,EBI-79452
SRC	P12931	1	EBI-519280,EBI-621482
STMN1	P16949	1	EBI-519280,EBI-445909
UCHL1	P09936	1	EBI-519280,EBI-714860
YES1	P07947	1	EBI-519280,EBI-515331
YWHAB	P31946	1	EBI-519280,EBI-359815
YWHAE	P62258	1	EBI-519280,EBI-356498
YWHAG	P61981	1	EBI-519280,EBI-359832

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 198

198

Cyclin-dependent kinase inhibitor 1B

PRO_0000190084

Regions

Motif

153 – 169

17

Nuclear localization signal Potential

Amino acid modifications

Modified residue

10

1

Phosphoserine; by UHMK1

Modified residue

74

1

Phosphotyrosine; by SRC

Modified residue

88

1

Phosphotyrosine; by ABL, LYN and SRC

Modified residue

89

1

Phosphotyrosine

Modified residue

140

1

Phosphoserine

Modified residue

157

1

Phosphothreonine; by PKB/AKT1

Modified residue

187

1

Phosphothreonine; by PKB/AKT1 and CDK2

Modified residue

198

1

Phosphothreonine; by PKB/AKT1; RPS6KA4 and RPS6KA5

Natural variations

Natural variant

15

1

R → W: dbSNP rs2066828.

VAR_011871

Natural variant

109

1

V → G: dbSNP rs2066827.

VAR_011872

Experimental info

Mutagenesis

10

1

S → A: Loss of phosphorylation by UHMK1. No translocation to the cytoplasm. Greater cell cycle arrest

Mutagenesis

10

1

S → D: Exported to the cytoplasm. Inhibits cell cycle arrest

Mutagenesis

10

1

S → E: Increased stability in vivo and in vitro

Mutagenesis

74

1

Y → F: No change in binding CDK4. Translocates to nucleus

Mutagenesis

88

1

Y → F: Abolishes LYN-mediated phosphorylation. Reduced CDK2 phosphorylation on T-187. Greater cell cycle arrest into S-phase. No effect on binding CDK2 complexes. Reduction of CDK4 binding. No nuclear translocation. Completely abolishes CDK4 binding; when associated with F-89

Mutagenesis

89

1

Y → F: No effect on binding CDK2 complexes. Reduction of CDK4 binding. No nuclear translocation. Completely abolishes CDK4 binding; when associated with F-88

Mutagenesis

157

1

T → 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

Mutagenesis

161

1

S → A: No change in PKB/AKT1-mediated phosphorylation

Mutagenesis

162

1

T → A: No change in PKB/AKT1-mediated phosphorylation

Mutagenesis

187

1

T → A or D: No change in PKB/AKT1- nor UHMK1-mediated phosphorylation

Mutagenesis

198

1

T → 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

Sequence conflict

22

1

E → D in AAD14244. Ref.2

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

198

Helix Strand Turn

Details...

Helix

38 – 49

12

Turn

50 – 53

4

Helix

54 – 60

7

Turn

64 – 67

4

Beta strand

71 – 74

4

Beta strand

77 – 80

4

Helix

86 – 89

4

Sequences

	Sequence		Length	Mass (Da)
	P46527-1 [UniParc]. Last modified November 1, 1995. Version 1. Checksum: 1118D58901CDF3FC	FASTA	198	22,073
	10 20 30 40 50 60 MSNVRVSNGS PSLERMDARQ AEHPKPSACR NLFGPVDHEE LTRDLEKHCR DMEEASQRKW 70 80 90 100 110 120 NFDFQNHKPL EGKYEWQEVE KGSLPEFYYR PPRPPKGACK VPAQESQDVS GSRPAAPLIG 130 140 150 160 170 180 APANSEDTHL VDPKTDPSDS QTGLAEQCAG IRKRPATDDS STQNKRANRT EENVSDGSPN 190 AGSVEQTPKK PGLRRRQT

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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], PROTEIN SEQUENCE OF 28-79 AND 104-152. Tissue: Kidney.
[2]	"Assignment of the human p27Kip1 gene to 12p13 and its analysis in leukemias." Pietenpol J.A., Bohlander S.K., Sato Y., Papadopoulos N., Liu B., Friedman C., Trask B.J., Roberts J.M., Kinzler K.W., Rowley J.D. Cancer Res. 55:1206-1210(1995) [PubMed: 7882309] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)." Rieder M.J., Braun A.C., Montoya M.A., Chung M.-W., Nguyen C.P., Nguyen D.A., Livingston R.J., Poel C.L., Robertson P.D., Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A. Submitted (FEB-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS TRP-15 AND GLY-109.
[4]	"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], VARIANT GLY-109. Tissue: Cervix.
[5]	"Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation." Montagnoli A., Fiore F., Eytan E., Carrano A.C., Draetta G.F., Hershko A., Pagano M. Genes Dev. 13:1181-1189(1999) [PubMed: 10323868] [Abstract] Cited for: UBIQUITINATION, PHOSPHORYLATION.
[6]	"Phosphorylation at serine 10, a major phosphorylation site of p27(Kip1), increases its protein stability." Ishida N., Kitagawa M., Hatakeyama S., Nakayama K. J. Biol. Chem. 275:25146-25154(2000) [PubMed: 10831586] [Abstract] Cited for: PHOSPHORYLATION AT SER-10, FUNCTION.
[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, PHOSPHORYLATION AT SER-10, SUBCELLULAR LOCATION, MUTAGENESIS OF SER-10 AND THR-187.
[8]	"Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization." Fujita N., Sato S., Katayama K., Tsuruo T. J. Biol. Chem. 277:28706-28713(2002) [PubMed: 12042314] [Abstract] Cited for: PHOSPHORYLATION AT SER-10; THR-187 AND THR-198, INTERACTION WITH AKT1 AND YWHAQ, SUBCELLULAR LOCATION, MUTAGENESIS OF SER-10; THR-157; THR-187 AND THR-198.
[9]	"Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer." Viglietto G., Motti M.L., Bruni P., Melillo R.M., D'Alessio A., Califano D., Vinci F., Chiappetta G., Tsichlis P., Bellacosa A., Fusco A., Santoro M. Nat. Med. 8:1136-1144(2002) [PubMed: 12244303] [Abstract] Cited for: PHOSPHORYLATION AT THR-157, SUBCELLULAR LOCATION, ASSOCIATED WITH BREAST CANCER, MUTAGENESIS OF THR-157.
[10]	"PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization." Shin I., Yakes F.M., Rojo F., Shin N.-Y., Bakin A.V., Baselga J., Arteaga C.L. Nat. Med. 8:1145-1152(2002) [PubMed: 12244301] [Abstract] Cited for: PHOSPHORYLATION AT THR-157, INTERACTION WITH AKT1, SUBCELLULAR LOCATION, FUNCTION, MUTAGENESIS OF THR-157; SER-161 AND THR-162.
[11]	"Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization." Fujita N., Sato S., Tsuruo T. J. Biol. Chem. 278:49254-49260(2003) [PubMed: 14504289] [Abstract] Cited for: PHOSPHORYLATION AT SER-10 AND THR-198, INTERACTION WITH YWHAE; YWHAH; SFN; YWHAQ; RPS6KA4 AND RPS6KA5, SUBCELLULAR LOCATION, MUTAGENESIS OF THR-157 AND THR-198.
[12]	"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.
[13]	"Akt-dependent T198 phosphorylation of cyclin-dependent kinase inhibitor p27kip1 in breast cancer." Motti M.L., De Marco C., Califano D., Fusco A., Viglietto G. Cell Cycle 3:1074-1080(2004) [PubMed: 15280662] [Abstract] Cited for: PHOSPHORYLATION AT THR-198, SUBCELLULAR LOCATION, MUTAGENESIS OF SER-10; THR-157; THR-187 AND THR-198.
[14]	"Large-scale characterization of HeLa cell nuclear phosphoproteins." Beausoleil S.A., Jedrychowski M., Schwartz D., Elias J.E., Villen J., Li J., Cohn M.A., Cantley L.C., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 101:12130-12135(2004) [PubMed: 15302935] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-10, MASS SPECTROMETRY. Tissue: Epithelium.
[15]	"Tyrosine phosphorylation modulates binding preference to cyclin-dependent kinases and subcellular localization of p27Kip1 in the acute promyelocytic leukemia cell line NB4." Kardinal C., Dangers M., Kardinal A., Koch A., Brandt D.T., Tamura T., Welte K. Blood 107:1133-1140(2006) [PubMed: 16195327] [Abstract] Cited for: PHOSPHORYLATION AT TYR-88 AND TYR-89, DEPHOSPHORYLATION, INTERACTION WITH GRB2; CDK2 AND CDK4, SUBCELLULAR LOCATION, MUTAGENESIS OF TYR-74; TYR-88 AND TYR-89.
[16]	"Germ-line mutations in p27(Kip1) cause a multiple endocrine neoplasia syndrome in rats and humans." Pellegata N.S., Quintanilla-Martinez L., Siggelkow H., Samson E., Bink K., Hoefler H., Fend F., Graw J., Atkinson M.J. Proc. Natl. Acad. Sci. U.S.A. 103:15558-15563(2006) [PubMed: 17030811] [Abstract] Cited for: ASSOCIATION WITH MEN4.
[17]	"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage." Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J. Science 316:1160-1166(2007) [PubMed: 17525332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-140, MASS SPECTROMETRY.
[18]	"Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex." Russo A.A., Jeffrey P.D., Patten A.K., Massague J., Pavletich N.P. Nature 382:325-331(1996) [PubMed: 8684460] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 23-106 OF COMPLEX WITH CDK2 AND CG2A.
[19]	"Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases." Grimmler M., Wang Y., Mund T., Cilensek Z., Keidel E.-M., Waddell M.B., Jaekel H., Kullmann M., Kriwacki R.W., Hengst L. Cell 128:269-280(2007) [PubMed: 17254966] [Abstract] Cited for: STRUCTURE BY NMR OF 22-104, PHOSPHORYLATION AT TYR-88, FUNCTION, INDUCTION, INTERACTION WITH LYN, MASS SPECTROMETRY, MUTAGENESIS OF TYR-88 AND TYR-89.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBLGenBankDDBJ

U10906 mRNA. Translation: AAA20240.1.
S76988, S76986 Genomic DNA. Translation: AAD14244.1.
AF480891 Genomic DNA. Translation: AAL78041.1.
BC001971 mRNA. Translation: AAH01971.1.

RefSeq

NP_004055.1.

UniGene

Hs.238990

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1H27	X-ray	2.20	E	25-35	[»]
1JSU	X-ray	2.30	C	23-106	[»]
2AST	X-ray	2.30	D	181-190	[»]

DisProt

DP00018.

ModBase

Search...

Protein-protein interaction databases

IntAct

P46527.

PTM databases

PhosphoSite

P46527.

Polymorphism databases

NIEHS-SNPs

Search...

2-D gel databases

SWISS-2DPAGE

P46527.

Genome annotation databases

Ensembl

ENSG00000111276. Homo sapiens. [Contig view]

GeneID

1027.

KEGG

hsa:1027.

Organism-specific databases

H-InvDB

HIX0010441.

HGNC

HGNC:1785. CDKN1B.

HPA

CAB003691.

MIM

600778. gene.
610755. phenotype.

PharmGKB

PA105.

GenAtlas

Search...

GeneCards

Search...

Phylogenomic databases

HOGENOM

P46527.

HOVERGEN

P46527.

Gene expression databases

ArrayExpress

P46527.

CleanEx

HS_CDKN1B.

GermOnline

ENSG00000111276. Homo sapiens.

Family and domain databases

InterPro

IPR003175. CDI.
IPR015456. Cyclin_inhib_p27.
[Graphical view]

PANTHER

PTHR10265. CDI. 1 hit.
PTHR10265:SF4. p27_Kip1. 1 hit.

Pfam

PF02234. CDI. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

LinkHub

P46527.

NextBio

4315.

SOURCE

Search...

Entry information

Entry name

CDN1B_HUMAN

Accession

Primary (citable) accession number: P46527
Secondary accession number(s): Q16307, Q9BUS6

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	November 1, 1995
Last modified:	November 4, 2008
This is version 98 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)