ID CDN1B_HUMAN Reviewed; 198 AA. AC P46527; Q16307; Q5U0H2; Q9BUS6; DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1995, sequence version 1. DT 22-JUL-2015, entry version 171. DE RecName: Full=Cyclin-dependent kinase inhibitor 1B; DE AltName: Full=Cyclin-dependent kinase inhibitor p27; DE AltName: Full=p27Kip1; GN Name=CDKN1B; Synonyms=KIP1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 28-79 AND 104-152. RC TISSUE=Kidney; RX PubMed=8033212; DOI=10.1016/0092-8674(94)90572-X; RA Polyak K., Lee M.-H., Erdjument-Bromage H., Koff A., Roberts J.M., RA Tempst P., Massague J.; RT "Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a RT potential mediator of extracellular antimitogenic signals."; RL Cell 78:59-66(1994). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=7882309; RA Pietenpol J.A., Bohlander S.K., Sato Y., Papadopoulos N., Liu B., RA Friedman C., Trask B.J., Roberts J.M., Kinzler K.W., Rowley J.D.; RT "Assignment of the human p27Kip1 gene to 12p13 and its analysis in RT leukemias."; RL Cancer Res. 55:1206-1210(1995). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLY-109. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor RT vector."; RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS TRP-15 AND GLY-109. RG NIEHS SNPs program; RL Submitted (FEB-2002) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLY-109. RC TISSUE=Cervix; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP UBIQUITINATION, AND PHOSPHORYLATION AT THR-187. RX PubMed=10323868; DOI=10.1101/gad.13.9.1181; RA Montagnoli A., Fiore F., Eytan E., Carrano A.C., Draetta G.F., RA Hershko A., Pagano M.; RT "Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation RT and trimeric complex formation."; RL Genes Dev. 13:1181-1189(1999). RN [7] RP PHOSPHORYLATION AT SER-10, AND FUNCTION. RX PubMed=10831586; DOI=10.1074/jbc.M001144200; RA Ishida N., Kitagawa M., Hatakeyama S., Nakayama K.; RT "Phosphorylation at serine 10, a major phosphorylation site of RT p27(Kip1), increases its protein stability."; RL J. Biol. Chem. 275:25146-25154(2000). RN [8] RP INTERACTION WITH UHMK1, PHOSPHORYLATION AT SER-10, SUBCELLULAR RP LOCATION, AND MUTAGENESIS OF SER-10 AND THR-187. RX PubMed=12093740; DOI=10.1093/emboj/cdf343; RA Boehm M., Yoshimoto T., Crook M.F., Nallamshetty S., True A., RA Nabel G.J., Nabel E.G.; RT "A growth factor-dependent nuclear kinase phosphorylates p27(Kip1) and RT regulates cell cycle progression."; RL EMBO J. 21:3390-3401(2002). RN [9] RP PHOSPHORYLATION AT SER-10; THR-187 AND THR-198, INTERACTION WITH AKT1 RP AND YWHAQ, SUBCELLULAR LOCATION, AND MUTAGENESIS OF SER-10; THR-157; RP THR-187 AND THR-198. RX PubMed=12042314; DOI=10.1074/jbc.M203668200; RA Fujita N., Sato S., Katayama K., Tsuruo T.; RT "Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 RT and cytoplasmic localization."; RL J. Biol. Chem. 277:28706-28713(2002). RN [10] RP PHOSPHORYLATION AT THR-157, SUBCELLULAR LOCATION, ASSOCIATION WITH RP BREAST CANCER, AND MUTAGENESIS OF THR-157. RX PubMed=12244303; DOI=10.1038/nm762; RA Viglietto G., Motti M.L., Bruni P., Melillo R.M., D'Alessio A., RA Califano D., Vinci F., Chiappetta G., Tsichlis P., Bellacosa A., RA Fusco A., Santoro M.; RT "Cytoplasmic relocalization and inhibition of the cyclin-dependent RT kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in RT breast cancer."; RL Nat. Med. 8:1136-1144(2002). RN [11] RP PHOSPHORYLATION AT THR-157, INTERACTION WITH AKT1, SUBCELLULAR RP LOCATION, FUNCTION, AND MUTAGENESIS OF THR-157; SER-161 AND THR-162. RX PubMed=12244301; DOI=10.1038/nm759; RA Shin I., Yakes F.M., Rojo F., Shin N.-Y., Bakin A.V., Baselga J., RA Arteaga C.L.; RT "PKB/Akt mediates cell-cycle progression by phosphorylation of RT p27(Kip1) at threonine 157 and modulation of its cellular RT localization."; RL Nat. Med. 8:1145-1152(2002). RN [12] RP PHOSPHORYLATION AT SER-10 AND THR-198, INTERACTION WITH YWHAE; YWHAH; RP SFN; YWHAQ; RPS6KA1 AND RPS6KA3, SUBCELLULAR LOCATION, AND MUTAGENESIS RP OF THR-157 AND THR-198. RX PubMed=14504289; DOI=10.1074/jbc.M306614200; RA Fujita N., Sato S., Tsuruo T.; RT "Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein RT S6 kinases promotes its binding to 14-3-3 and cytoplasmic RT localization."; RL J. Biol. Chem. 278:49254-49260(2003). RN [13] RP INTERACTION WITH SPDYA. RX PubMed=12972555; DOI=10.1091/mbc.E02-12-0820; RA Porter L.A., Kong-Beltran M., Donoghue D.J.; RT "Spy1 interacts with p27Kip1 to allow G1/S progression."; RL Mol. Biol. Cell 14:3664-3674(2003). RN [14] RP PHOSPHORYLATION AT THR-198, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP SER-10; THR-157; THR-187 AND THR-198. RX PubMed=15280662; RA Motti M.L., De Marco C., Califano D., Fusco A., Viglietto G.; RT "Akt-dependent T198 phosphorylation of cyclin-dependent kinase RT inhibitor p27kip1 in breast cancer."; RL Cell Cycle 3:1074-1080(2004). RN [15] RP INTERACTION WITH CDK1. RX PubMed=16007079; DOI=10.1038/ncb1284; RA Aleem E., Kiyokawa H., Kaldis P.; RT "Cdc2-cyclin E complexes regulate the G1/S phase transition."; RL Nat. Cell Biol. 7:831-836(2005). RN [16] RP PHOSPHORYLATION AT TYR-88 AND TYR-89, DEPHOSPHORYLATION, INTERACTION RP WITH GRB2; CDK2 AND CDK4, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP TYR-74; TYR-88 AND TYR-89. RX PubMed=16195327; DOI=10.1182/blood-2005-05-1771; RA Kardinal C., Dangers M., Kardinal A., Koch A., Brandt D.T., Tamura T., RA Welte K.; RT "Tyrosine phosphorylation modulates binding preference to cyclin- RT dependent kinases and subcellular localization of p27Kip1 in the acute RT promyelocytic leukemia cell line NB4."; RL Blood 107:1133-1140(2006). RN [17] RP INTERACTION WITH CDK4, AND FUNCTION. RX PubMed=16782892; DOI=10.1128/MCB.02006-05; RA Bockstaele L., Kooken H., Libert F., Paternot S., Dumont J.E., RA de Launoit Y., Roger P.P., Coulonval K.; RT "Regulated activating Thr172 phosphorylation of cyclin-dependent RT kinase 4(CDK4): its relationship with cyclins and CDK 'inhibitors'."; RL Mol. Cell. Biol. 26:5070-5085(2006). RN [18] RP UBIQUITINATION, AND MUTAGENESIS OF THR-187. RX PubMed=16880511; DOI=10.1128/MCB.01630-05; RA Sabile A., Meyer A.M., Wirbelauer C., Hess D., Kogel U., Scheffner M., RA Krek W.; RT "Regulation of p27 degradation and S-phase progression by Ro52 RING RT finger protein."; RL Mol. Cell. Biol. 26:5994-6004(2006). RN [19] RP ASSOCIATION WITH MEN4. RX PubMed=17030811; DOI=10.1073/pnas.0603877103; RA Pellegata N.S., Quintanilla-Martinez L., Siggelkow H., Samson E., RA Bink K., Hoefler H., Fend F., Graw J., Atkinson M.J.; RT "Germ-line mutations in p27(Kip1) cause a multiple endocrine neoplasia RT syndrome in rats and humans."; RL Proc. Natl. Acad. Sci. U.S.A. 103:15558-15563(2006). RN [20] RP PHOSPHORYLATION AT TYR-74 AND TYR-88 BY SRC. RX PubMed=17254967; DOI=10.1016/j.cell.2006.11.049; RA Chu I., Sun J., Arnaout A., Kahn H., Hanna W., Narod S., Sun P., RA Tan C.K., Hengst L., Slingerland J.; RT "p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2."; RL Cell 128:281-294(2007). RN [21] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Embryonic kidney; RX PubMed=17525332; DOI=10.1126/science.1140321; RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.; RT "ATM and ATR substrate analysis reveals extensive protein networks RT responsive to DNA damage."; RL Science 316:1160-1166(2007). RN [22] RP INTERACTION WITH PIM1, AND PHOSPHORYLATION AT THR-157 AND THR-198. RX PubMed=18593906; DOI=10.1158/0008-5472.CAN-08-0634; RA Morishita D., Katayama R., Sekimizu K., Tsuruo T., Fujita N.; RT "Pim kinases promote cell cycle progression by phosphorylating and RT down-regulating p27Kip1 at the transcriptional and posttranscriptional RT levels."; RL Cancer Res. 68:5076-5085(2008). RN [23] RP INTERACTION WITH CDK4, PHOSPHORYLATION, FUNCTION, AND MUTAGENESIS OF RP TYR-74; TYR-88 AND TYR-89. RX PubMed=19075005; DOI=10.1128/MCB.00898-08; RA Ray A., James M.K., Larochelle S., Fisher R.P., Blain S.W.; RT "p27Kip1 inhibits cyclin D-cyclin-dependent kinase 4 by two RT independent modes."; RL Mol. Cell. Biol. 29:986-999(2009). RN [24] RP PHOSPHORYLATION AT TYR-88 BY JAK2. RX PubMed=21423214; DOI=10.1038/onc.2011.68; RA Jakel H., Weinl C., Hengst L.; RT "Phosphorylation of p27Kip1 by JAK2 directly links cytokine receptor RT signaling to cell cycle control."; RL Oncogene 30:3502-3512(2011). RN [25] RP PHOSPHORYLATION AT THR-157 AND THR-198 BY CAMK1. RX PubMed=23707388; DOI=10.1016/j.cellsig.2013.05.012; RA Mallampalli R.K., Kaercher L., Snavely C., Pulijala R., Chen B.B., RA Coon T., Zhao J., Agassandian M.; RT "Fbxl12 triggers G1 arrest by mediating degradation of calmodulin RT kinase I."; RL Cell. Signal. 25:2047-2059(2013). RN [26] RP PHOSPHORYLATION AT THR-187 BY CDK1 AND CDK2. RX PubMed=23478441; DOI=10.1016/j.molcel.2013.02.004; RA Rossi M., Duan S., Jeong Y.T., Horn M., Saraf A., Florens L., RA Washburn M.P., Antebi A., Pagano M.; RT "Regulation of the CRL4(Cdt2) ubiquitin ligase and cell-cycle exit by RT the SCF(Fbxo11) ubiquitin ligase."; RL Mol. Cell 49:1159-1166(2013). RN [27] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 23-106 IN COMPLEX WITH CDK2 RP AND CG2A. RX PubMed=8684460; DOI=10.1038/382325a0; RA Russo A.A., Jeffrey P.D., Patten A.K., Massague J., Pavletich N.P.; RT "Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor RT bound to the cyclin A-Cdk2 complex."; RL Nature 382:325-331(1996). RN [28] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 181-190 IN COMPLEX WITH SKP1; RP SKP2 AND CKS1B, PHOSPHORYLATION AT THR-187, MUTAGENESIS OF GLU-185 AND RP THR-187, AND UBIQUITINATION. RX PubMed=16209941; DOI=10.1016/j.molcel.2005.09.003; RA Hao B., Zheng N., Schulman B.A., Wu G., Miller J.J., Pagano M., RA Pavletich N.P.; RT "Structural basis of the Cks1-dependent recognition of p27(Kip1) by RT the SCF(Skp2) ubiquitin ligase."; RL Mol. Cell 20:9-19(2005). RN [29] RP STRUCTURE BY NMR OF 22-104, PHOSPHORYLATION AT TYR-88, FUNCTION, RP INDUCTION, INTERACTION WITH LYN, IDENTIFICATION BY MASS SPECTROMETRY, RP AND MUTAGENESIS OF TYR-88 AND TYR-89. RX PubMed=17254966; DOI=10.1016/j.cell.2006.11.047; RA Grimmler M., Wang Y., Mund T., Cilensek Z., Keidel E.-M., RA Waddell M.B., Jaekel H., Kullmann M., Kriwacki R.W., Hengst L.; RT "Cdk-inhibitory activity and stability of p27Kip1 are directly RT regulated by oncogenic tyrosine kinases."; RL Cell 128:269-280(2007). RN [30] RP DEPHOSPHORYLATION BY PPM1H AT THR-187. RX PubMed=22586611; DOI=10.1158/2159-8290.CD-11-0062; RA Lee-Hoeflich S.T., Pham T.Q., Dowbenko D., Munroe X., Lee J., Li L., RA Zhou W., Haverty P.M., Pujara K., Stinson J., Chan S.M., RA Eastham-Anderson J., Pandita A., Seshagiri S., Hoeflich K.P., RA Turashvili G., Gelmon K.A., Aparicio S.A., Davis D.P., RA Sliwkowski M.X., Stern H.M.; RT "PPM1H is a p27 phosphatase implicated in trastuzumab resistance."; RL Cancer Discov. 1:326-337(2011). RN [31] RP VARIANT LEU-69, AND CHARACTERIZATION OF VARIANT LEU-69. RX PubMed=20824794; DOI=10.1002/humu.21354; RA Molatore S., Marinoni I., Lee M., Pulz E., Ambrosio M.R., RA degli Uberti E.C., Zatelli M.C., Pellegata N.S.; RT "A novel germline CDKN1B mutation causing multiple endocrine tumors: RT clinical, genetic and functional characterization."; RL Hum. Mutat. 31:E1825-E1835(2010). CC -!- FUNCTION: Important regulator of cell cycle progression. Involved CC in G1 arrest. Potent inhibitor of cyclin E- and cyclin A-CDK2 CC complexes. Forms a complex with cyclin type D-CDK4 complexes and CC is involved in the assembly, stability, and modulation of CCND1- CC CDK4 complex activation. Acts either as an inhibitor or an CC activator of cyclin type D-CDK4 complexes depending on its CC phosphorylation state and/or stoichometry. CC {ECO:0000269|PubMed:10831586, ECO:0000269|PubMed:12244301, CC ECO:0000269|PubMed:16782892, ECO:0000269|PubMed:17254966, CC ECO:0000269|PubMed:19075005}. CC -!- SUBUNIT: Forms a ternary complex with CCNE1/CDK2/CDKN1B. Interacts CC directly with CCNE1; the interaction is inhibited by CDK2- CC dependent phosphorylation on Thr-187. Interacts with COPS5, CC subunit of the COP9 signalosome complex; the interaction leads to CC CDKN1B degradation. Interacts with NUP50; the interaction leads to CC nuclear import and degradation of phosphorylated CDKN1B. Interacts CC with CCND1 and SNX6 (By similarity). Interacts (Thr-198- CC phosphorylated form) with 14-3-3 proteins, binds strongly YWHAQ, CC weakly YWHAE and YWHAH, but not YWHAB nor YWHAZ; the interaction CC with YWHAQ results in translocation to the cytoplasm. Interacts CC with AKT1 and LYN; the interactions lead to cytoplasmic CC mislocation, phosphorylation of CDKN1B and inhibition of cell CC cycle arrest. Interacts (unphosphorylated form) with CDK2. Forms a CC ternary complex, cyclin D/CDK4/CDKN1B. Interacts (phosphorylated CC on Tyr-88 and Tyr-89) with CDK4; the interaction is required for CC cyclin D/CDK4 complex assembly, induces nuclear translocation and CC activates the CDK4 kinase activity. Interacts with GRB2. Interacts CC with PIM1. Identified in a complex with SKP1, SKP2 and CKS1B. CC Interacts with UHMK1; the interaction leads to cytoplasmic CC mislocation, phosphorylation of CDKN1B and inhibition of cell CC cycle arrest. Interacts also with CDK1. Dephosphorylated on Thr- CC 187 by PPM1H, leading to CDKN1B stability (PubMed:22586611). CC {ECO:0000250, ECO:0000269|PubMed:12042314, CC ECO:0000269|PubMed:12093740, ECO:0000269|PubMed:12244301, CC ECO:0000269|PubMed:12972555, ECO:0000269|PubMed:14504289, CC ECO:0000269|PubMed:16007079, ECO:0000269|PubMed:16195327, CC ECO:0000269|PubMed:16209941, ECO:0000269|PubMed:16782892, CC ECO:0000269|PubMed:17254966, ECO:0000269|PubMed:18593906, CC ECO:0000269|PubMed:19075005, ECO:0000269|PubMed:22586611, CC ECO:0000269|PubMed:8684460}. CC -!- INTERACTION: CC P00520:Abl1 (xeno); NbExp=2; IntAct=EBI-519280, EBI-914519; CC P20248:CCNA2; NbExp=13; IntAct=EBI-519280, EBI-457097; CC P24385:CCND1; NbExp=2; IntAct=EBI-519280, EBI-375001; CC P24864:CCNE1; NbExp=7; IntAct=EBI-519280, EBI-519526; CC O96020:CCNE2; NbExp=2; IntAct=EBI-519280, EBI-375033; CC P24941:CDK2; NbExp=18; IntAct=EBI-519280, EBI-375096; CC P11802:CDK4; NbExp=5; IntAct=EBI-519280, EBI-295644; CC Q00535:CDK5; NbExp=7; IntAct=EBI-519280, EBI-1041567; CC O15111:CHUK; NbExp=4; IntAct=EBI-519280, EBI-81249; CC Q92905:COPS5; NbExp=3; IntAct=EBI-519280, EBI-594661; CC Q62120:Jak2 (xeno); NbExp=7; IntAct=EBI-519280, EBI-646604; CC O00505:KPNA3; NbExp=4; IntAct=EBI-519280, EBI-358297; CC O15131:KPNA5; NbExp=6; IntAct=EBI-519280, EBI-540602; CC P07948:LYN; NbExp=2; IntAct=EBI-519280, EBI-79452; CC P33993:MCM7; NbExp=2; IntAct=EBI-519280, EBI-355924; CC Q13309:SKP2; NbExp=4; IntAct=EBI-519280, EBI-456291; CC Q12933:TRAF2; NbExp=2; IntAct=EBI-519280, EBI-355744; CC P27348:YWHAQ; NbExp=4; IntAct=EBI-519280, EBI-359854; CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Endosome {ECO:0000250}. CC Note=Nuclear and cytoplasmic in quiescent cells. AKT- or RSK- CC mediated phosphorylation on Thr-198, binds 14-3-3, translocates to CC the cytoplasm and promotes cell cycle progression. Mitogen- CC activated UHMK1 phosphorylation on Ser-10 also results in CC translocation to the cytoplasm and cell cycle progression. CC Phosphorylation on Ser-10 facilitates nuclear export. Translocates CC to the nucleus on phosphorylation of Tyr-88 and Tyr-89. CC Colocalizes at the endosome with SNX6; this leads to lysosomal CC degradation (By similarity). {ECO:0000250}. CC -!- TISSUE SPECIFICITY: Expressed in all tissues tested. Highest CC levels in skeletal muscle, lowest in liver and kidney. CC -!- INDUCTION: Maximal levels in quiescence cells and early G(1). CC Levels decrease after mitogen stimulation as cells progress toward CC S-phase. {ECO:0000269|PubMed:17254966}. CC -!- DOMAIN: A peptide sequence containing only AA 28-79 retains CC substantial Kip1 cyclin A/CDK2 inhibitory activity. CC -!- PTM: Phosphorylated; phosphorylation occurs on serine, threonine CC and tyrosine residues. Phosphorylation on Ser-10 is the major site CC of phosphorylation in resting cells, takes place at the G(0)-G(1) CC phase and leads to protein stability. Phosphorylation on other CC sites is greatly enhanced by mitogens, growth factors, cMYC and in CC certain cancer cell lines. The phosphorylated form found in the CC cytoplasm is inactivate. Phosphorylation on Thr-198 is required CC for interaction with 14-3-3 proteins. Phosphorylation on Thr-187, CC by CDK1 and CDK2 leads to protein ubiquitination and proteasomal CC degradation. Tyrosine phosphorylation promotes this process. CC Phosphorylation by PKB/AKT1 can be suppressed by LY294002, an CC inhibitor of the catalytic subunit of PI3K. Phosphorylation on CC Tyr-88 and Tyr-89 has no effect on binding CDK2, but is required CC for binding CDK4. Dephosphorylated on tyrosine residues by G-CSF. CC {ECO:0000269|PubMed:10323868, ECO:0000269|PubMed:10831586, CC ECO:0000269|PubMed:12042314, ECO:0000269|PubMed:12093740, CC ECO:0000269|PubMed:14504289, ECO:0000269|PubMed:15280662, CC ECO:0000269|PubMed:16195327, ECO:0000269|PubMed:16209941, CC ECO:0000269|PubMed:17254966, ECO:0000269|PubMed:17254967, CC ECO:0000269|PubMed:18593906, ECO:0000269|PubMed:21423214, CC ECO:0000269|PubMed:23478441, ECO:0000269|PubMed:23707388}. CC -!- PTM: Ubiquitinated; in the cytoplasm by the KPC complex (composed CC of RNF123/KPC1 and UBAC1/KPC2) and, in the nucleus, by SCF(SKP2). CC The latter requires prior phosphorylation on Thr-187. CC Ubiquitinated; by a TRIM21-containing SCF(SKP2)-like complex; CC leads to its degradation. {ECO:0000269|PubMed:10323868, CC ECO:0000269|PubMed:12042314, ECO:0000269|PubMed:16209941, CC ECO:0000269|PubMed:23478441}. CC -!- PTM: Subject to degradation in the lysosome. Interaction with SNX6 CC promotes lysosomal degradation (By similarity). {ECO:0000250}. CC -!- DISEASE: Multiple endocrine neoplasia 4 (MEN4) [MIM:610755]: CC Multiple endocrine neoplasia (MEN) syndromes are inherited cancer CC syndromes of the thyroid. MEN4 is a MEN-like syndrome with a CC phenotypic overlap of both MEN1 and MEN2. Note=The disease is CC caused by mutations affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Decreased levels of p27Kip1, mainly due to CC proteasomal degradation, are found in various epithelial tumors CC originating from lung, breast, colon, ovary, esophagus, thyroid CC and prostate. CC -!- SIMILARITY: Belongs to the CDI family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology CC and Haematology; CC URL="http://atlasgeneticsoncology.org/Genes/CDKN1BID116.html"; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/cdkn1b/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U10906; AAA20240.1; -; mRNA. DR EMBL; S76988; AAD14244.1; -; Genomic_DNA. DR EMBL; S76986; AAD14244.1; JOINED; Genomic_DNA. DR EMBL; BT019553; AAV38360.1; -; mRNA. DR EMBL; BT019554; AAV38361.1; -; mRNA. DR EMBL; AF480891; AAL78041.1; -; Genomic_DNA. DR EMBL; BC001971; AAH01971.1; -; mRNA. DR CCDS; CCDS8653.1; -. DR RefSeq; NP_004055.1; NM_004064.4. DR UniGene; Hs.238990; -. DR PDB; 1H27; X-ray; 2.20 A; E=25-35. DR PDB; 1JSU; X-ray; 2.30 A; C=23-106. DR PDB; 2AST; X-ray; 2.30 A; D=181-190. DR PDBsum; 1H27; -. DR PDBsum; 1JSU; -. DR PDBsum; 2AST; -. DR DisProt; DP00018; -. DR ProteinModelPortal; P46527; -. DR SMR; P46527; 25-93. DR BioGrid; 107461; 73. DR DIP; DIP-33341N; -. DR IntAct; P46527; 52. DR MINT; MINT-239177; -. DR STRING; 9606.ENSP00000228872; -. DR PhosphoSite; P46527; -. DR BioMuta; CDKN1B; -. DR SWISS-2DPAGE; P46527; -. DR MaxQB; P46527; -. DR PaxDb; P46527; -. DR PRIDE; P46527; -. DR DNASU; 1027; -. DR Ensembl; ENST00000228872; ENSP00000228872; ENSG00000111276. DR GeneID; 1027; -. DR KEGG; hsa:1027; -. DR UCSC; uc001rat.2; human. DR CTD; 1027; -. DR GeneCards; GC12P012867; -. DR HGNC; HGNC:1785; CDKN1B. DR HPA; CAB003691; -. DR HPA; CAB021888; -. DR MIM; 600778; gene. DR MIM; 610755; phenotype. DR neXtProt; NX_P46527; -. DR Orphanet; 652; Multiple endocrine neoplasia type 1. DR Orphanet; 276152; Multiple endocrine neoplasia type 4. DR PharmGKB; PA105; -. DR eggNOG; NOG245842; -. DR GeneTree; ENSGT00530000063588; -. DR HOGENOM; HOG000294081; -. DR HOVERGEN; HBG073988; -. DR InParanoid; P46527; -. DR KO; K06624; -. DR OMA; YPKPSAC; -. DR OrthoDB; EOG7GJ6HD; -. DR PhylomeDB; P46527; -. DR TreeFam; TF101038; -. DR Reactome; REACT_1156; Orc1 removal from chromatin. DR Reactome; REACT_12564; AKT phosphorylates targets in the cytosol. DR Reactome; REACT_1574; Cyclin E associated events during G1/S transition. DR Reactome; REACT_1625; p53-Dependent G1 DNA Damage Response. DR Reactome; REACT_169168; Senescence-Associated Secretory Phenotype (SASP). DR Reactome; REACT_169185; DNA Damage/Telomere Stress Induced Senescence. DR Reactome; REACT_355303; RHO GTPases activate CIT. DR Reactome; REACT_355468; Constitutive Signaling by AKT1 E17K in Cancer. DR Reactome; REACT_821; Cyclin D associated events in G1. DR Reactome; REACT_9003; SCF(Skp2)-mediated degradation of p27/p21. DR Reactome; REACT_9029; Cyclin A:Cdk2-associated events at S phase entry. DR ChiTaRS; CDKN1B; human. DR EvolutionaryTrace; P46527; -. DR GeneWiki; CDKN1B; -. DR GenomeRNAi; 1027; -. DR NextBio; 4315; -. DR PMAP-CutDB; P46527; -. DR PRO; PR:P46527; -. DR Proteomes; UP000005640; Chromosome 12. DR Bgee; P46527; -. DR CleanEx; HS_CDKN1B; -. DR ExpressionAtlas; P46527; baseline and differential. DR Genevisible; P46527; HS. DR GO; GO:0031464; C:Cul4A-RING E3 ubiquitin ligase complex; IDA:MGI. DR GO; GO:0005737; C:cytoplasm; IDA:HGNC. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005768; C:endosome; IEA:UniProtKB-SubCell. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL. DR GO; GO:0004861; F:cyclin-dependent protein serine/threonine kinase inhibitor activity; TAS:ProtInc. DR GO; GO:0019903; F:protein phosphatase binding; IPI:BHF-UCL. DR GO; GO:0005072; F:transforming growth factor beta receptor, cytoplasmic mediator activity; TAS:ProtInc. DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB. DR GO; GO:0048102; P:autophagic cell death; IDA:BHF-UCL. DR GO; GO:0007050; P:cell cycle arrest; IMP:HGNC. DR GO; GO:0071236; P:cellular response to antibiotic; IEA:Ensembl. DR GO; GO:0071285; P:cellular response to lithium ion; IDA:MGI. DR GO; GO:0071407; P:cellular response to organic cyclic compound; IEA:Ensembl. DR GO; GO:0006977; P:DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; TAS:Reactome. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome. DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IDA:BHF-UCL. DR GO; GO:0045087; P:innate immune response; TAS:Reactome. DR GO; GO:0048839; P:inner ear development; IEA:Ensembl. DR GO; GO:0000278; P:mitotic cell cycle; TAS:Reactome. DR GO; GO:0071850; P:mitotic cell cycle arrest; IDA:UniProtKB. DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0030308; P:negative regulation of cell growth; IDA:BHF-UCL. DR GO; GO:0008285; P:negative regulation of cell proliferation; IDA:UniProtKB. DR GO; GO:0051271; P:negative regulation of cellular component movement; IEA:Ensembl. DR GO; GO:0045736; P:negative regulation of cyclin-dependent protein serine/threonine kinase activity; IEA:Ensembl. DR GO; GO:0060770; P:negative regulation of epithelial cell proliferation involved in prostate gland development; IEA:Ensembl. DR GO; GO:0033673; P:negative regulation of kinase activity; IDA:UniProtKB. DR GO; GO:0045930; P:negative regulation of mitotic cell cycle; IDA:UniProtKB. DR GO; GO:0042326; P:negative regulation of phosphorylation; IDA:BHF-UCL. DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB. DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome. DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome. DR GO; GO:0010942; P:positive regulation of cell death; IDA:UniProtKB. DR GO; GO:0008284; P:positive regulation of cell proliferation; IEA:Ensembl. DR GO; GO:0031116; P:positive regulation of microtubule polymerization; IEA:Ensembl. DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:MGI. DR GO; GO:0006813; P:potassium ion transport; IEA:Ensembl. DR GO; GO:0000079; P:regulation of cyclin-dependent protein serine/threonine kinase activity; TAS:ProtInc. DR GO; GO:0043200; P:response to amino acid; IEA:Ensembl. DR GO; GO:0046686; P:response to cadmium ion; IEA:Ensembl. DR GO; GO:0042493; P:response to drug; IEA:Ensembl. DR GO; GO:0032355; P:response to estradiol; IEA:Ensembl. DR GO; GO:0009749; P:response to glucose; IEA:Ensembl. DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl. DR GO; GO:0043434; P:response to peptide hormone; IEA:Ensembl. DR GO; GO:0007605; P:sensory perception of sound; IEA:Ensembl. DR GO; GO:0007264; P:small GTPase mediated signal transduction; TAS:Reactome. DR InterPro; IPR003175; CDI. DR InterPro; IPR029843; CDKN1B. DR PANTHER; PTHR10265; PTHR10265; 1. DR PANTHER; PTHR10265:SF9; PTHR10265:SF9; 1. DR Pfam; PF02234; CDI; 1. PE 1: Evidence at protein level; KW 3D-structure; Cell cycle; Complete proteome; Cytoplasm; KW Direct protein sequencing; Endosome; Nucleus; Phosphoprotein; KW Polymorphism; Protein kinase inhibitor; Proto-oncogene; KW Reference proteome; Ubl conjugation. FT CHAIN 1 198 Cyclin-dependent kinase inhibitor 1B. FT /FTId=PRO_0000190084. FT MOTIF 153 169 Nuclear localization signal. FT {ECO:0000255}. FT MOD_RES 10 10 Phosphoserine; by UHMK1. FT {ECO:0000269|PubMed:10831586, FT ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:12093740, FT ECO:0000269|PubMed:14504289}. FT MOD_RES 74 74 Phosphotyrosine; by SRC. FT {ECO:0000269|PubMed:17254967}. FT MOD_RES 88 88 Phosphotyrosine; by ABL, LYN, SRC and FT JAK2. {ECO:0000269|PubMed:16195327, FT ECO:0000269|PubMed:17254966, FT ECO:0000269|PubMed:17254967, FT ECO:0000269|PubMed:21423214}. FT MOD_RES 89 89 Phosphotyrosine. FT {ECO:0000269|PubMed:16195327}. FT MOD_RES 157 157 Phosphothreonine; by CaMK1, PKB/AKT1 and FT PIM1. {ECO:0000269|PubMed:12244301, FT ECO:0000269|PubMed:12244303, FT ECO:0000269|PubMed:18593906, FT ECO:0000269|PubMed:23707388}. FT MOD_RES 170 170 Phosphothreonine. FT {ECO:0000250|UniProtKB:P46414}. FT MOD_RES 187 187 Phosphothreonine; by PKB/AKT1, CDK1 and FT CDK2. {ECO:0000269|PubMed:10323868, FT ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:16209941, FT ECO:0000269|PubMed:23478441}. FT MOD_RES 198 198 Phosphothreonine; by CaMK1, PKB/AKT1, FT RPS6KA1, RPS6KA3 and PIM1. FT {ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:14504289, FT ECO:0000269|PubMed:15280662, FT ECO:0000269|PubMed:18593906, FT ECO:0000269|PubMed:23707388}. FT VARIANT 15 15 R -> W (in dbSNP:rs2066828). FT {ECO:0000269|Ref.4}. FT /FTId=VAR_011871. FT VARIANT 69 69 P -> L (found in a patient with multiple FT endocrine tumors; germline mutation; FT reduced expression levels; shows impaired FT binding to CDK2). FT {ECO:0000269|PubMed:20824794}. FT /FTId=VAR_064429. FT VARIANT 109 109 V -> G (in dbSNP:rs2066827). FT {ECO:0000269|PubMed:15489334, FT ECO:0000269|Ref.3, ECO:0000269|Ref.4}. FT /FTId=VAR_011872. FT MUTAGEN 10 10 S->A: Loss of phosphorylation by UHMK1. FT No translocation to the cytoplasm. FT Greater cell cycle arrest. FT {ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:12093740, FT ECO:0000269|PubMed:15280662}. FT MUTAGEN 10 10 S->D: Exported to the cytoplasm. Inhibits FT cell cycle arrest. FT {ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:12093740, FT ECO:0000269|PubMed:15280662}. FT MUTAGEN 10 10 S->E: Increased stability in vivo and in FT vitro. {ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:12093740, FT ECO:0000269|PubMed:15280662}. FT MUTAGEN 74 74 Y->F: No change in binding CDK4 and no FT inhibition of CDK4 activity. Translocates FT to nucleus. No effect on in vitro FT phosphorylation of CDK4 by CCNH-CDK7. FT {ECO:0000269|PubMed:16195327, FT ECO:0000269|PubMed:19075005}. FT MUTAGEN 88 88 Y->F: Abolishes LYN-mediated FT phosphorylation, reduceS CDK2-mediated FT phosphorylation on T-187, has greater FT cell cycle arrest into S-phase, no effect FT on binding CDK2 complexes, reduced CDK4 FT binding and inhibits CDK4 enzyme FT activity. No nuclear translocation. No FT effect on in vitro phosphorylation of FT CDK4 by CCNH-CDK7. Completely abolishes FT CDK4 binding; when associated with F-89. FT {ECO:0000269|PubMed:16195327, FT ECO:0000269|PubMed:17254966, FT ECO:0000269|PubMed:19075005}. FT MUTAGEN 89 89 Y->F: No effect on binding CDK2 FT complexes, reduced CDK4 binding and FT greatly inhibits CDK4 enzyme activity. No FT nuclear translocation. Inhibits in vitro FT phosphorylation of CDK4 by CCNH-CDK7. FT Completely abolishes CDK4 binding; when FT associated with F-88. FT {ECO:0000269|PubMed:16195327, FT ECO:0000269|PubMed:17254966, FT ECO:0000269|PubMed:19075005}. FT MUTAGEN 157 157 T->A: Greatly reduced PKB/AKT1-mediated FT phosphorylation. Nuclear location. FT Inhibits cyclin E/CDK2 cell cycle FT progression. No effect on binding AKT1. FT Completely abolishes PKB/AKT1-mediated FT phosphorylation and no cytoplasmic FT translocation; when associated with A- FT 198. {ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:12244301, FT ECO:0000269|PubMed:12244303, FT ECO:0000269|PubMed:14504289, FT ECO:0000269|PubMed:15280662}. FT MUTAGEN 161 161 S->A: No change in PKB/AKT1-mediated FT phosphorylation. FT {ECO:0000269|PubMed:12244301}. FT MUTAGEN 162 162 T->A: No change in PKB/AKT1-mediated FT phosphorylation. FT {ECO:0000269|PubMed:12244301}. FT MUTAGEN 185 185 E->A,D,Q: Strongly reduced ubiquitination FT by a TRIM21-containing SCF(SKP2) complex. FT {ECO:0000269|PubMed:16209941}. FT MUTAGEN 187 187 T->A,D: No change in PKB/AKT1- nor UHMK1- FT mediated phosphorylation. FT {ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:12093740, FT ECO:0000269|PubMed:15280662, FT ECO:0000269|PubMed:16209941, FT ECO:0000269|PubMed:16880511}. FT MUTAGEN 187 187 T->A: Abolishes phosphorylation-dependent FT ubiquitination. FT {ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:12093740, FT ECO:0000269|PubMed:15280662, FT ECO:0000269|PubMed:16209941, FT ECO:0000269|PubMed:16880511}. FT MUTAGEN 198 198 T->A,D: Abolishes PKB/AKT1-mediated FT phosphorylation. 46% cytoplasmic FT location. Greatly reduced binding to FT YWHAQ. Equally reduced binding; when FT associated with A-10 and A-187. No FT nuclear import; when associated with A- FT 157. Completely abolishes PKB/AKT1- FT mediated phosphorylation and no FT cytoplasmic translocation; when FT associated with A-157. FT {ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:14504289, FT ECO:0000269|PubMed:15280662}. FT CONFLICT 22 22 E -> D (in Ref. 2; AAD14244). FT {ECO:0000305}. FT HELIX 38 49 {ECO:0000244|PDB:1JSU}. FT TURN 50 53 {ECO:0000244|PDB:1JSU}. FT HELIX 54 60 {ECO:0000244|PDB:1JSU}. FT TURN 64 67 {ECO:0000244|PDB:1JSU}. FT STRAND 71 74 {ECO:0000244|PDB:1JSU}. FT STRAND 77 80 {ECO:0000244|PDB:1JSU}. FT HELIX 86 89 {ECO:0000244|PDB:1JSU}. SQ SEQUENCE 198 AA; 22073 MW; 1118D58901CDF3FC CRC64; MSNVRVSNGS PSLERMDARQ AEHPKPSACR NLFGPVDHEE LTRDLEKHCR DMEEASQRKW NFDFQNHKPL EGKYEWQEVE KGSLPEFYYR PPRPPKGACK VPAQESQDVS GSRPAAPLIG APANSEDTHL VDPKTDPSDS QTGLAEQCAG IRKRPATDDS STQNKRANRT EENVSDGSPN AGSVEQTPKK PGLRRRQT //