CDK4_HUMAN
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 03-AUG-2022, entry version 248.
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=42; IntAct=EBI-295644, EBI-375001;
CC P11802; P30279: CCND2; NbExp=15; IntAct=EBI-295644, EBI-748789;
CC P11802; P30281: CCND3; NbExp=35; 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=9; 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 also may
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="http://atlasgeneticsoncology.org/Genes/CDK4ID238ch12q14.html";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/cdk4/";
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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 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 AlphaFoldDB; P11802; -.
DR SMR; P11802; -.
DR BioGRID; 107454; 274.
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; 128.
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 BioMuta; CDK4; -.
DR DMDM; 1168867; -.
DR EPD; P11802; -.
DR jPOST; P11802; -.
DR MassIVE; P11802; -.
DR MaxQB; P11802; -.
DR PaxDb; P11802; -.
DR PeptideAtlas; P11802; -.
DR PRIDE; P11802; -.
DR ProteomicsDB; 4694; -.
DR ProteomicsDB; 52805; -. [P11802-1]
DR ABCD; P11802; 1 sequenced antibody.
DR Antibodypedia; 4190; 1123 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 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; THTHCWH; -.
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; 291 hits in 1124 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 99 other tissues.
DR ExpressionAtlas; P11802; baseline and differential.
DR Genevisible; P11802; HS.
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:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0016592; C:mediator complex; IBA:GO_Central.
DR GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB.
DR GO; GO:0005730; C:nucleolus; IDA:UniProtKB.
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:0008353; F:RNA polymerase II CTD heptapeptide repeat kinase activity; IBA:GO_Central.
DR GO; GO:0060612; P:adipose tissue development; IEA:Ensembl.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IEA:Ensembl.
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; IMP:BHF-UCL.
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:0010468; P:regulation of gene expression; IMP:BHF-UCL.
DR GO; GO:0046626; P:regulation of insulin receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0046890; P:regulation of lipid biosynthetic process; IEA:Ensembl.
DR GO; GO:0050994; P:regulation of lipid catabolic process; IEA:Ensembl.
DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0060260; P:regulation of transcription initiation from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0061469; P:regulation of type B pancreatic cell proliferation; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:UniProtKB.
DR GO; GO:0007165; P:signal transduction; IEA:Ensembl.
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 Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
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 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
