GenomeNet

Database: UniProt
Entry: P11802
LinkDB: P11802
Original site: P11802 
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   31-JUL-2019, entry version 231.
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;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; 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.,
RA   Klehmann-Hieb E., De Plaen E., Hankeln T.,
RA   Meyer Zum Bueschenfelde K.-H., Beach D.;
RT   "A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T
RT   lymphocytes in 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.,
RA   Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA   Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA   Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA   Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA   Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA   Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA   Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA   Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA   Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA   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.,
RA   Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA   Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA   Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA   Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA   Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA   Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA   Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA   Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA   Nakai K., Yada T., Nakamura Y., Ohara O., 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.,
RA   Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA   Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA   Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA   Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA   Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA   Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA   Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA   Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA   Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA   Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA   Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA   Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA   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.,
RA   Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA   Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA   Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA   Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA   Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA   Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA   Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA   Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA   Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA   Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA   Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA   Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA   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.,
RA   Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA   Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA   Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA   Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA   Kucherlapati R., Weinstock G., 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.,
RA   Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA   Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA   Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA   Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA   Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA   Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA   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
RT   project: 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
RT   the 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
RT   sarcomas.";
RL   Cancer Res. 53:5535-5541(1993).
RN   [13]
RP   FUNCTION.
RX   PubMed=9003781;
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
RT   different 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-
RT   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.,
RA   Regnier-Ricard F., Gisselbrecht S., Varin-Blank N.;
RT   "Characterization of VIK-1: a new Vav-interacting Kruppel-like
RT   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
RT   kinase 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
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA   Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT   a 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
RT   independent 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
RT   CDK6 activating mutation.";
RL   Mol. Cell. Biol. 29:4188-4200(2009).
RN   [25]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-172, AND IDENTIFICATION
RP   BY 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   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.,
RA   Buerckstuemmer T., 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   [27]
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.,
RA   Marston Linehan W., Bratslavsky G., Mollapour M.;
RT   "The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and
RT   enhance drug binding.";
RL   Nat. Commun. 7:12037-12037(2016).
RN   [28]
RP   IDENTIFICATION IN A COMPLEX WITH HSP90; HSP70; CDC37; PPP5C; TSC1;
RP   TSC2; 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.,
RA   Murphy R.L., Rensing N., Shapiro O., Panaretou B., Prodromou C.,
RA   Loh S.N., Gutmann D.H., Bourboulia D., Bratslavsky G., Wong M.,
RA   Mollapour M.;
RT   "Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates
RT   folding of kinase and non-kinase clients.";
RL   EMBO J. 36:3650-3665(2017).
RN   [29]
RP   X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF THR-172-PHOSPHORYLATED WILD
RP   TYPE 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.,
RA   Holding F.P., McMenamin R.L., Yon J., Chopra R., Lengauer C.,
RA   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   [30]
RP   X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF NONPHOSPHORYLATED FORM IN
RP   COMPLEX WITH CCND3, PHOSPHORYLATION AT THR-172, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY.
RX   PubMed=19237555; DOI=10.1073/pnas.0809674106;
RA   Takaki T., Echalier A., Brown N.R., Hunt T., Endicott J.A.,
RA   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   [31]
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
RT   of mutations in sporadic metastatic malignant melanoma.";
RL   Int. J. Cancer 72:780-783(1997).
RN   [32]
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.,
RA   Spatz A., 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   [33]
RP   ERRATUM.
RA   Soufir N., Avril M.-F., Chompret A., Demenais F., Bombled J.,
RA   Spatz A., Stoppa-Lyonnet D., Benard J., Bressac-De Paillerets B.;
RL   Hum. Mol. Genet. 7:941-941(1998).
RN   [34]
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.,
RA   Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA   O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA   Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA   Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA   Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA   Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA   West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA   Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA   DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA   Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA   Yuen S.T., Leung S.Y., Wooster R., 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
CC       that phosphorylate and inhibit members of the retinoblastoma (RB)
CC       protein family including RB1 and regulate the cell-cycle during
CC       G(1)/S transition. Phosphorylation of RB1 allows dissociation of
CC       the transcription factor E2F from the RB/E2F complexes and the
CC       subsequent transcription of E2F target genes which are responsible
CC       for the progression through the G(1) phase. Hypophosphorylates RB1
CC       in early G(1) phase. Cyclin D-CDK4 complexes are major integrators
CC       of various mitogenenic and antimitogenic signals. Also
CC       phosphorylates SMAD3 in a cell-cycle-dependent manner and
CC       represses its transcriptional activity. Component of the ternary
CC       complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation
CC       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,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216;
CC         EC=2.7.11.22; Evidence={ECO:0000269|PubMed:19075005,
CC         ECO:0000269|PubMed:19237565, 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
CC       of a D-type cyclin are necessary for enzymatic activity. Full
CC       activation of the cyclin-D-CDK4 complex appears to require other
CC       factors such as recruitment of the substrate via a substrate
CC       recruitment motif, and/or formation of the CDKN1B ternary complex.
CC       Inhibited by INK4 family members. In resting cells, the non-
CC       tyrosine-phosphorylated form of CDKN1B prevents phosphorylation at
CC       Thr-172 and inactivation, while, in proliferating cells, tyrosine
CC       phosphorylation of CDKN1B allows phosphorylation of Thr-172 of
CC       CDK4 and subsequent activation. {ECO:0000269|PubMed:19487459}.
CC   -!- SUBUNIT: Component of the D-CDK4 complex, composed of CDK4 and
CC       some D-type G1 cyclin (CCND1, CCND2 or CCND3). Interacts directly
CC       in the complex with CCND1, CCND2 or CCND3. Interacts with SEI1 and
CC       ZNF655. Forms a ternary complex, cyclin D-CDK4-CDKN1B, involved in
CC       modulating CDK4 enzymatic activity. Interacts directly with CDKN1B
CC       (phosphorylated on 'Tyr-88' and 'Tyr-89'); the interaction allows
CC       assembly of the cyclin D-CDK4 complex, Thr-172 phosphorylation,
CC       nuclear translocation and enhances the cyclin D-CDK4 complex
CC       activity. CDK4 activity is either inhibited or enhanced depending
CC       on stoichiometry of complex. The non-tyrosine-phosphorylated form
CC       of CDKN1B prevents T-loop phosphorylation of CDK4 producing
CC       inactive CDK4. Interacts (unphosphorylated form) with CDK2. Also
CC       forms ternary complexes with CDKN1A or CDKN2A. Interacts directly
CC       with CDKN1A (via its N-terminal); the interaction promotes the
CC       assembly of the cyclin D-CDK4 complex, its nuclear translocation
CC       and promotes the cyclin D-dependent enzyme activity of CDK4.
CC       Interacts with CCND1; the interaction is prevented with the
CC       binding of CCND1 to INSM1 during cell cycle progression. Probably
CC       forms a complex composed of chaperones HSP90 and HSP70, co-
CC       chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT,
CC       RAF1 and NR3C1; this complex does not contain co-chaperones
CC       STIP1/HOP and PTGES3/p23 (PubMed:29127155). Interacts with CEBPA
CC       (when phosphorylated) (PubMed:15107404). Interacts with FNIP1 and
CC       FNIP2 (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:27353360,
CC       ECO:0000269|PubMed:29127155, ECO:0000269|PubMed:9106657}.
CC   -!- INTERACTION:
CC       P24385:CCND1; NbExp=29; IntAct=EBI-295644, EBI-375001;
CC       P30279:CCND2; NbExp=12; IntAct=EBI-295644, EBI-748789;
CC       P30281:CCND3; NbExp=27; IntAct=EBI-295644, EBI-375013;
CC       Q16543:CDC37; NbExp=11; IntAct=EBI-295644, EBI-295634;
CC       P50613:CDK7; NbExp=2; IntAct=EBI-295644, EBI-1245958;
CC       P38936:CDKN1A; NbExp=6; IntAct=EBI-295644, EBI-375077;
CC       P46527:CDKN1B; NbExp=6; IntAct=EBI-295644, EBI-519280;
CC       P42771:CDKN2A; NbExp=13; IntAct=EBI-295644, EBI-375053;
CC       P42772:CDKN2B; NbExp=15; IntAct=EBI-295644, EBI-711280;
CC       P42773:CDKN2C; NbExp=17; IntAct=EBI-295644, EBI-711290;
CC       P55273:CDKN2D; NbExp=18; IntAct=EBI-295644, EBI-745859;
CC       Q9UJC3:HOOK1; NbExp=11; IntAct=EBI-295644, EBI-746704;
CC       P08238:HSP90AB1; NbExp=3; IntAct=EBI-295644, EBI-352572;
CC       Q9UKT9:IKZF3; NbExp=4; IntAct=EBI-295644, EBI-747204;
CC       P01106:MYC; NbExp=2; IntAct=EBI-295644, EBI-447544;
CC       P28749:RBL1; NbExp=2; IntAct=EBI-295644, EBI-971402;
CC       Q8N720:ZNF655; NbExp=5; IntAct=EBI-295644, EBI-625509;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Membrane.
CC       Note=Cytoplasmic when non-complexed. Forms a cyclin D-CDK4 complex
CC       in the cytoplasm as cells progress through G(1) phase. The complex
CC       accumulates on the nuclear membrane and enters the nucleus on
CC       transition from G(1) to S phase. Also present in nucleoli and
CC       heterochromatin lumps. Colocalizes with RB1 after release into the
CC       nucleus.
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         Note=No experimental confirmation available.;
CC   -!- PTM: Phosphorylation at Thr-172 is required for enzymatic
CC       activity. Phosphorylated, in vitro, at this site by CCNH-CDK7,
CC       but, in vivo, appears to be phosphorylated by a proline-directed
CC       kinase. In the cyclin D-CDK4-CDKN1B complex, this phosphorylation
CC       and consequent CDK4 enzyme activity, is dependent on the tyrosine
CC       phosphorylation state of CDKN1B. Thus, in proliferating cells,
CC       CDK4 within the complex is phosphorylated on Thr-172 in the T-
CC       loop. In resting cells, phosphorylation on Thr-172 is prevented by
CC       the non-tyrosine-phosphorylated form of CDKN1B.
CC       {ECO:0000269|PubMed:16782892, ECO:0000269|PubMed:19075005,
CC       ECO:0000269|PubMed:19237555, ECO:0000269|PubMed:19237565,
CC       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
CC       also may 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
CC       associated with variations affecting the gene represented in this
CC       entry.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC
CC       Ser/Thr protein kinase family. CDC2/CDKX subfamily. {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC       and Haematology;
CC       URL="http://atlasgeneticsoncology.org/Genes/CDK4ID238ch12q14.html";
CC   -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC       URL="http://egp.gs.washington.edu/data/cdk4/";
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; 1LD2; Model; -; A=1-303.
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   PDBsum; 1LD2; -.
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   SMR; P11802; -.
DR   BioGrid; 107454; 217.
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; 100.
DR   MINT; P11802; -.
DR   STRING; 9606.ENSP00000257904; -.
DR   BindingDB; P11802; -.
DR   ChEMBL; CHEMBL331; -.
DR   DrugBank; DB03496; Flavopiridol.
DR   DrugBank; DB09073; Palbociclib.
DR   DrugBank; DB02733; Purvalanol.
DR   DrugBank; DB11730; Ribociclib.
DR   GuidetoPHARMACOLOGY; 1976; -.
DR   iPTMnet; P11802; -.
DR   PhosphoSitePlus; P11802; -.
DR   BioMuta; CDK4; -.
DR   DMDM; 1168867; -.
DR   EPD; P11802; -.
DR   jPOST; P11802; -.
DR   MaxQB; P11802; -.
DR   PaxDb; P11802; -.
DR   PeptideAtlas; P11802; -.
DR   PRIDE; P11802; -.
DR   ProteomicsDB; 4694; -.
DR   ProteomicsDB; 52805; -. [P11802-1]
DR   DNASU; 1019; -.
DR   Ensembl; ENST00000257904; ENSP00000257904; ENSG00000135446. [P11802-1]
DR   GeneID; 1019; -.
DR   KEGG; hsa:1019; -.
DR   UCSC; uc001spv.4; human. [P11802-1]
DR   CTD; 1019; -.
DR   DisGeNET; 1019; -.
DR   GeneCards; CDK4; -.
DR   HGNC; HGNC:1773; CDK4.
DR   HPA; CAB013116; -.
DR   HPA; CAB069405; -.
DR   HPA; HPA006024; -.
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   eggNOG; KOG0594; Eukaryota.
DR   eggNOG; ENOG410XPP3; LUCA.
DR   GeneTree; ENSGT00940000154770; -.
DR   HOGENOM; HOG000233024; -.
DR   InParanoid; P11802; -.
DR   KO; K02089; -.
DR   OMA; TFSPHKR; -.
DR   OrthoDB; 988547at2759; -.
DR   PhylomeDB; P11802; -.
DR   TreeFam; TF101022; -.
DR   BRENDA; 2.7.11.22; 2681.
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   SignaLink; P11802; -.
DR   SIGNOR; P11802; -.
DR   ChiTaRS; CDK4; human.
DR   EvolutionaryTrace; P11802; -.
DR   GeneWiki; Cyclin-dependent_kinase_4; -.
DR   GenomeRNAi; 1019; -.
DR   PRO; PR:P11802; -.
DR   Proteomes; UP000005640; Chromosome 12.
DR   Bgee; ENSG00000135446; Expressed in 225 organ(s), highest expression level in right ovary.
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:0097129; C:cyclin D2-CDK4 complex; IEA:Ensembl.
DR   GO; GO:0000307; C:cyclin-dependent protein kinase holoenzyme complex; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR   GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB.
DR   GO; GO:0005730; C:nucleolus; IDA:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR   GO; GO:0005667; C:transcription factor 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:0044877; F:protein-containing complex binding; IEA:Ensembl.
DR   GO; GO:0060612; P:adipose tissue development; IEA:Ensembl.
DR   GO; GO:0031100; P:animal organ regeneration; 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:0007623; P:circadian rhythm; IEA:Ensembl.
DR   GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IMP:BHF-UCL.
DR   GO; GO:0002088; P:lens development in camera-type eye; IEA:Ensembl.
DR   GO; GO:0071157; P:negative regulation of cell cycle arrest; IDA:UniProtKB.
DR   GO; GO:2000134; P:negative regulation of G1/S transition of mitotic cell cycle; TAS:Reactome.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR   GO; GO:0045787; P:positive regulation of cell cycle; TAS:Reactome.
DR   GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:BHF-UCL.
DR   GO; GO:0045793; P:positive regulation of cell size; IEA:Ensembl.
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:0045727; P:positive regulation of translation; IEA:Ensembl.
DR   GO; GO:0006468; P:protein phosphorylation; IDA:BHF-UCL.
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:0042493; P:response to drug; IEP:UniProtKB.
DR   GO; GO:0055093; P:response to hyperoxia; IEA:Ensembl.
DR   GO; GO:0010288; P:response to lead ion; IEA:Ensembl.
DR   GO; GO:0033574; P:response to testosterone; IEA:Ensembl.
DR   GO; GO:0009636; P:response to toxic substance; IEA:Ensembl.
DR   GO; GO:0007165; P:signal transduction; IEA:Ensembl.
DR   GO; GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome.
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;
KW   Cell cycle; Cell division; Complete proteome; Cytoplasm;
KW   Disease mutation; Kinase; Membrane; Nucleotide-binding; Nucleus;
KW   Phosphoprotein; Polymorphism; Reference proteome;
KW   Serine/threonine-protein kinase; Transferase.
FT   INIT_MET      1      1       Removed. {ECO:0000244|PubMed:19413330}.
FT   CHAIN         2    303       Cyclin-dependent kinase 4.
FT                                /FTId=PRO_0000085778.
FT   DOMAIN        6    295       Protein kinase. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159}.
FT   NP_BIND      12     20       ATP. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159}.
FT   REGION       50     56       Required for binding D-type cyclins.
FT   COMPBIAS     42     48       Poly-Gly.
FT   ACT_SITE    140    140       Proton acceptor. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159, ECO:0000255|PROSITE-
FT                                ProRule:PRU10027}.
FT   BINDING      35     35       ATP. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159}.
FT   MOD_RES       2      2       N-acetylalanine.
FT                                {ECO:0000244|PubMed:19413330}.
FT   MOD_RES     172    172       Phosphothreonine.
FT                                {ECO:0000244|PubMed:19369195,
FT                                ECO:0000269|PubMed:16782892,
FT                                ECO:0000269|PubMed:19237555,
FT                                ECO:0000269|PubMed:19237565,
FT                                ECO:0000269|PubMed:19487459}.
FT   VAR_SEQ       1    120       Missing (in isoform 2).
FT                                {ECO:0000303|PubMed:14702039}.
FT                                /FTId=VSP_056487.
FT   VARIANT      24     24       R -> C (in CMM3; somatic and familial;
FT                                generates a dominant oncogene resistant
FT                                to inhibition by p16(INK4a);
FT                                dbSNP:rs11547328).
FT                                {ECO:0000269|PubMed:7652577,
FT                                ECO:0000269|PubMed:8528263}.
FT                                /FTId=VAR_006200.
FT   VARIANT      24     24       R -> H (in CMM3; dbSNP:rs104894340).
FT                                {ECO:0000269|PubMed:9425228}.
FT                                /FTId=VAR_006201.
FT   VARIANT      41     41       N -> S (in CMM3; sporadic;
FT                                dbSNP:rs144890720).
FT                                {ECO:0000269|PubMed:9311594}.
FT                                /FTId=VAR_021152.
FT   VARIANT      82     82       R -> Q (in dbSNP:rs3211612).
FT                                {ECO:0000269|Ref.5}.
FT                                /FTId=VAR_029153.
FT   VARIANT     122    122       R -> H (in dbSNP:rs34386532).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041976.
FT   MUTAGEN     172    172       T->A: Weak enzyme activity towards RB1,
FT                                but no effect on binding of CCDN1 nor
FT                                CCDN3. {ECO:0000269|PubMed:16782892}.
FT   MUTAGEN     172    172       T->E: Retains moderate enzyme activity.
FT                                {ECO:0000269|PubMed:16782892}.
FT   MUTAGEN     173    173       P->S: No effect on in vitro
FT                                phosphorylation by CDK7. Greatly reduced
FT                                T-172 phosphorylation and enzyme
FT                                activity. {ECO:0000269|PubMed:19487459}.
FT   CONFLICT    117    117       I -> L (in Ref. 6; BAG36447).
FT                                {ECO:0000305}.
FT   STRAND        7     13       {ECO:0000244|PDB:2W96}.
FT   STRAND       15     17       {ECO:0000244|PDB:3G33}.
FT   STRAND       20     24       {ECO:0000244|PDB:2W96}.
FT   TURN         26     28       {ECO:0000244|PDB:2W96}.
FT   STRAND       31     40       {ECO:0000244|PDB:2W96}.
FT   HELIX        51     63       {ECO:0000244|PDB:2W96}.
FT   HELIX        64     66       {ECO:0000244|PDB:2W96}.
FT   STRAND       74     82       {ECO:0000244|PDB:2W96}.
FT   STRAND       84     94       {ECO:0000244|PDB:2W96}.
FT   STRAND       97     99       {ECO:0000244|PDB:2W9Z}.
FT   HELIX       100    105       {ECO:0000244|PDB:2W96}.
FT   TURN        109    111       {ECO:0000244|PDB:2W9F}.
FT   HELIX       114    133       {ECO:0000244|PDB:2W96}.
FT   TURN        143    145       {ECO:0000244|PDB:2W96}.
FT   STRAND      146    148       {ECO:0000244|PDB:2W96}.
FT   TURN        150    152       {ECO:0000244|PDB:2W9Z}.
FT   STRAND      154    156       {ECO:0000244|PDB:2W96}.
FT   HELIX       162    169       {ECO:0000244|PDB:2W96}.
FT   HELIX       172    175       {ECO:0000244|PDB:3G33}.
FT   TURN        183    185       {ECO:0000244|PDB:2W96}.
FT   STRAND      186    189       {ECO:0000244|PDB:2W96}.
FT   HELIX       195    208       {ECO:0000244|PDB:2W96}.
FT   STRAND      209    211       {ECO:0000244|PDB:2W96}.
FT   HELIX       219    230       {ECO:0000244|PDB:2W96}.
FT   TURN        235    237       {ECO:0000244|PDB:3G33}.
FT   STRAND      242    244       {ECO:0000244|PDB:2W99}.
FT   HELIX       246    248       {ECO:0000244|PDB:3G33}.
FT   HELIX       257    260       {ECO:0000244|PDB:2W99}.
FT   HELIX       266    275       {ECO:0000244|PDB:2W96}.
FT   HELIX       280    282       {ECO:0000244|PDB:2W96}.
FT   HELIX       286    290       {ECO:0000244|PDB:2W96}.
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
//
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