ID CDK4_HUMAN Reviewed; 303 AA. AC P11802; B2R9A0; B4DNF9; O00576; Q6FG61; DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1995, sequence version 2. DT 27-MAR-2024, entry version 257. DE RecName: Full=Cyclin-dependent kinase 4; DE EC=2.7.11.22; DE AltName: Full=Cell division protein kinase 4; DE AltName: Full=PSK-J3; GN Name=CDK4; 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] (ISOFORM 1). RA Hanks S.K.; RL Submitted (FEB-1987) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=9192850; DOI=10.1006/geno.1997.4727; RA Elkahloun A.G., Krizman D.B., Wang Z., Hofmann T.A., Roe B.A., RA Meltzer P.S.; RT "Transcript mapping in a 46-kb sequenced region at the core of 12q13.3 RT amplification in human cancers."; RL Genomics 42:295-301(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT CMM3 CYS-24, AND RP CHARACTERIZATION OF VARIANT CYS-24. RX PubMed=7652577; DOI=10.1126/science.7652577; RA Wolfel T., Hauer M., Schneider J., Serrano M., Wolfel C., Klehmann-Hieb E., RA De Plaen E., Hankeln T., Meyer Zum Bueschenfelde K.-H., Beach D.; RT "A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in RT a human melanoma."; RL Science 269:1281-1284(1995). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT CMM3 CYS-24, AND RP CHARACTERIZATION OF VARIANT CYS-24. RX PubMed=8528263; DOI=10.1038/ng0196-97; RA Zuo L., Weger J., Yang Q., Goldstein A.M., Tucker M.A., Walker G.J., RA Hayward N., Dracopoli N.C.; RT "Germline mutations in the p16INK4a binding domain of CDK4 in familial RT melanoma."; RL Nat. Genet. 12:97-99(1996). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLN-82. RG NIEHS SNPs program; RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Embryo; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16541075; DOI=10.1038/nature04569; RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., RA Gibbs R.A.; RT "The finished DNA sequence of human chromosome 12."; RL Nature 440:346-351(2006). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Muscle; 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 [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 88-188 (ISOFORM 1). RX PubMed=2948189; DOI=10.1073/pnas.84.2.388; RA Hanks S.K.; RT "Homology probing: identification of cDNA clones encoding members of the RT protein-serine kinase family."; RL Proc. Natl. Acad. Sci. U.S.A. 84:388-392(1987). RN [12] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 95-182. RX PubMed=8221695; RA Khatib Z.A., Matsushime H., Valentine M., Shapiro D.N., Sherr C.J., RA Look A.T.; RT "Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas."; RL Cancer Res. 53:5535-5541(1993). RN [13] RP FUNCTION. RX PubMed=9003781; DOI=10.1002/j.1460-2075.1996.tb01097.x; RA Kitagawa M., Higashi H., Jung H.K., Suzuki-Takahashi I., Ikeda M., RA Tamai K., Kato J., Segawa K., Yoshida E., Nishimura S., Taya Y.; RT "The consensus motif for phosphorylation by cyclin D1-Cdk4 is different RT from that for phosphorylation by cyclin A/E-Cdk2."; RL EMBO J. 15:7060-7069(1996). RN [14] RP INTERACTION WITH CDKN1A; CCND1 AND CCND3, SUBCELLULAR LOCATION, AND RP CATALYTIC ACTIVITY. RX PubMed=9106657; DOI=10.1101/gad.11.7.847; RA LaBaer J., Garrett M.D., Stevenson L.F., Slingerland J.M., Sandhu C., RA Chou H.S., Fattaey A., Harlow E.; RT "New functional activities for the p21 family of CDK inhibitors."; RL Genes Dev. 11:847-862(1997). RN [15] RP INTERACTION WITH SEI1. RX PubMed=10580009; DOI=10.1101/gad.13.22.3027; RA Sugimoto M., Nakamura T., Ohtani N., Hampson L., Hampson I.N., RA Shimamoto A., Furuichi Y., Okumura K., Niwa S., Taya Y., Hara E.; RT "Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1)."; RL Genes Dev. 13:3027-3033(1999). RN [16] RP INTERACTION WITH CEBPA. RX PubMed=15107404; DOI=10.1101/gad.1183304; RA Wang G.L., Iakova P., Wilde M., Awad S., Timchenko N.A.; RT "Liver tumors escape negative control of proliferation via PI3K/Akt- RT mediated block of C/EBP alpha growth inhibitory activity."; RL Genes Dev. 18:912-925(2004). RN [17] RP FUNCTION. RX PubMed=15241418; DOI=10.1038/nature02650; RA Matsuura I., Denissova N.G., Wang G., He D., Long J., Liu F.; RT "Cyclin-dependent kinases regulate the antiproliferative function of RT Smads."; RL Nature 430:226-231(2004). RN [18] RP INTERACTION WITH ZNF655. RX PubMed=15558030; DOI=10.1038/sj.onc.1208043; RA Houlard M., Romero-Portillo F., Germani A., Depaux A., Regnier-Ricard F., RA Gisselbrecht S., Varin-Blank N.; RT "Characterization of VIK-1: a new Vav-interacting Kruppel-like protein."; RL Oncogene 24:28-38(2005). RN [19] RP PHOSPHORYLATION AT THR-172, INTERACTION WITH CCND1; CCND3; CDKN2A AND RP CDKN1B, AND MUTAGENESIS OF THR-172. 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 [20] RP SUBCELLULAR LOCATION, FUNCTION, AND INTERACTION WITH CCND2. RX PubMed=18827403; DOI=10.1247/csf.08019; RA Wang Z., Xie Y., Zhang L., Zhang H., An X., Wang T., Meng A.; RT "Migratory localization of cyclin D2-Cdk4 complex suggests a spatial RT regulation of the G1-S transition."; RL Cell Struct. Funct. 33:171-183(2008). RN [21] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [22] RP INTERACTION WITH CCND1. RX PubMed=19124461; DOI=10.1074/jbc.m808843200; RA Zhang T., Liu W.D., Saunee N.A., Breslin M.B., Lan M.S.; RT "Zinc finger transcription factor INSM1 interrupts cyclin D1 and CDK4 RT binding and induces cell cycle arrest."; RL J. Biol. Chem. 284:5574-5581(2009). RN [23] RP INTERACTION WITH CDKN1B, PHOSPHORYLATION, AND CATALYTIC ACTIVITY. 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 [24] RP PHOSPHORYLATION AT THR-172, ACTIVITY REGULATION, AND MUTAGENESIS OF RP PRO-173. RX PubMed=19487459; DOI=10.1128/mcb.01823-08; RA Bockstaele L., Bisteau X., Paternot S., Roger P.P.; RT "Differential regulation of cyclin-dependent kinase 4 (CDK4) and CDK6, RT evidence that CDK4 might not be activated by CDK7, and design of a CDK6 RT activating mutation."; RL Mol. Cell. Biol. 29:4188-4200(2009). RN [25] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-172, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [26] RP SUBCELLULAR LOCATION, AND INTERACTION WITH CCND1. RX PubMed=20399237; DOI=10.1016/j.bbamcr.2010.04.001; RA Kim H., Kang M., Lee S.A., Kwak T.K., Jung O., Lee H.J., Kim S.H., RA Lee J.W.; RT "TM4SF5 accelerates G1/S phase progression via cytosolic p27Kip1 expression RT and RhoA activity."; RL Biochim. Biophys. Acta 1803:975-982(2010). RN [27] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [28] RP INTERACTION WITH FNIP1 AND FNIP2. RX PubMed=27353360; DOI=10.1038/ncomms12037; RA Woodford M.R., Dunn D.M., Blanden A.R., Capriotti D., Loiselle D., RA Prodromou C., Panaretou B., Hughes P.F., Smith A., Ackerman W., RA Haystead T.A., Loh S.N., Bourboulia D., Schmidt L.S., Marston Linehan W., RA Bratslavsky G., Mollapour M.; RT "The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance RT drug binding."; RL Nat. Commun. 7:12037-12037(2016). RN [29] RP IDENTIFICATION IN A COMPLEX WITH HSP90; HSP70; CDC37; PPP5C; TSC1; TSC2; RP AKT; RAF1 AND NR3C1. RX PubMed=29127155; DOI=10.15252/embj.201796700; RA Woodford M.R., Sager R.A., Marris E., Dunn D.M., Blanden A.R., Murphy R.L., RA Rensing N., Shapiro O., Panaretou B., Prodromou C., Loh S.N., Gutmann D.H., RA Bourboulia D., Bratslavsky G., Wong M., Mollapour M.; RT "Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding RT of kinase and non-kinase clients."; RL EMBO J. 36:3650-3665(2017). RN [30] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF THR-172-PHOSPHORYLATED WILD TYPE RP AND MUTANTS ALA-172; PHE-172 AND ASP-172 IN COMPLEX WITH CCND1, RP IDENTIFICATION BY MASS SPECTROMETRY, PHOSPHORYLATION AT THR-172, AND RP CATALYTIC ACTIVITY. RX PubMed=19237565; DOI=10.1073/pnas.0809645106; RA Day P.J., Cleasby A., Tickle I.J., O'Reilly M., Coyle J.E., Holding F.P., RA McMenamin R.L., Yon J., Chopra R., Lengauer C., Jhoti H.; RT "Crystal structure of human CDK4 in complex with a D-type cyclin."; RL Proc. Natl. Acad. Sci. U.S.A. 106:4166-4170(2009). RN [31] RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF NONPHOSPHORYLATED FORM IN COMPLEX RP WITH CCND3, PHOSPHORYLATION AT THR-172, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RX PubMed=19237555; DOI=10.1073/pnas.0809674106; RA Takaki T., Echalier A., Brown N.R., Hunt T., Endicott J.A., Noble M.E.; RT "The structure of CDK4/cyclin D3 has implications for models of CDK RT activation."; RL Proc. Natl. Acad. Sci. U.S.A. 106:4171-4176(2009). RN [32] RP VARIANT CMM3 SER-41. RX PubMed=9311594; RX DOI=10.1002/(sici)1097-0215(19970904)72:5<780::aid-ijc13>3.0.co;2-d; RA Guldberg P., Kirkin A.F., Gronbaek K., thor Straten P., Ahrenkiel V., RA Zeuthen J.; RT "Complete scanning of the CDK4 gene by denaturing gradient gel RT electrophoresis: a novel missense mutation but low overall frequency of RT mutations in sporadic metastatic malignant melanoma."; RL Int. J. Cancer 72:780-783(1997). RN [33] RP VARIANT CMM3 HIS-24. RX PubMed=9425228; DOI=10.1093/hmg/7.2.209; RA Soufir N., Avril M.-F., Chompret A., Demenais F., Bombled J., Spatz A., RA Stoppa-Lyonnet D., Benard J., Bressac-De Paillerets B.; RT "Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone RT families in France."; RL Hum. Mol. Genet. 7:209-216(1998). RN [34] RP ERRATUM OF PUBMED:9425228. RA Soufir N., Avril M.-F., Chompret A., Demenais F., Bombled J., Spatz A., RA Stoppa-Lyonnet D., Benard J., Bressac-De Paillerets B.; RL Hum. Mol. Genet. 7:941-941(1998). RN [35] RP VARIANT [LARGE SCALE ANALYSIS] HIS-122. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). CC -!- FUNCTION: Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that CC phosphorylate and inhibit members of the retinoblastoma (RB) protein CC family including RB1 and regulate the cell-cycle during G(1)/S CC transition. Phosphorylation of RB1 allows dissociation of the CC transcription factor E2F from the RB/E2F complexes and the subsequent CC transcription of E2F target genes which are responsible for the CC progression through the G(1) phase. Hypophosphorylates RB1 in early CC G(1) phase. Cyclin D-CDK4 complexes are major integrators of various CC mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a CC cell-cycle-dependent manner and represses its transcriptional activity. CC Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for CC nuclear translocation and activity of the cyclin D-CDK4 complex. CC {ECO:0000269|PubMed:15241418, ECO:0000269|PubMed:18827403, CC ECO:0000269|PubMed:9003781}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.22; CC Evidence={ECO:0000269|PubMed:19075005, ECO:0000269|PubMed:19237565, CC ECO:0000269|PubMed:9106657}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.22; Evidence={ECO:0000269|PubMed:19075005, CC ECO:0000269|PubMed:19237565, ECO:0000269|PubMed:9106657}; CC -!- ACTIVITY REGULATION: Both phosphorylation at Thr-172 and binding of a CC D-type cyclin are necessary for enzymatic activity. Full activation of CC the cyclin-D-CDK4 complex appears to require other factors such as CC recruitment of the substrate via a substrate recruitment motif, and/or CC formation of the CDKN1B ternary complex. Inhibited by INK4 family CC members. In resting cells, the non-tyrosine-phosphorylated form of CC CDKN1B prevents phosphorylation at Thr-172 and inactivation, while, in CC proliferating cells, tyrosine phosphorylation of CDKN1B allows CC phosphorylation of Thr-172 of CDK4 and subsequent activation. CC {ECO:0000269|PubMed:19487459}. CC -!- SUBUNIT: Component of the D-CDK4 complex, composed of CDK4 and some D- CC type G1 cyclin (CCND1, CCND2 or CCND3). Interacts directly in the CC complex with CCND1, CCND2 or CCND3. Interacts with SEI1 and ZNF655. CC Forms a ternary complex, cyclin D-CDK4-CDKN1B, involved in modulating CC CDK4 enzymatic activity. Interacts directly with CDKN1B (phosphorylated CC on 'Tyr-88' and 'Tyr-89'); the interaction allows assembly of the CC cyclin D-CDK4 complex, Thr-172 phosphorylation, nuclear translocation CC and enhances the cyclin D-CDK4 complex activity. CDK4 activity is CC either inhibited or enhanced depending on stoichiometry of complex. The CC non-tyrosine-phosphorylated form of CDKN1B prevents T-loop CC phosphorylation of CDK4 producing inactive CDK4. Interacts CC (unphosphorylated form) with CDK2. Also forms ternary complexes with CC CDKN1A or CDKN2A. Interacts directly with CDKN1A (via its N-terminal); CC the interaction promotes the assembly of the cyclin D-CDK4 complex, its CC nuclear translocation and promotes the cyclin D-dependent enzyme CC activity of CDK4. Interacts with CCND1; the interaction is prevented CC with the binding of CCND1 to INSM1 during cell cycle progression. CC Probably forms a complex composed of chaperones HSP90 and HSP70, co- CC chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 CC and NR3C1; this complex does not contain co-chaperones STIP1/HOP and CC PTGES3/p23 (PubMed:29127155). Interacts with CEBPA (when CC phosphorylated) (PubMed:15107404). Interacts with FNIP1 and FNIP2 CC (PubMed:27353360). {ECO:0000250|UniProtKB:P30285, CC ECO:0000269|PubMed:10580009, ECO:0000269|PubMed:15107404, CC ECO:0000269|PubMed:15558030, ECO:0000269|PubMed:16782892, CC ECO:0000269|PubMed:18827403, ECO:0000269|PubMed:19075005, CC ECO:0000269|PubMed:19124461, ECO:0000269|PubMed:19237555, CC ECO:0000269|PubMed:19237565, ECO:0000269|PubMed:20399237, CC ECO:0000269|PubMed:27353360, ECO:0000269|PubMed:29127155, CC ECO:0000269|PubMed:9106657}. CC -!- INTERACTION: CC P11802; Q9UH17: APOBEC3B; NbExp=9; IntAct=EBI-295644, EBI-2967317; CC P11802; P24385: CCND1; NbExp=44; IntAct=EBI-295644, EBI-375001; CC P11802; P30279: CCND2; NbExp=15; IntAct=EBI-295644, EBI-748789; CC P11802; P30281: CCND3; NbExp=38; IntAct=EBI-295644, EBI-375013; CC P11802; Q16543: CDC37; NbExp=14; IntAct=EBI-295644, EBI-295634; CC P11802; P50613: CDK7; NbExp=2; IntAct=EBI-295644, EBI-1245958; CC P11802; P38936: CDKN1A; NbExp=8; IntAct=EBI-295644, EBI-375077; CC P11802; P46527: CDKN1B; NbExp=11; IntAct=EBI-295644, EBI-519280; CC P11802; P42771: CDKN2A; NbExp=16; IntAct=EBI-295644, EBI-375053; CC P11802; P42772: CDKN2B; NbExp=20; IntAct=EBI-295644, EBI-711280; CC P11802; P42773: CDKN2C; NbExp=23; IntAct=EBI-295644, EBI-711290; CC P11802; P55273: CDKN2D; NbExp=25; IntAct=EBI-295644, EBI-745859; CC P11802; Q9UJC3: HOOK1; NbExp=14; IntAct=EBI-295644, EBI-746704; CC P11802; P08238: HSP90AB1; NbExp=5; IntAct=EBI-295644, EBI-352572; CC P11802; Q9UKT9: IKZF3; NbExp=6; IntAct=EBI-295644, EBI-747204; CC P11802; Q0VD86: INCA1; NbExp=3; IntAct=EBI-295644, EBI-6509505; CC P11802; P01106: MYC; NbExp=2; IntAct=EBI-295644, EBI-447544; CC P11802; Q9ULD0: OGDHL; NbExp=3; IntAct=EBI-295644, EBI-3940481; CC P11802; P28749: RBL1; NbExp=2; IntAct=EBI-295644, EBI-971402; CC P11802; P09936: UCHL1; NbExp=4; IntAct=EBI-295644, EBI-714860; CC P11802; Q8N720: ZNF655; NbExp=6; IntAct=EBI-295644, EBI-625509; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:18827403}. Nucleus CC {ECO:0000269|PubMed:18827403, ECO:0000269|PubMed:20399237, CC ECO:0000269|PubMed:9106657}. Nucleus membrane CC {ECO:0000269|PubMed:18827403}. Note=Cytoplasmic when non-complexed. CC Forms a cyclin D-CDK4 complex in the cytoplasm as cells progress CC through G(1) phase. The complex accumulates on the nuclear membrane and CC enters the nucleus on transition from G(1) to S phase. Also present in CC nucleoli and heterochromatin lumps. Colocalizes with RB1 after release CC into the nucleus. {ECO:0000269|PubMed:18827403}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P11802-1; Sequence=Displayed; CC Name=2; CC IsoId=P11802-2; Sequence=VSP_056487; CC -!- PTM: Phosphorylation at Thr-172 is required for enzymatic activity. CC Phosphorylated, in vitro, at this site by CCNH-CDK7, but, in vivo, CC appears to be phosphorylated by a proline-directed kinase. In the CC cyclin D-CDK4-CDKN1B complex, this phosphorylation and consequent CDK4 CC enzyme activity, is dependent on the tyrosine phosphorylation state of CC CDKN1B. Thus, in proliferating cells, CDK4 within the complex is CC phosphorylated on Thr-172 in the T-loop. In resting cells, CC phosphorylation on Thr-172 is prevented by the non-tyrosine- CC phosphorylated form of CDKN1B. {ECO:0000269|PubMed:16782892, CC ECO:0000269|PubMed:19075005, ECO:0000269|PubMed:19237555, CC ECO:0000269|PubMed:19237565, ECO:0000269|PubMed:19487459}. CC -!- DISEASE: Melanoma, cutaneous malignant 3 (CMM3) [MIM:609048]: A CC malignant neoplasm of melanocytes, arising de novo or from a pre- CC existing benign nevus, which occurs most often in the skin but may also CC involve other sites. {ECO:0000269|PubMed:7652577, CC ECO:0000269|PubMed:8528263, ECO:0000269|PubMed:9311594, CC ECO:0000269|PubMed:9425228}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr CC protein kinase family. CDC2/CDKX subfamily. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/238/CDK4"; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/cdk4/"; 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; M14505; AAA35673.1; -; mRNA. DR EMBL; U81031; AAC39521.2; -; Genomic_DNA. DR EMBL; Z48970; CAA88834.1; -; mRNA. DR EMBL; U37022; AAC50506.1; -; Genomic_DNA. DR EMBL; AF507942; AAM23014.1; -; Genomic_DNA. DR EMBL; AK297901; BAG60221.1; -; mRNA. DR EMBL; AK313701; BAG36447.1; -; mRNA. DR EMBL; CR407668; CAG28596.1; -; mRNA. DR EMBL; CR542247; CAG47043.1; -; mRNA. DR EMBL; AC025165; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471054; EAW97058.1; -; Genomic_DNA. DR EMBL; BC003644; AAH03644.1; -; mRNA. DR EMBL; BC005864; AAH05864.1; -; mRNA. DR EMBL; BC010153; AAH10153.1; -; mRNA. DR EMBL; S67448; AAD13991.1; -; Genomic_DNA. DR CCDS; CCDS8953.1; -. [P11802-1] DR PIR; I52695; I52695. DR PIR; S52841; S52841. DR RefSeq; NP_000066.1; NM_000075.3. [P11802-1] DR PDB; 2W96; X-ray; 2.30 A; B=1-303. DR PDB; 2W99; X-ray; 2.80 A; B=1-303. DR PDB; 2W9F; X-ray; 2.85 A; B=1-303. DR PDB; 2W9Z; X-ray; 2.45 A; B=1-303. DR PDB; 3G33; X-ray; 3.00 A; A/C=1-303. DR PDB; 5FWK; EM; 3.90 A; K=1-303. DR PDB; 5FWL; EM; 9.00 A; K=1-303. DR PDB; 5FWM; EM; 8.00 A; K=1-303. DR PDB; 5FWP; EM; 7.20 A; K=1-303. DR PDB; 6P8E; X-ray; 2.30 A; B=2-303. DR PDB; 6P8F; X-ray; 2.89 A; B=2-303. DR PDB; 6P8G; X-ray; 2.80 A; B=2-303. DR PDB; 6P8H; X-ray; 3.19 A; B=2-303. DR PDB; 7SJ3; X-ray; 2.51 A; A=2-303. DR PDBsum; 2W96; -. DR PDBsum; 2W99; -. DR PDBsum; 2W9F; -. DR PDBsum; 2W9Z; -. DR PDBsum; 3G33; -. DR PDBsum; 5FWK; -. DR PDBsum; 5FWL; -. DR PDBsum; 5FWM; -. DR PDBsum; 5FWP; -. DR PDBsum; 6P8E; -. DR PDBsum; 6P8F; -. DR PDBsum; 6P8G; -. DR PDBsum; 6P8H; -. DR PDBsum; 7SJ3; -. DR AlphaFoldDB; P11802; -. DR EMDB; EMD-3337; -. DR EMDB; EMD-3338; -. DR EMDB; EMD-3339; -. DR EMDB; EMD-3340; -. DR EMDB; EMD-3341; -. DR EMDB; EMD-3342; -. DR EMDB; EMD-3343; -. DR EMDB; EMD-3344; -. DR SMR; P11802; -. DR BioGRID; 107454; 290. DR ComplexPortal; CPX-2010; Cyclin D1-CDK4 complex. DR ComplexPortal; CPX-2011; Cyclin D2-CDK4 complex. DR ComplexPortal; CPX-2012; Cyclin D3-CDK4 complex. DR CORUM; P11802; -. DR DIP; DIP-875N; -. DR ELM; P11802; -. DR IntAct; P11802; 130. DR MINT; P11802; -. DR STRING; 9606.ENSP00000257904; -. DR BindingDB; P11802; -. DR ChEMBL; CHEMBL331; -. DR DrugBank; DB12001; Abemaciclib. DR DrugBank; DB03496; Alvocidib. DR DrugBank; DB12010; Fostamatinib. DR DrugBank; DB09073; Palbociclib. DR DrugBank; DB02733; Purvalanol. DR DrugBank; DB11730; Ribociclib. DR DrugBank; DB15442; Trilaciclib. DR DrugCentral; P11802; -. DR GuidetoPHARMACOLOGY; 1976; -. DR GlyGen; P11802; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P11802; -. DR MetOSite; P11802; -. DR PhosphoSitePlus; P11802; -. DR SwissPalm; P11802; -. DR BioMuta; CDK4; -. DR DMDM; 1168867; -. DR CPTAC; CPTAC-3070; -. DR EPD; P11802; -. DR jPOST; P11802; -. DR MassIVE; P11802; -. DR MaxQB; P11802; -. DR PaxDb; 9606-ENSP00000257904; -. DR PeptideAtlas; P11802; -. DR ProteomicsDB; 4694; -. DR ProteomicsDB; 52805; -. [P11802-1] DR Pumba; P11802; -. DR ABCD; P11802; 1 sequenced antibody. DR Antibodypedia; 4190; 1247 antibodies from 47 providers. DR DNASU; 1019; -. DR Ensembl; ENST00000257904.11; ENSP00000257904.5; ENSG00000135446.17. [P11802-1] DR GeneID; 1019; -. DR KEGG; hsa:1019; -. DR MANE-Select; ENST00000257904.11; ENSP00000257904.5; NM_000075.4; NP_000066.1. DR UCSC; uc001spv.4; human. [P11802-1] DR AGR; HGNC:1773; -. DR CTD; 1019; -. DR DisGeNET; 1019; -. DR GeneCards; CDK4; -. DR HGNC; HGNC:1773; CDK4. DR HPA; ENSG00000135446; Low tissue specificity. DR MalaCards; CDK4; -. DR MIM; 123829; gene. DR MIM; 609048; phenotype. DR neXtProt; NX_P11802; -. DR OpenTargets; ENSG00000135446; -. DR Orphanet; 99970; Dedifferentiated liposarcoma. DR Orphanet; 618; Familial melanoma. DR Orphanet; 99971; Well-differentiated liposarcoma. DR PharmGKB; PA102; -. DR VEuPathDB; HostDB:ENSG00000135446; -. DR eggNOG; KOG0594; Eukaryota. DR GeneTree; ENSGT00940000154770; -. DR InParanoid; P11802; -. DR OMA; TPNESEW; -. DR OrthoDB; 244018at2759; -. DR PhylomeDB; P11802; -. DR TreeFam; TF101022; -. DR BRENDA; 2.7.11.22; 2681. DR PathwayCommons; P11802; -. DR Reactome; R-HSA-187577; SCF(Skp2)-mediated degradation of p27/p21. DR Reactome; R-HSA-2559580; Oxidative Stress Induced Senescence. DR Reactome; R-HSA-2559582; Senescence-Associated Secretory Phenotype (SASP). DR Reactome; R-HSA-2559585; Oncogene Induced Senescence. DR Reactome; R-HSA-3214858; RMTs methylate histone arginines. DR Reactome; R-HSA-381340; Transcriptional regulation of white adipocyte differentiation. DR Reactome; R-HSA-69231; Cyclin D associated events in G1. DR Reactome; R-HSA-75815; Ubiquitin-dependent degradation of Cyclin D. DR Reactome; R-HSA-8849470; PTK6 Regulates Cell Cycle. DR Reactome; R-HSA-8878166; Transcriptional regulation by RUNX2. DR Reactome; R-HSA-912446; Meiotic recombination. DR Reactome; R-HSA-9616222; Transcriptional regulation of granulopoiesis. DR Reactome; R-HSA-9630791; Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4. DR Reactome; R-HSA-9630794; Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6. DR Reactome; R-HSA-9632697; Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4. DR Reactome; R-HSA-9632700; Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6. DR Reactome; R-HSA-9661069; Defective binding of RB1 mutants to E2F1,(E2F2, E2F3). DR Reactome; R-HSA-9754119; Drug-mediated inhibition of CDK4/CDK6 activity. DR SignaLink; P11802; -. DR SIGNOR; P11802; -. DR BioGRID-ORCS; 1019; 299 hits in 1210 CRISPR screens. DR ChiTaRS; CDK4; human. DR EvolutionaryTrace; P11802; -. DR GeneWiki; Cyclin-dependent_kinase_4; -. DR GenomeRNAi; 1019; -. DR Pharos; P11802; Tclin. DR PRO; PR:P11802; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; P11802; Protein. DR Bgee; ENSG00000135446; Expressed in ganglionic eminence and 101 other cell types or tissues. DR ExpressionAtlas; P11802; baseline and differential. DR GO; GO:0005923; C:bicellular tight junction; IEA:Ensembl. DR GO; GO:0000785; C:chromatin; IDA:UniProtKB. DR GO; GO:0097128; C:cyclin D1-CDK4 complex; IPI:ComplexPortal. DR GO; GO:0097129; C:cyclin D2-CDK4 complex; IPI:ComplexPortal. DR GO; GO:0097130; C:cyclin D3-CDK4 complex; IPI:ComplexPortal. DR GO; GO:0000307; C:cyclin-dependent protein kinase holoenzyme complex; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0031965; C:nuclear membrane; IDA:HPA. DR GO; GO:0005730; C:nucleolus; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005667; C:transcription regulator complex; IEA:Ensembl. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0030332; F:cyclin binding; IPI:UniProtKB. DR GO; GO:0004693; F:cyclin-dependent protein serine/threonine kinase activity; IDA:BHF-UCL. DR GO; GO:0016538; F:cyclin-dependent protein serine/threonine kinase regulator activity; TAS:Reactome. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW. DR GO; GO:0071353; P:cellular response to interleukin-4; IEA:Ensembl. DR GO; GO:1904637; P:cellular response to ionomycin; IEA:Ensembl. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl. DR GO; GO:1904628; P:cellular response to phorbol 13-acetate 12-myristate; IEA:Ensembl. DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IDA:UniProt. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:BHF-UCL. DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IMP:BHF-UCL. DR GO; GO:0010971; P:positive regulation of G2/M transition of mitotic cell cycle; IDA:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IDA:BHF-UCL. DR GO; GO:0051726; P:regulation of cell cycle; IDA:UniProtKB. DR GO; GO:0010389; P:regulation of G2/M transition of mitotic cell cycle; IBA:GO_Central. DR GO; GO:0010468; P:regulation of gene expression; IMP:BHF-UCL. DR GO; GO:0060260; P:regulation of transcription initiation by RNA polymerase II; TAS:Reactome. DR GO; GO:0061469; P:regulation of type B pancreatic cell proliferation; IEA:Ensembl. DR GO; GO:0010033; P:response to organic substance; IBA:GO_Central. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:UniProtKB. DR GO; GO:0007165; P:signal transduction; IBA:GO_Central. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR24056; CELL DIVISION PROTEIN KINASE; 1. DR PANTHER; PTHR24056:SF129; CYCLIN-DEPENDENT KINASE 4; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; P11802; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; ATP-binding; Cell cycle; KW Cell division; Cytoplasm; Disease variant; Kinase; Membrane; KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome; KW Serine/threonine-protein kinase; Transferase. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:19413330" FT CHAIN 2..303 FT /note="Cyclin-dependent kinase 4" FT /id="PRO_0000085778" FT DOMAIN 6..295 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 50..56 FT /note="Required for binding D-type cyclins" FT ACT_SITE 140 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 12..20 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 35 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:19413330" FT MOD_RES 172 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:16782892, FT ECO:0000269|PubMed:19237555, ECO:0000269|PubMed:19237565, FT ECO:0000269|PubMed:19487459, ECO:0007744|PubMed:19369195" FT VAR_SEQ 1..120 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_056487" FT VARIANT 24 FT /note="R -> C (in CMM3; somatic and familial; generates a FT dominant oncogene resistant to inhibition by p16(INK4a); FT dbSNP:rs11547328)" FT /evidence="ECO:0000269|PubMed:7652577, FT ECO:0000269|PubMed:8528263" FT /id="VAR_006200" FT VARIANT 24 FT /note="R -> H (in CMM3; dbSNP:rs104894340)" FT /evidence="ECO:0000269|PubMed:9425228" FT /id="VAR_006201" FT VARIANT 41 FT /note="N -> S (in CMM3; sporadic; dbSNP:rs144890720)" FT /evidence="ECO:0000269|PubMed:9311594" FT /id="VAR_021152" FT VARIANT 82 FT /note="R -> Q (in dbSNP:rs3211612)" FT /evidence="ECO:0000269|Ref.5" FT /id="VAR_029153" FT VARIANT 122 FT /note="R -> H (in dbSNP:rs34386532)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041976" FT MUTAGEN 172 FT /note="T->A: Weak enzyme activity towards RB1, but no FT effect on binding of CCDN1 nor CCDN3." FT /evidence="ECO:0000269|PubMed:16782892" FT MUTAGEN 172 FT /note="T->E: Retains moderate enzyme activity." FT /evidence="ECO:0000269|PubMed:16782892" FT MUTAGEN 173 FT /note="P->S: No effect on in vitro phosphorylation by CDK7. FT Greatly reduced T-172 phosphorylation and enzyme activity." FT /evidence="ECO:0000269|PubMed:19487459" FT CONFLICT 117 FT /note="I -> L (in Ref. 6; BAG36447)" FT /evidence="ECO:0000305" FT STRAND 7..13 FT /evidence="ECO:0007829|PDB:2W96" FT STRAND 15..17 FT /evidence="ECO:0007829|PDB:3G33" FT STRAND 20..24 FT /evidence="ECO:0007829|PDB:2W96" FT TURN 26..28 FT /evidence="ECO:0007829|PDB:2W96" FT STRAND 31..40 FT /evidence="ECO:0007829|PDB:2W96" FT STRAND 47..49 FT /evidence="ECO:0007829|PDB:6P8G" FT HELIX 51..63 FT /evidence="ECO:0007829|PDB:2W96" FT HELIX 64..66 FT /evidence="ECO:0007829|PDB:2W96" FT STRAND 74..82 FT /evidence="ECO:0007829|PDB:2W96" FT STRAND 84..94 FT /evidence="ECO:0007829|PDB:2W96" FT STRAND 97..99 FT /evidence="ECO:0007829|PDB:2W9Z" FT HELIX 100..105 FT /evidence="ECO:0007829|PDB:2W96" FT TURN 109..111 FT /evidence="ECO:0007829|PDB:2W9F" FT HELIX 114..133 FT /evidence="ECO:0007829|PDB:2W96" FT TURN 143..145 FT /evidence="ECO:0007829|PDB:2W96" FT STRAND 146..148 FT /evidence="ECO:0007829|PDB:2W96" FT TURN 150..152 FT /evidence="ECO:0007829|PDB:2W9Z" FT STRAND 154..156 FT /evidence="ECO:0007829|PDB:2W96" FT HELIX 162..169 FT /evidence="ECO:0007829|PDB:2W96" FT HELIX 172..175 FT /evidence="ECO:0007829|PDB:3G33" FT HELIX 178..180 FT /evidence="ECO:0007829|PDB:7SJ3" FT TURN 183..185 FT /evidence="ECO:0007829|PDB:2W96" FT STRAND 186..189 FT /evidence="ECO:0007829|PDB:2W96" FT HELIX 195..208 FT /evidence="ECO:0007829|PDB:2W96" FT STRAND 209..211 FT /evidence="ECO:0007829|PDB:2W96" FT HELIX 219..230 FT /evidence="ECO:0007829|PDB:2W96" FT HELIX 235..237 FT /evidence="ECO:0007829|PDB:6P8E" FT STRAND 242..244 FT /evidence="ECO:0007829|PDB:2W99" FT HELIX 246..248 FT /evidence="ECO:0007829|PDB:6P8E" FT HELIX 257..259 FT /evidence="ECO:0007829|PDB:6P8E" FT HELIX 266..275 FT /evidence="ECO:0007829|PDB:2W96" FT HELIX 280..282 FT /evidence="ECO:0007829|PDB:2W96" FT HELIX 286..290 FT /evidence="ECO:0007829|PDB:2W96" FT HELIX 293..295 FT /evidence="ECO:0007829|PDB:6P8E" SQ SEQUENCE 303 AA; 33730 MW; 0916A0C07403A33A CRC64; MATSRYEPVA EIGVGAYGTV YKARDPHSGH FVALKSVRVP NGGGGGGGLP ISTVREVALL RRLEAFEHPN VVRLMDVCAT SRTDREIKVT LVFEHVDQDL RTYLDKAPPP GLPAETIKDL MRQFLRGLDF LHANCIVHRD LKPENILVTS GGTVKLADFG LARIYSYQMA LTPVVVTLWY RAPEVLLQST YATPVDMWSV GCIFAEMFRR KPLFCGNSEA DQLGKIFDLI GLPPEDDWPR DVSLPRGAFP PRGPRPVQSV VPEMEESGAQ LLLEMLTFNP HKRISAFRAL QHSYLHKDEG NPE //