P46527 (CDN1B_HUMAN) Reviewed, UniProtKB/Swiss-Prot

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.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. Ref.7 Ref.11 Ref.18 Ref.23 Ref.27
Subunit structure	Forms a ternary compex 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. 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. Ref.8 Ref.9 Ref.11 Ref.12 Ref.13 Ref.16 Ref.17 Ref.18 Ref.22 Ref.23 Ref.27
Subcellular location	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. Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.14 Ref.17
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 G1. Levels decrease after mitogen stimulation as cells progress toward S-phase. Ref.27
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)-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 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. Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.14 Ref.15 Ref.17 Ref.21 Ref.22 Ref.23 Ref.24 Ref.26 Ref.27 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. Ref.6 Ref.19 Ref.26 Subject to degradation in the lysosome. Interaction with SNX6 promotes lysosomal degradation By similarity.
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. Ref.20
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.
Sequence similarities	Belongs to the CDI family.

Ontologies

Keywords
Biological process	Cell cycle
Cellular component	Cytoplasm Endosome Nucleus
Coding sequence diversity	Polymorphism
Disease	Proto-oncogene
Molecular function	Protein kinase inhibitor
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest Traceable author statement. Source: Reactome G1 phase of mitotic cell cycle Traceable author statement. Source: Reactome G1/S transition of mitotic cell cycle Inferred from direct assay. Source: BHF-UCL S phase of mitotic cell cycle Traceable author statement. Source: Reactome activation of cysteine-type endopeptidase activity involved in apoptotic process Inferred from direct assay. Source: UniProtKB autophagic cell death Inferred from direct assay. Source: BHF-UCL cellular response to lithium ion Inferred from direct assay. Source: MGI fibroblast growth factor receptor signaling pathway Traceable author statement. Source: Reactome induction of apoptosis Inferred from direct assay. Source: BHF-UCL mitotic cell cycle arrest Inferred from direct assay. Source: UniProtKB negative regulation of cell growth Inferred from direct assay. Source: BHF-UCL negative regulation of mitotic cell cycle Inferred from direct assay. Source: UniProtKB negative regulation of transcription, DNA-dependent Inferred from direct assay. Source: UniProtKB nerve growth factor receptor signaling pathway Traceable author statement. Source: Reactome phosphatidylinositol-mediated signaling Traceable author statement. Source: Reactome positive regulation of protein catabolic process Inferred from direct assay. Source: MGI
Cellular component	cytosol Traceable author statement. Source: Reactome endosome Inferred from electronic annotation. Source: UniProtKB-SubCell nucleoplasm Traceable author statement. Source: Reactome
Molecular function	cyclin-dependent protein kinase activity Inferred from experiment. Source: Reactome cyclin-dependent protein kinase inhibitor activity Traceable author statement. Source: ProtInc protein phosphatase binding Inferred from physical interaction. Source: BHF-UCL transforming growth factor beta receptor, cytoplasmic mediator activity Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Abl1	P00520	2	EBI-519280,EBI-914519	From a different organism.
CCNA2	P20248	12	EBI-519280,EBI-457097
CCND1	P24385	2	EBI-519280,EBI-375001
CCNE1	P24864	6	EBI-519280,EBI-519526
CCNE2	O96020	2	EBI-519280,EBI-375033
CDK2	P24941	12	EBI-519280,EBI-375096
CDK4	P11802	2	EBI-519280,EBI-295644
CDK5	Q00535	4	EBI-519280,EBI-1041567
COPS5	Q92905	3	EBI-519280,EBI-594661
KPNA3	O00505	4	EBI-519280,EBI-358297
KPNA5	O15131	5	EBI-519280,EBI-540602
LYN	P07948	2	EBI-519280,EBI-79452

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 Ref.7 Ref.8 Ref.9 Ref.12 Ref.15

Modified residue

74

1

Phosphotyrosine; by SRC

Modified residue

88

1

Phosphotyrosine; by ABL, LYN, SRC and JAK2 Ref.17 Ref.27

Modified residue

89

1

Phosphotyrosine Ref.17

Modified residue

140

1

Phosphoserine Ref.21

Modified residue

157

1

Phosphothreonine; by PKB/AKT1 and PIM1 Ref.10 Ref.11 Ref.22

Modified residue

187

1

Phosphothreonine; by PKB/AKT1 and CDK2 Ref.9 Ref.26

Modified residue

198

1

Phosphothreonine; by PKB/AKT1, RPS6KA1, RPS6KA3 and PIM1 Ref.9 Ref.12 Ref.14 Ref.22

Natural variations

Natural variant

15

1

R → W. Ref.4
Corresponds to variant rs2066828 [ dbSNP | Ensembl ].

VAR_011871

Natural variant

69

1

P → L Found in a patient with multiple endocrine tumors; germline mutation; reduced expression levels; shows impaired binding to CDK2. Ref.28

VAR_064429

Natural variant

109

1

V → G. Ref.3 Ref.4 Ref.5
Corresponds to variant rs2066827 [ dbSNP | Ensembl ].

VAR_011872

Experimental info

Mutagenesis

10

1

S → A: Loss of phosphorylation by UHMK1. No translocation to the cytoplasm. Greater cell cycle arrest. Ref.8 Ref.9 Ref.14

Mutagenesis

10

1

S → D: Exported to the cytoplasm. Inhibits cell cycle arrest. Ref.8 Ref.9 Ref.14

Mutagenesis

10

1

S → E: Increased stability in vivo and in vitro. Ref.8 Ref.9 Ref.14

Mutagenesis

74

1

Y → 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. Ref.17 Ref.23

Mutagenesis

88

1

Y → 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. Ref.17 Ref.23 Ref.27

Mutagenesis

89

1

Y → 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. Ref.17 Ref.23 Ref.27

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. Ref.9 Ref.10 Ref.11 Ref.12 Ref.14

Mutagenesis

161

1

S → A: No change in PKB/AKT1-mediated phosphorylation. Ref.11

Mutagenesis

162

1

T → A: No change in PKB/AKT1-mediated phosphorylation. Ref.11

Mutagenesis

185

1

E → A, D or Q: Strongly reduced ubiquitination by a TRIM21-containing SCF(SKP2) complex. Ref.26

Mutagenesis

187

1

T → A or D: No change in PKB/AKT1- nor UHMK1-mediated phosphorylation. Ref.8 Ref.9 Ref.14 Ref.19 Ref.26

Mutagenesis

187

1

T → A: Abolishes phosphorylation-dependent ubiquitination. Ref.8 Ref.9 Ref.14 Ref.19 Ref.26

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. Ref.9 Ref.12 Ref.14

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 [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]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT GLY-109.
[4]	NIEHS SNPs program Submitted (FEB-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS TRP-15 AND GLY-109.
[5]	"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.
[6]	"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.
[7]	"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.
[8]	"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.
[9]	"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.
[10]	"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, ASSOCIATION WITH BREAST CANCER, MUTAGENESIS OF THR-157.
[11]	"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.
[12]	"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; RPS6KA1 AND RPS6KA3, SUBCELLULAR LOCATION, MUTAGENESIS OF THR-157 AND THR-198.
[13]	"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.
[14]	"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.
[15]	"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: Cervix carcinoma.
[16]	"Cdc2-cyclin E complexes regulate the G1/S phase transition." Aleem E., Kiyokawa H., Kaldis P. Nat. Cell Biol. 7:831-836(2005) [PubMed: 16007079] [Abstract] Cited for: INTERACTION WITH CDK1.
[17]	"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.
[18]	"Regulated activating Thr172 phosphorylation of cyclin-dependent kinase 4(CDK4): its relationship with cyclins and CDK 'inhibitors'." Bockstaele L., Kooken H., Libert F., Paternot S., Dumont J.E., de Launoit Y., Roger P.P., Coulonval K. Mol. Cell. Biol. 26:5070-5085(2006) [PubMed: 16782892] [Abstract] Cited for: INTERACTION WITH CDK4, FUNCTION.
[19]	"Regulation of p27 degradation and S-phase progression by Ro52 RING finger protein." Sabile A., Meyer A.M., Wirbelauer C., Hess D., Kogel U., Scheffner M., Krek W. Mol. Cell. Biol. 26:5994-6004(2006) [PubMed: 16880511] [Abstract] Cited for: UBIQUITINATION, MUTAGENESIS OF THR-187.
[20]	"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.
[21]	"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. Tissue: Embryonic kidney.
[22]	"Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels." Morishita D., Katayama R., Sekimizu K., Tsuruo T., Fujita N. Cancer Res. 68:5076-5085(2008) [PubMed: 18593906] [Abstract] Cited for: INTERACTION WITH PIM1, PHOSPHORYLATION AT THR-157 AND THR-198.
[23]	"p27Kip1 inhibits cyclin D-cyclin-dependent kinase 4 by two independent modes." Ray A., James M.K., Larochelle S., Fisher R.P., Blain S.W. Mol. Cell. Biol. 29:986-999(2009) [PubMed: 19075005] [Abstract] Cited for: INTERACTION WITH CDK4, PHOSPHORYLATION, FUNCTION, MUTAGENESIS OF TYR-74; TYR-88 AND TYR-89.
[24]	"Phosphorylation of p27Kip1 by JAK2 directly links cytokine receptor signaling to cell cycle control." Jakel H., Weinl C., Hengst L. Oncogene 30:3502-3512(2011) [PubMed: 21423214] [Abstract] Cited for: PHOSPHORYLATION BY JAK2 AT TYR-88.
[25]	"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.
[26]	"Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase." Hao B., Zheng N., Schulman B.A., Wu G., Miller J.J., Pagano M., Pavletich N.P. Mol. Cell 20:9-19(2005) [PubMed: 16209941] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 181-190 IN COMPLEX WITH SKP1; SKP2 AND CKS1B, PHOSPHORYLATION AT THR-187, MUTAGENESIS OF GLU-185 AND THR-187, UBIQUITINATION.
[27]	"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.
[28]	"A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization." Molatore S., Marinoni I., Lee M., Pulz E., Ambrosio M.R., degli Uberti E.C., Zatelli M.C., Pellegata N.S. Hum. Mutat. 31:E1825-E1835(2010) [PubMed: 20824794] [Abstract] Cited for: VARIANT LEU-69, CHARACTERIZATION OF VARIANT LEU-69.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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.

IPI

IPI00006991.

RefSeq

NP_004055.1. NM_004064.3.

UniGene

Hs.238990.

3D structure databases

PDBe
RCSB PDB
PDBj

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	[»]

ProteinModelPortal

P46527.

SMR

P46527. Positions 25-93.

DisProt

DP00018.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-33341N.

IntAct

P46527. 37 interactions.

MINT

MINT-239177.

STRING

P46527.

PTM databases

PhosphoSite

P46527.

Polymorphism databases

DMDM

1168871.

2D gel databases

SWISS-2DPAGE

P46527.

Proteomic databases

PRIDE

P46527.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000228872; ENSP00000228872; ENSG00000111276.

GeneID

1027.

KEGG

hsa:1027.

UCSC

uc001rat.1. human.

Organism-specific databases

CTD

1027.

GeneCards

GC12P012867.

H-InvDB

HIX0010441.

HGNC

HGNC:1785. CDKN1B.

HPA

CAB003691.
CAB021888.

MIM

600778. gene.
610755. phenotype.

neXtProt

NX_P46527.

Orphanet

652. Multiple endocrine neoplasia type 1.

PharmGKB

PA105.

GenAtlas

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Phylogenomic databases

HOVERGEN

HBG073988.

OMA

AEYPKPS.

OrthoDB

EOG4ZGPDC.

PhylomeDB

P46527.

Enzyme and pathway databases

Pathway_Interaction_DB

pi3kciaktpathway. Class I PI3K signaling events mediated by Akt.
hnf3apathway. FOXA1 transcription factor network.
foxopathway. FoxO family signaling.
avb3_integrin_pathway. Integrins in angiogenesis.
telomerasepathway. Regulation of Telomerase.

Reactome

REACT_111102. Signal Transduction.
REACT_152. Cell Cycle, Mitotic.
REACT_1538. Cell Cycle Checkpoints.
REACT_383. DNA Replication.

Gene expression databases

ArrayExpress

P46527.

Bgee

P46527.

CleanEx

HS_CDKN1B.

Genevestigator

P46527.

GermOnline

ENSG00000111276. Homo sapiens.

Family and domain databases

InterPro

IPR003175. CDI.
[Graphical view]

KO

K06624.

PANTHER

PTHR10265. CDI. 1 hit.

Pfam

PF02234. CDI. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

4315.

PMAP-CutDB

P46527.

SOURCE

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Entry information

Entry name

CDN1B_HUMAN

Accession

Primary (citable) accession number: P46527
Secondary accession number(s): Q16307, Q5U0H2, Q9BUS6

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	November 1, 1995
Last modified:	January 25, 2012
This is version 135 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.