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 27-MAR-2024, entry version 236. DE RecName: Full=Cyclin-dependent kinase inhibitor 1B; DE AltName: Full=Cyclin-dependent kinase inhibitor p27 {ECO:0000303|PubMed:28666995}; DE AltName: Full=p27Kip1 {ECO:0000303|PubMed:8033212}; GN Name=CDKN1B {ECO:0000303|PubMed:20824794}; GN Synonyms=KIP1 {ECO:0000303|PubMed:10831586}, p27 GN {ECO:0000303|PubMed:15509543}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 28-79 AND 104-152, AND RP TISSUE SPECIFICITY. 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 potential RT 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 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 project: RT 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., Hershko A., RA Pagano M.; RT "Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and RT 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 p27(Kip1), RT increases its protein stability."; RL J. Biol. Chem. 275:25146-25154(2000). RN [8] RP INTERACTION WITH UHMK1, PHOSPHORYLATION AT SER-10, SUBCELLULAR LOCATION, RP 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., Nabel G.J., RA 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 AND RP YWHAQ, SUBCELLULAR LOCATION, AND MUTAGENESIS OF SER-10; THR-157; THR-187 RP 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 and RT cytoplasmic localization."; RL J. Biol. Chem. 277:28706-28713(2002). RN [10] RP PHOSPHORYLATION AT THR-157, SUBCELLULAR LOCATION, ASSOCIATION WITH BREAST RP 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., Fusco A., RA Santoro M.; RT "Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase RT inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer."; RL Nat. Med. 8:1136-1144(2002). RN [11] RP PHOSPHORYLATION AT THR-157, INTERACTION WITH AKT1, SUBCELLULAR LOCATION, RP 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 p27(Kip1) at RT threonine 157 and modulation of its cellular localization."; RL Nat. Med. 8:1145-1152(2002). RN [12] RP PHOSPHORYLATION AT SER-10 AND THR-198, INTERACTION WITH YWHAE; YWHAH; SFN; RP YWHAQ; RPS6KA1 AND RPS6KA3, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP 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 S6 RT kinases promotes its binding to 14-3-3 and cytoplasmic 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 TISSUE SPECIFICITY. RX PubMed=15509543; DOI=10.1016/s0002-9440(10)63430-x; RA Gooch J.L., Toro J.J., Guler R.L., Barnes J.L.; RT "Calcineurin A-alpha but not A-beta is required for normal kidney RT development and function."; RL Am. J. Pathol. 165:1755-1765(2004). RN [15] 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 inhibitor RT p27kip1 in breast cancer."; RL Cell Cycle 3:1074-1080(2004). RN [16] 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 [17] RP PHOSPHORYLATION AT TYR-88 AND TYR-89, DEPHOSPHORYLATION, INTERACTION WITH RP GRB2; CDK2 AND CDK4, SUBCELLULAR LOCATION, AND MUTAGENESIS OF TYR-74; RP 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-dependent RT kinases and subcellular localization of p27Kip1 in the acute promyelocytic RT leukemia cell line NB4."; RL Blood 107:1133-1140(2006). RN [18] 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 kinase RT 4(CDK4): its relationship with cyclins and CDK 'inhibitors'."; RL Mol. Cell. Biol. 26:5070-5085(2006). RN [19] 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 finger RT protein."; RL Mol. Cell. Biol. 26:5994-6004(2006). RN [20] RP INVOLVEMENT IN MEN4. RX PubMed=17030811; DOI=10.1073/pnas.0603877103; RA Pellegata N.S., Quintanilla-Martinez L., Siggelkow H., Samson E., Bink K., RA 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 [21] 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., Tan C.K., RA Hengst L., Slingerland J.; RT "p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2."; RL Cell 128:281-294(2007). RN [22] 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, Hurov K.E., RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., RA 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 [23] 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 down- RT regulating p27Kip1 at the transcriptional and posttranscriptional levels."; RL Cancer Res. 68:5076-5085(2008). RN [24] 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 independent RT modes."; RL Mol. Cell. Biol. 29:986-999(2009). RN [25] 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., Sliwkowski M.X., RA Stern H.M.; RT "PPM1H is a p27 phosphatase implicated in trastuzumab resistance."; RL Cancer Discov. 1:326-337(2011). RN [26] 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 [27] 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., Coon T., RA Zhao J., Agassandian M.; RT "Fbxl12 triggers G1 arrest by mediating degradation of calmodulin kinase RT I."; RL Cell. Signal. 25:2047-2059(2013). RN [28] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-10, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [29] 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 the RT SCF(Fbxo11) ubiquitin ligase."; RL Mol. Cell 49:1159-1166(2013). RN [30] RP INTERACTION WITH HSPA8. RX PubMed=26775844; DOI=10.1016/j.bbrc.2016.01.072; RA Imamura Y., Wang P.L., Masuno K., Sogawa N.; RT "Salivary protein histatin 3 regulates cell proliferation by enhancing RT p27(Kip1) and heat shock cognate protein 70 ubiquitination."; RL Biochem. Biophys. Res. Commun. 470:269-274(2016). RN [31] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 23-106 IN COMPLEX WITH CCNA2 AND RP CDK2. 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 bound RT to the cyclin A-Cdk2 complex."; RL Nature 382:325-331(1996). RN [32] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 181-190 IN COMPLEX WITH SKP1; SKP2 RP AND CKS1B, PHOSPHORYLATION AT THR-187, MUTAGENESIS OF GLU-185 AND THR-187, RP 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 the RT SCF(Skp2) ubiquitin ligase."; RL Mol. Cell 20:9-19(2005). RN [33] RP STRUCTURE BY NMR OF 22-104, PHOSPHORYLATION AT TYR-88, FUNCTION, INDUCTION, RP INTERACTION WITH LYN, IDENTIFICATION BY MASS SPECTROMETRY, AND MUTAGENESIS RP 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., Waddell M.B., RA Jaekel H., Kullmann M., Kriwacki R.W., Hengst L.; RT "Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by RT oncogenic tyrosine kinases."; RL Cell 128:269-280(2007). RN [34] {ECO:0007744|PDB:5UQ3} RP X-RAY CRYSTALLOGRAPHY (3.60 ANGSTROMS) IN COMPLEX WITH CDK2 AND SPDYA, RP FUNCTION, AND SUBUNIT. RX PubMed=28666995; DOI=10.15252/embj.201796905; RA McGrath D.A., Fifield B.A., Marceau A.H., Tripathi S., Porter L.A., RA Rubin S.M.; RT "Structural basis of divergent cyclin-dependent kinase activation by RT Spy1/RINGO proteins."; RL EMBO J. 36:2251-2262(2017). RN [35] 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. Inhibits the CC kinase activity of CDK2 bound to cyclin A, but has little inhibitory CC activity on CDK2 bound to SPDYA (PubMed:28666995). Involved in G1 CC arrest. Potent inhibitor of cyclin E- and cyclin A-CDK2 complexes. CC Forms a complex with cyclin type D-CDK4 complexes and is involved in CC the assembly, stability, and modulation of CCND1-CDK4 complex CC activation. Acts either as an inhibitor or an activator of cyclin type CC D-CDK4 complexes depending on its phosphorylation state and/or CC stoichometry. {ECO:0000269|PubMed:10831586, CC ECO:0000269|PubMed:12244301, ECO:0000269|PubMed:16782892, CC ECO:0000269|PubMed:17254966, ECO:0000269|PubMed:19075005, CC ECO:0000269|PubMed:28666995}. CC -!- SUBUNIT: Forms a ternary complex composed of CCNE1, CDK2 and CDKN1B. CC Interacts directly with CCNE1; the interaction is inhibited by CDK2- CC dependent phosphorylation on Thr-187. Interacts with COPS5, subunit of CC the COP9 signalosome complex; the interaction leads to CDKN1B CC degradation. Interacts with NUP50; the interaction leads to nuclear CC import and degradation of phosphorylated CDKN1B. Interacts with CCND1 CC and SNX6 (By similarity). Interacts (Thr-198-phosphorylated form) with CC 14-3-3 proteins, binds strongly YWHAQ, weakly YWHAE and YWHAH, but not CC YWHAB nor YWHAZ; the interaction with YWHAQ results in translocation to CC the cytoplasm (PubMed:14504289). Interacts with AKT1 and LYN; the CC interactions lead to cytoplasmic mislocation, phosphorylation of CDKN1B CC and inhibition of cell cycle arrest (PubMed:12042314, PubMed:12244301, CC PubMed:17254966). Forms a ternary complex with CCNA2 and CDK2; CDKN1B CC inhibits the kinase activity of CDK2 through conformational CC rearrangements. Interacts (unphosphorylated form) with CDK2. Forms a CC complex with CDK2 and SPDYA, but does not directly interact with SPDYA CC (PubMed:12972555, PubMed:28666995). Forms a ternary complex composed of CC cyclin D, CDK4 and CDKN1B. Interacts (phosphorylated on Tyr-88 and Tyr- CC 89) with CDK4; the interaction is required for cyclin D and CDK4 CC complex assembly, induces nuclear translocation and activates the CDK4 CC kinase activity. Interacts with GRB2 (PubMed:16195327). Interacts with CC PIM1 (PubMed:18593906). Identified in a complex with SKP1, SKP2 and CC CKS1B (PubMed:16209941). Interacts with UHMK1; the interaction leads to CC cytoplasmic mislocation, phosphorylation of CDKN1B and inhibition of CC cell cycle arrest (PubMed:12093740). Interacts also with CDK1 CC (PubMed:16007079). Dephosphorylated on Thr-187 by PPM1H, leading to CC CDKN1B stability (PubMed:22586611). Interacts with HSPA8; the CC interaction may be associated with susceptibility to ubiquitination CC (PubMed:26775844). {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:26775844, ECO:0000269|PubMed:28666995, CC ECO:0000269|PubMed:8684460}. CC -!- INTERACTION: CC P46527; Q8N9N5-2: BANP; NbExp=3; IntAct=EBI-519280, EBI-11524452; CC P46527; P78396: CCNA1; NbExp=6; IntAct=EBI-519280, EBI-375065; CC P46527; P20248: CCNA2; NbExp=18; IntAct=EBI-519280, EBI-457097; CC P46527; P14635: CCNB1; NbExp=4; IntAct=EBI-519280, EBI-495332; CC P46527; P24385: CCND1; NbExp=10; IntAct=EBI-519280, EBI-375001; CC P46527; P30279: CCND2; NbExp=6; IntAct=EBI-519280, EBI-748789; CC P46527; P30281: CCND3; NbExp=6; IntAct=EBI-519280, EBI-375013; CC P46527; P24864: CCNE1; NbExp=10; IntAct=EBI-519280, EBI-519526; CC P46527; O96020: CCNE2; NbExp=4; IntAct=EBI-519280, EBI-375033; CC P46527; P06493: CDK1; NbExp=6; IntAct=EBI-519280, EBI-444308; CC P46527; P24941: CDK2; NbExp=27; IntAct=EBI-519280, EBI-375096; CC P46527; P11802: CDK4; NbExp=11; IntAct=EBI-519280, EBI-295644; CC P46527; Q00535: CDK5; NbExp=11; IntAct=EBI-519280, EBI-1041567; CC P46527; O15111: CHUK; NbExp=4; IntAct=EBI-519280, EBI-81249; CC P46527; Q92905: COPS5; NbExp=3; IntAct=EBI-519280, EBI-594661; CC P46527; Q13616: CUL1; NbExp=2; IntAct=EBI-519280, EBI-359390; CC P46527; O00505: KPNA3; NbExp=4; IntAct=EBI-519280, EBI-358297; CC P46527; O15131: KPNA5; NbExp=6; IntAct=EBI-519280, EBI-540602; CC P46527; P07948: LYN; NbExp=2; IntAct=EBI-519280, EBI-79452; CC P46527; P33993: MCM7; NbExp=2; IntAct=EBI-519280, EBI-355924; CC P46527; Q5JR59-3: MTUS2; NbExp=3; IntAct=EBI-519280, EBI-11522433; CC P46527; P11309-1: PIM1; NbExp=2; IntAct=EBI-519280, EBI-1018629; CC P46527; P61586: RHOA; NbExp=3; IntAct=EBI-519280, EBI-446668; CC P46527; Q15418: RPS6KA1; NbExp=2; IntAct=EBI-519280, EBI-963034; CC P46527; Q9UQR0-1: SCML2; NbExp=2; IntAct=EBI-519280, EBI-16087037; CC P46527; Q13309: SKP2; NbExp=4; IntAct=EBI-519280, EBI-456291; CC P46527; Q5MJ70: SPDYA; NbExp=3; IntAct=EBI-519280, EBI-7125479; CC P46527; P16949: STMN1; NbExp=3; IntAct=EBI-519280, EBI-445909; CC P46527; Q9NVV9: THAP1; NbExp=3; IntAct=EBI-519280, EBI-741515; CC P46527; Q12933: TRAF2; NbExp=6; IntAct=EBI-519280, EBI-355744; CC P46527; P00520: Abl1; Xeno; NbExp=2; IntAct=EBI-519280, EBI-914519; CC P46527; Q62120: Jak2; Xeno; NbExp=7; IntAct=EBI-519280, EBI-646604; CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Endosome {ECO:0000250}. CC Note=Nuclear and cytoplasmic in quiescent cells. AKT- or RSK-mediated CC phosphorylation on Thr-198, binds 14-3-3, translocates to the cytoplasm CC and promotes cell cycle progression. Mitogen-activated UHMK1 CC phosphorylation on Ser-10 also results in translocation to the CC cytoplasm and cell cycle progression. Phosphorylation on Ser-10 CC facilitates nuclear export. Translocates to the nucleus on CC phosphorylation of Tyr-88 and Tyr-89. Colocalizes at the endosome with CC SNX6; this leads to lysosomal degradation (By similarity). CC {ECO:0000250}. CC -!- TISSUE SPECIFICITY: Expressed in kidney (at protein level) CC (PubMed:15509543). Expressed in all tissues tested (PubMed:8033212). CC Highest levels in skeletal muscle, lowest in liver and kidney CC (PubMed:8033212). {ECO:0000269|PubMed:15509543, CC ECO:0000269|PubMed:8033212}. CC -!- INDUCTION: Maximal levels in quiescence cells and early G(1). Levels CC decrease after mitogen stimulation as cells progress toward S-phase. CC {ECO:0000269|PubMed:17254966}. CC -!- DOMAIN: A peptide sequence containing only AA 28-79 retains substantial CC Kip1 cyclin A/CDK2 inhibitory activity. CC -!- PTM: Phosphorylated; phosphorylation occurs on serine, threonine and CC tyrosine residues. Phosphorylation on Ser-10 is the major site of CC phosphorylation in resting cells, takes place at the G(0)-G(1) phase CC and leads to protein stability. Phosphorylation on other sites is CC greatly enhanced by mitogens, growth factors, cMYC and in certain CC cancer cell lines. The phosphorylated form found in the cytoplasm is CC inactivate. Phosphorylation on Thr-198 is required for interaction with CC 14-3-3 proteins. Phosphorylation on Thr-187, by CDK1 and CDK2 leads to CC protein ubiquitination and proteasomal degradation. Tyrosine CC phosphorylation promotes this process. Phosphorylation by PKB/AKT1 can CC be suppressed by LY294002, an inhibitor of the catalytic subunit of CC PI3K. Phosphorylation on Tyr-88 and Tyr-89 has no effect on binding CC CDK2, but is required for binding CDK4. Dephosphorylated on tyrosine CC residues by G-CSF. {ECO:0000269|PubMed:10323868, CC ECO:0000269|PubMed:10831586, ECO:0000269|PubMed:12042314, CC ECO:0000269|PubMed:12093740, ECO:0000269|PubMed:14504289, CC ECO:0000269|PubMed:15280662, ECO:0000269|PubMed:16195327, CC ECO:0000269|PubMed:16209941, ECO:0000269|PubMed:17254966, CC ECO:0000269|PubMed:17254967, ECO:0000269|PubMed:18593906, CC ECO:0000269|PubMed:21423214, ECO:0000269|PubMed:23478441, CC ECO:0000269|PubMed:23707388}. CC -!- PTM: Ubiquitinated; in the cytoplasm by the KPC complex (composed of CC RNF123/KPC1 and UBAC1/KPC2) and, in the nucleus, by SCF(SKP2). The CC latter requires prior phosphorylation on Thr-187. Ubiquitinated; by a CC TRIM21-containing SCF(SKP2)-like complex; leads to its degradation. CC {ECO:0000269|PubMed:10323868, ECO:0000269|PubMed:12042314, CC ECO:0000269|PubMed:16209941, 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]: Multiple CC endocrine neoplasia (MEN) syndromes are inherited cancer syndromes of CC the thyroid. MEN4 is a MEN-like syndrome with a phenotypic overlap of CC both MEN1 and MEN2. {ECO:0000269|PubMed:17030811}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Decreased levels of p27Kip1, mainly due to proteasomal CC degradation, are found in various epithelial tumors originating from CC lung, breast, colon, ovary, esophagus, thyroid and prostate. CC -!- SIMILARITY: Belongs to the CDI family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/116/CDKN1B"; 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 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 PDB; 5UQ3; X-ray; 3.60 A; C=1-198. DR PDB; 6ATH; X-ray; 1.82 A; C=22-85. DR PDB; 6P8E; X-ray; 2.30 A; C=25-93. DR PDB; 6P8F; X-ray; 2.89 A; C=25-106. DR PDB; 6P8G; X-ray; 2.80 A; C=25-93. DR PDB; 7B5L; EM; 3.80 A; P=1-198. DR PDB; 7B5M; EM; 3.91 A; P=1-198. DR PDB; 7B5R; EM; 3.80 A; P=1-198. DR PDB; 7OR8; X-ray; 1.80 A; P=187-198. DR PDB; 7ORG; X-ray; 1.80 A; P=187-198. DR PDB; 7ORH; X-ray; 1.80 A; P=187-198. DR PDB; 7ORS; X-ray; 1.80 A; P=187-198. DR PDB; 7ORT; X-ray; 2.33 A; P=187-198. DR PDB; 8BYA; EM; 3.38 A; C=1-158, G=181-190. DR PDB; 8BYL; EM; 3.50 A; D=1-198. DR PDBsum; 1H27; -. DR PDBsum; 1JSU; -. DR PDBsum; 2AST; -. DR PDBsum; 5UQ3; -. DR PDBsum; 6ATH; -. DR PDBsum; 6P8E; -. DR PDBsum; 6P8F; -. DR PDBsum; 6P8G; -. DR PDBsum; 7B5L; -. DR PDBsum; 7B5M; -. DR PDBsum; 7B5R; -. DR PDBsum; 7OR8; -. DR PDBsum; 7ORG; -. DR PDBsum; 7ORH; -. DR PDBsum; 7ORS; -. DR PDBsum; 7ORT; -. DR PDBsum; 8BYA; -. DR PDBsum; 8BYL; -. DR AlphaFoldDB; P46527; -. DR BMRB; P46527; -. DR EMDB; EMD-12037; -. DR EMDB; EMD-12040; -. DR EMDB; EMD-12048; -. DR EMDB; EMD-16327; -. DR SMR; P46527; -. DR BioGRID; 107461; 135. DR CORUM; P46527; -. DR DIP; DIP-33341N; -. DR IntAct; P46527; 83. DR MINT; P46527; -. DR STRING; 9606.ENSP00000228872; -. DR ChEMBL; CHEMBL3758070; -. DR MoonDB; P46527; Predicted. DR GlyGen; P46527; 5 sites, 1 O-linked glycan (5 sites). DR iPTMnet; P46527; -. DR PhosphoSitePlus; P46527; -. DR BioMuta; CDKN1B; -. DR CPTAC; CPTAC-1237; -. DR CPTAC; CPTAC-1238; -. DR EPD; P46527; -. DR jPOST; P46527; -. DR MassIVE; P46527; -. DR PaxDb; 9606-ENSP00000228872; -. DR PeptideAtlas; P46527; -. DR ProteomicsDB; 55741; -. DR Pumba; P46527; -. DR TopDownProteomics; P46527; -. DR Antibodypedia; 3295; 3048 antibodies from 48 providers. DR DNASU; 1027; -. DR Ensembl; ENST00000228872.9; ENSP00000228872.4; ENSG00000111276.12. DR Ensembl; ENST00000614874.2; ENSP00000507272.1; ENSG00000111276.12. DR GeneID; 1027; -. DR KEGG; hsa:1027; -. DR MANE-Select; ENST00000228872.9; ENSP00000228872.4; NM_004064.5; NP_004055.1. DR AGR; HGNC:1785; -. DR CTD; 1027; -. DR DisGeNET; 1027; -. DR GeneCards; CDKN1B; -. DR GeneReviews; CDKN1B; -. DR HGNC; HGNC:1785; CDKN1B. DR HPA; ENSG00000111276; Low tissue specificity. DR MalaCards; CDKN1B; -. DR MIM; 600778; gene. DR MIM; 610755; phenotype. DR neXtProt; NX_P46527; -. DR OpenTargets; ENSG00000111276; -. DR Orphanet; 652; Multiple endocrine neoplasia type 1. DR Orphanet; 276152; Multiple endocrine neoplasia type 4. DR PharmGKB; PA105; -. DR VEuPathDB; HostDB:ENSG00000111276; -. DR eggNOG; KOG4743; Eukaryota. DR GeneTree; ENSGT00940000159852; -. DR HOGENOM; CLU_077692_2_0_1; -. DR InParanoid; P46527; -. DR OMA; THLRDQK; -. DR OrthoDB; 4144394at2759; -. DR PhylomeDB; P46527; -. DR TreeFam; TF101038; -. DR PathwayCommons; P46527; -. DR Reactome; R-HSA-187577; SCF(Skp2)-mediated degradation of p27/p21. DR Reactome; R-HSA-198323; AKT phosphorylates targets in the cytosol. DR Reactome; R-HSA-2559582; Senescence-Associated Secretory Phenotype (SASP). DR Reactome; R-HSA-2559586; DNA Damage/Telomere Stress Induced Senescence. DR Reactome; R-HSA-5625900; RHO GTPases activate CIT. DR Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer. DR Reactome; R-HSA-6804116; TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest. DR Reactome; R-HSA-69202; Cyclin E associated events during G1/S transition. DR Reactome; R-HSA-69231; Cyclin D associated events in G1. DR Reactome; R-HSA-69563; p53-Dependent G1 DNA Damage Response. DR Reactome; R-HSA-69656; Cyclin A:Cdk2-associated events at S phase entry. DR Reactome; R-HSA-8849470; PTK6 Regulates Cell Cycle. DR Reactome; R-HSA-9607240; FLT3 Signaling. DR Reactome; R-HSA-9617828; FOXO-mediated transcription of cell cycle genes. DR Reactome; R-HSA-9634638; Estrogen-dependent nuclear events downstream of ESR-membrane signaling. DR Reactome; R-HSA-9661069; Defective binding of RB1 mutants to E2F1,(E2F2, E2F3). DR SignaLink; P46527; -. DR SIGNOR; P46527; -. DR BioGRID-ORCS; 1027; 28 hits in 1176 CRISPR screens. DR ChiTaRS; CDKN1B; human. DR EvolutionaryTrace; P46527; -. DR GeneWiki; CDKN1B; -. DR GenomeRNAi; 1027; -. DR Pharos; P46527; Tbio. DR PRO; PR:P46527; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; P46527; Protein. DR Bgee; ENSG00000111276; Expressed in pigmented layer of retina and 215 other cell types or tissues. DR ExpressionAtlas; P46527; baseline and differential. DR GO; GO:0031464; C:Cul4A-RING E3 ubiquitin ligase complex; IDA:MGI. DR GO; GO:0005737; C:cytoplasm; IDA:HGNC-UCL. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005768; C:endosome; IEA:UniProtKB-SubCell. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL. DR GO; GO:0030332; F:cyclin binding; IPI:CAFA. DR GO; GO:0019914; F:cyclin-dependent protein kinase activating kinase regulator activity; EXP:DisProt. DR GO; GO:0004861; F:cyclin-dependent protein serine/threonine kinase inhibitor activity; IDA:UniProtKB. DR GO; GO:0030544; F:Hsp70 protein binding; IEA:Ensembl. DR GO; GO:0060090; F:molecular adaptor activity; EXP:DisProt. DR GO; GO:0140678; F:molecular function inhibitor activity; IMP:DisProt. DR GO; GO:0019901; F:protein kinase binding; IPI:CAFA. DR GO; GO:0004860; F:protein kinase inhibitor activity; IMP:CAFA. DR GO; GO:0019903; F:protein phosphatase binding; IPI:BHF-UCL. DR GO; GO:0044877; F:protein-containing complex binding; IPI:CAFA. DR GO; GO:0051087; F:protein-folding chaperone binding; IBA:GO_Central. DR GO; GO:1990757; F:ubiquitin ligase activator activity; EXP:DisProt. DR GO; GO:0031625; F:ubiquitin protein ligase binding; EXP:DisProt. DR GO; GO:0048102; P:autophagic cell death; IDA:BHF-UCL. DR GO; GO:0071236; P:cellular response to antibiotic; IEA:Ensembl. DR GO; GO:0071456; P:cellular response to hypoxia; 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:0090398; P:cellular senescence; TAS:Reactome. DR GO; GO:0006977; P:DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; TAS:Reactome. DR GO; GO:1904019; P:epithelial cell apoptotic process; IEA:Ensembl. DR GO; GO:0060767; P:epithelial cell proliferation involved in prostate gland development; IEA:Ensembl. DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IBA:GO_Central. DR GO; GO:0007507; P:heart development; ISS:BHF-UCL. DR GO; GO:0048839; P:inner ear development; IEA:Ensembl. DR GO; GO:0051179; P:localization; IDA:DisProt. DR GO; GO:1905179; P:negative regulation of cardiac muscle tissue regeneration; ISS:BHF-UCL. DR GO; GO:0030308; P:negative regulation of cell growth; IDA:BHF-UCL. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:BHF-UCL. DR GO; GO:1904030; P:negative regulation of cyclin-dependent protein kinase activity; IMP:CAFA. DR GO; GO:0045736; P:negative regulation of cyclin-dependent protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:1904036; P:negative regulation of epithelial cell apoptotic process; 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; IBA:GO_Central. DR GO; GO:0042326; P:negative regulation of phosphorylation; IDA:BHF-UCL. DR GO; GO:1904706; P:negative regulation of vascular associated smooth muscle cell proliferation; IMP:BHF-UCL. DR GO; GO:0007219; P:Notch signaling pathway; IEA:Ensembl. DR GO; GO:0051168; P:nuclear export; IMP:DisProt. DR GO; GO:0001890; P:placenta development; IEA:Ensembl. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IEA:Ensembl. DR GO; GO:0045740; P:positive regulation of DNA replication; TAS:Reactome. 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:0001934; P:positive regulation of protein phosphorylation; IEA:Ensembl. DR GO; GO:0006813; P:potassium ion transport; IEA:Ensembl. DR GO; GO:0051726; P:regulation of cell cycle; IMP:HGNC-UCL. DR GO; GO:1902806; P:regulation of cell cycle G1/S phase transition; IMP:GO_Central. DR GO; GO:0030334; P:regulation of cell migration; IEA:Ensembl. DR GO; GO:0000079; P:regulation of cyclin-dependent protein serine/threonine kinase activity; IDA:GO_Central. DR GO; GO:0007096; P:regulation of exit from mitosis; IEA:Ensembl. DR GO; GO:2000045; P:regulation of G1/S transition of mitotic cell cycle; IDA:BHF-UCL. DR GO; GO:1902746; P:regulation of lens fiber cell differentiation; IEA:Ensembl. 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:0032355; P:response to estradiol; IEA:Ensembl. DR GO; GO:0009749; P:response to glucose; IEA:Ensembl. DR GO; GO:0043434; P:response to peptide hormone; IEA:Ensembl. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0007605; P:sensory perception of sound; IEA:Ensembl. DR DisProt; DP00018; -. DR Gene3D; 4.10.365.10; p27; 1. DR IDEAL; IID00049; -. DR InterPro; IPR003175; CDI_dom. DR InterPro; IPR044898; CDI_dom_sf. DR PANTHER; PTHR10265; CYCLIN-DEPENDENT KINASE INHIBITOR 1; 1. DR PANTHER; PTHR10265:SF9; CYCLIN-DEPENDENT KINASE INHIBITOR 1B; 1. DR Pfam; PF02234; CDI; 1. DR SWISS-2DPAGE; P46527; -. DR Genevisible; P46527; HS. PE 1: Evidence at protein level; KW 3D-structure; Cell cycle; Cytoplasm; Direct protein sequencing; Endosome; KW Nucleus; Phosphoprotein; Protein kinase inhibitor; Reference proteome; KW Tumor suppressor; Ubl conjugation. FT CHAIN 1..198 FT /note="Cyclin-dependent kinase inhibitor 1B" FT /id="PRO_0000190084" FT REGION 1..34 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 51..91 FT /note="Interaction with CDK2" FT /evidence="ECO:0000269|PubMed:28666995" FT REGION 85..198 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 153..169 FT /note="Nuclear localization signal" FT /evidence="ECO:0000255" FT COMPBIAS 158..172 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 10 FT /note="Phosphoserine; by UHMK1" FT /evidence="ECO:0000269|PubMed:10831586, FT ECO:0000269|PubMed:12042314, ECO:0000269|PubMed:12093740, FT ECO:0000269|PubMed:14504289, ECO:0007744|PubMed:23186163" FT MOD_RES 74 FT /note="Phosphotyrosine; by SRC" FT /evidence="ECO:0000269|PubMed:17254967" FT MOD_RES 88 FT /note="Phosphotyrosine; by ABL, LYN, SRC and JAK2" FT /evidence="ECO:0000269|PubMed:16195327, FT ECO:0000269|PubMed:17254966, ECO:0000269|PubMed:17254967, FT ECO:0000269|PubMed:21423214" FT MOD_RES 89 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:16195327" FT MOD_RES 157 FT /note="Phosphothreonine; by CaMK1, PKB/AKT1 and PIM1" FT /evidence="ECO:0000269|PubMed:12244301, FT ECO:0000269|PubMed:12244303, ECO:0000269|PubMed:18593906, FT ECO:0000269|PubMed:23707388" FT MOD_RES 170 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P46414" FT MOD_RES 187 FT /note="Phosphothreonine; by PKB/AKT1, CDK1 and CDK2" FT /evidence="ECO:0000269|PubMed:10323868, FT ECO:0000269|PubMed:12042314, ECO:0000269|PubMed:16209941, FT ECO:0000269|PubMed:23478441" FT MOD_RES 198 FT /note="Phosphothreonine; by CaMK1, PKB/AKT1, RPS6KA1, FT RPS6KA3 and PIM1" FT /evidence="ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:14504289, ECO:0000269|PubMed:15280662, FT ECO:0000269|PubMed:18593906, ECO:0000269|PubMed:23707388" FT VARIANT 15 FT /note="R -> W (in dbSNP:rs2066828)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_011871" FT VARIANT 69 FT /note="P -> L (found in a patient with multiple endocrine FT tumors; germline mutation; reduced expression levels; shows FT impaired binding to CDK2; dbSNP:rs777354267)" FT /evidence="ECO:0000269|PubMed:20824794" FT /id="VAR_064429" FT VARIANT 109 FT /note="V -> G (in dbSNP:rs2066827)" FT /evidence="ECO:0000269|PubMed:15489334, ECO:0000269|Ref.3, FT ECO:0000269|Ref.4" FT /id="VAR_011872" FT MUTAGEN 10 FT /note="S->A: Loss of phosphorylation by UHMK1. No FT translocation to the cytoplasm. Greater cell cycle arrest." FT /evidence="ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:12093740, ECO:0000269|PubMed:15280662" FT MUTAGEN 10 FT /note="S->D: Exported to the cytoplasm. Inhibits cell cycle FT arrest." FT /evidence="ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:12093740, ECO:0000269|PubMed:15280662" FT MUTAGEN 10 FT /note="S->E: Increased stability in vivo and in vitro." FT /evidence="ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:12093740, ECO:0000269|PubMed:15280662" FT MUTAGEN 74 FT /note="Y->F: No change in binding CDK4 and no inhibition of FT CDK4 activity. Translocates to nucleus. No effect on in FT vitro phosphorylation of CDK4 by CCNH-CDK7." FT /evidence="ECO:0000269|PubMed:16195327, FT ECO:0000269|PubMed:19075005" FT MUTAGEN 88 FT /note="Y->F: Abolishes LYN-mediated phosphorylation, FT reduces CDK2-mediated phosphorylation on T-187, has greater FT cell cycle arrest into S-phase, no effect on binding CDK2 FT complexes, reduced CDK4 binding and inhibits CDK4 enzyme FT activity. No nuclear translocation. No effect on in vitro FT phosphorylation of CDK4 by CCNH-CDK7. Completely abolishes FT CDK4 binding; when associated with F-89." FT /evidence="ECO:0000269|PubMed:16195327, FT ECO:0000269|PubMed:17254966, ECO:0000269|PubMed:19075005" FT MUTAGEN 89 FT /note="Y->F: No effect on binding CDK2 complexes, reduced FT CDK4 binding and greatly inhibits CDK4 enzyme activity. No FT nuclear translocation. Inhibits in vitro phosphorylation of FT CDK4 by CCNH-CDK7. Completely abolishes CDK4 binding; when FT associated with F-88." FT /evidence="ECO:0000269|PubMed:16195327, FT ECO:0000269|PubMed:17254966, ECO:0000269|PubMed:19075005" FT MUTAGEN 157 FT /note="T->A: Greatly reduced PKB/AKT1-mediated FT phosphorylation. Nuclear location. Inhibits cyclin E/CDK2 FT cell cycle progression. No effect on binding AKT1. FT Completely abolishes PKB/AKT1-mediated phosphorylation and FT no cytoplasmic translocation; when associated with A-198." FT /evidence="ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:12244301, ECO:0000269|PubMed:12244303, FT ECO:0000269|PubMed:14504289, ECO:0000269|PubMed:15280662" FT MUTAGEN 161 FT /note="S->A: No change in PKB/AKT1-mediated FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12244301" FT MUTAGEN 162 FT /note="T->A: No change in PKB/AKT1-mediated FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12244301" FT MUTAGEN 185 FT /note="E->A,D,Q: Strongly reduced ubiquitination by a FT TRIM21-containing SCF(SKP2) complex." FT /evidence="ECO:0000269|PubMed:16209941" FT MUTAGEN 187 FT /note="T->A,D: No change in PKB/AKT1- nor UHMK1-mediated FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:12093740, ECO:0000269|PubMed:15280662, FT ECO:0000269|PubMed:16209941, ECO:0000269|PubMed:16880511" FT MUTAGEN 187 FT /note="T->A: Abolishes phosphorylation-dependent FT ubiquitination." FT /evidence="ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:12093740, ECO:0000269|PubMed:15280662, FT ECO:0000269|PubMed:16209941, ECO:0000269|PubMed:16880511" FT MUTAGEN 198 FT /note="T->A,D: Abolishes PKB/AKT1-mediated phosphorylation. FT 46% cytoplasmic location. Greatly reduced binding to YWHAQ. FT Equally reduced binding; when associated with A-10 and FT A-187. No nuclear import; when associated with A-157. FT Completely abolishes PKB/AKT1-mediated phosphorylation and FT no cytoplasmic translocation; when associated with A-157." FT /evidence="ECO:0000269|PubMed:12042314, FT ECO:0000269|PubMed:14504289, ECO:0000269|PubMed:15280662" FT CONFLICT 22 FT /note="E -> D (in Ref. 2; AAD14244)" FT /evidence="ECO:0000305" FT HELIX 38..47 FT /evidence="ECO:0007829|PDB:6ATH" FT TURN 50..53 FT /evidence="ECO:0007829|PDB:1JSU" FT HELIX 55..60 FT /evidence="ECO:0007829|PDB:6ATH" FT TURN 64..67 FT /evidence="ECO:0007829|PDB:6ATH" FT STRAND 71..78 FT /evidence="ECO:0007829|PDB:6ATH" FT HELIX 86..89 FT /evidence="ECO:0007829|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 //