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Database: UniProt
Entry: Q9UM73
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Original site: Q9UM73 
ID   ALK_HUMAN               Reviewed;        1620 AA.
AC   Q9UM73; Q4ZFX9; Q53QQ6; Q53RZ4; Q59FI3; Q9Y4K6;
DT   27-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT   18-MAY-2010, sequence version 3.
DT   07-OCT-2020, entry version 208.
DE   RecName: Full=ALK tyrosine kinase receptor {ECO:0000305};
DE            EC=2.7.10.1;
DE   AltName: Full=Anaplastic lymphoma kinase;
DE   AltName: CD_antigen=CD246;
DE   Flags: Precursor;
GN   Name=ALK {ECO:0000312|HGNC:HGNC:427};
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], SUBCELLULAR LOCATION, TISSUE SPECIFICITY,
RP   GLYCOSYLATION, AND VARIANT VAL-1461.
RX   PubMed=9174053; DOI=10.1038/sj.onc.1201062;
RA   Morris S.W., Naeve C.W., Mathew P., James P.L., Kirstein M.N., Cui X.,
RA   Witte D.P.;
RT   "ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's
RT   lymphoma, encodes a novel neural receptor tyrosine kinase that is highly
RT   related to leukocyte tyrosine kinase (LTK).";
RL   Oncogene 14:2175-2188(1997).
RN   [2]
RP   ERRATUM OF PUBMED:9174053.
RA   Morris S.W., Naeve C.W., Mathew P., James P.L., Kirstein M.N., Cui X.,
RA   Witte D.P.;
RL   Oncogene 15:2883-2883(1997).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS VAL-1461; ARG-1491 AND GLU-1529.
RX   PubMed=9053841; DOI=10.1038/sj.onc.1200849;
RA   Iwahara T., Fujimoto J., Wen D., Cupples R., Bucay N., Arakawa T., Mori S.,
RA   Ratzkin B., Yamamoto T.;
RT   "Molecular characterization of ALK, a receptor tyrosine kinase expressed
RT   specifically in the nervous system.";
RL   Oncogene 14:439-449(1997).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS VAL-1461; ARG-1491 AND
RP   GLU-1529.
RC   TISSUE=Brain;
RA   Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA   Ohara O., Nagase T., Kikuno R.F.;
RL   Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15815621; DOI=10.1038/nature03466;
RA   Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA   Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA   Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA   Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA   Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA   Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA   Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA   Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA   Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA   McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA   Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA   Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA   Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA   Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA   Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA   Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA   Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA   Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA   Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA   Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA   Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA   Wilson R.K.;
RT   "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT   4.";
RL   Nature 434:724-731(2005).
RN   [6]
RP   PARTIAL NUCLEOTIDE SEQUENCE [MRNA], CHROMOSOMAL TRANSLOCATION WITH NPM1,
RP   AND VARIANT VAL-1461.
RX   PubMed=8122112; DOI=10.1126/science.8122112;
RA   Morris S.W., Kirstein M.N., Valentine M.B., Dittmer K.G., Shapiro D.N.,
RA   Saltman D.L., Look A.T.;
RT   "Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-
RT   Hodgkin's lymphoma.";
RL   Science 263:1281-1284(1994).
RN   [7]
RP   FUNCTION AS AN ONCOGENE.
RX   PubMed=11387242; DOI=10.1096/fj.00-0678fje;
RA   Simonitsch I., Polgar D., Hajek M., Duchek P., Skrzypek B., Fassl S.,
RA   Lamprecht A., Schmidt G., Krupitza G., Cerni C.;
RT   "The cytoplasmic truncated receptor tyrosine kinase ALK homodimer
RT   immortalizes and cooperates with ras in cellular transformation.";
RL   FASEB J. 15:1416-1418(2001).
RN   [8]
RP   PHOSPHORYLATION, AND FUNCTION.
RX   PubMed=11121404; DOI=10.1074/jbc.m007333200;
RA   Souttou B., Carvalho N.B., Raulais D., Vigny M.;
RT   "Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces
RT   neuronal differentiation through the mitogen-activated protein kinase
RT   pathway.";
RL   J. Biol. Chem. 276:9526-9531(2001).
RN   [9]
RP   INTERACTION WITH PTN, AND FUNCTION.
RX   PubMed=11278720; DOI=10.1074/jbc.m010660200;
RA   Stoica G.E., Kuo A., Aigner A., Sunitha I., Souttou B., Malerczyk C.,
RA   Caughey D.J., Wen D., Karavanov A., Riegel A.T., Wellstein A.;
RT   "Identification of anaplastic lymphoma kinase as a receptor for the growth
RT   factor pleiotrophin.";
RL   J. Biol. Chem. 276:16772-16779(2001).
RN   [10]
RP   CHROMOSOMAL TRANSLOCATION WITH ALO17 AND CARS.
RX   PubMed=12112524; DOI=10.1002/gcc.10033;
RA   Cools J., Wlodarska I., Somers R., Mentens N., Pedeutour F., Maes B.,
RA   De Wolf-Peeters C., Pauwels P., Hagemeijer A., Marynen P.;
RT   "Identification of novel fusion partners of ALK, the anaplastic lymphoma
RT   kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic
RT   tumor.";
RL   Genes Chromosomes Cancer 34:354-362(2002).
RN   [11]
RP   FUNCTION.
RX   PubMed=11809760; DOI=10.1074/jbc.m112354200;
RA   Powers C., Aigner A., Stoica G.E., McDonnell K., Wellstein A.;
RT   "Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting
RT   for glioblastoma growth.";
RL   J. Biol. Chem. 277:14153-14158(2002).
RN   [12]
RP   FUNCTION.
RX   PubMed=12107166; DOI=10.1074/jbc.m203963200;
RA   Bowden E.T., Stoica G.E., Wellstein A.;
RT   "Anti-apoptotic signaling of pleiotrophin through its receptor, anaplastic
RT   lymphoma kinase.";
RL   J. Biol. Chem. 277:35862-35868(2002).
RN   [13]
RP   INTERACTION WITH MDK, AND FUNCTION.
RX   PubMed=12122009; DOI=10.1074/jbc.m205749200;
RA   Stoica G.E., Kuo A., Powers C., Bowden E.T., Sale E.B., Riegel A.T.,
RA   Wellstein A.;
RT   "Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth
RT   factor for different cell types.";
RL   J. Biol. Chem. 277:35990-35998(2002).
RN   [14]
RP   INTERACTION WITH CBL; IRS1; PIK3R1; PLCG1 AND SHC1, AND FUNCTION IN
RP   PHOSPHORYLATION OF CBL; IRS1 AND SHC1.
RX   PubMed=15226403; DOI=10.1242/jcs.01183;
RA   Motegi A., Fujimoto J., Kotani M., Sakuraba H., Yamamoto T.;
RT   "ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth.";
RL   J. Cell Sci. 117:3319-3329(2004).
RN   [15]
RP   SUBSTRATE SPECIFICITY, AND PHOSPHORYLATION AT TYR-1278.
RX   PubMed=15938644; DOI=10.1021/bi0472954;
RA   Donella-Deana A., Marin O., Cesaro L., Gunby R.H., Ferrarese A.,
RA   Coluccia A.M., Tartari C.J., Mologni L., Scapozza L.,
RA   Gambacorti-Passerini C., Pinna L.A.;
RT   "Unique substrate specificity of anaplastic lymphoma kinase (ALK):
RT   development of phosphoacceptor peptides for the assay of ALK activity.";
RL   Biochemistry 44:8533-8542(2005).
RN   [16]
RP   ROLE IN GLIOBLASTOMA.
RX   PubMed=15908427; DOI=10.1074/jbc.m502614200;
RA   Lu K.V., Jong K.A., Kim G.Y., Singh J., Dia E.Q., Yoshimoto K., Wang M.Y.,
RA   Cloughesy T.F., Nelson S.F., Mischel P.S.;
RT   "Differential induction of glioblastoma migration and growth by two forms
RT   of pleiotrophin.";
RL   J. Biol. Chem. 280:26953-26964(2005).
RN   [17]
RP   SUBCELLULAR LOCATION, SUBUNIT, ACTIVITY REGULATION, AND FUNCTION.
RX   PubMed=16317043; DOI=10.1242/jcs.02695;
RA   Gouzi J.Y., Moog-Lutz C., Vigny M., Brunet-de Carvalho N.;
RT   "Role of the subcellular localization of ALK tyrosine kinase domain in
RT   neuronal differentiation of PC12 cells.";
RL   J. Cell Sci. 118:5811-5823(2005).
RN   [18]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-1078; TYR-1096; TYR-1131 AND
RP   TYR-1604, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=15592455; DOI=10.1038/nbt1046;
RA   Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA   Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT   "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells.";
RL   Nat. Biotechnol. 23:94-101(2005).
RN   [19]
RP   CHROMOSOMAL TRANSLOCATION WITH SEC31A.
RX   PubMed=16161041; DOI=10.1002/ijc.21490;
RA   Panagopoulos I., Nilsson T., Domanski H.A., Isaksson M., Lindblom P.,
RA   Mertens F., Mandahl N.;
RT   "Fusion of the SEC31L1 and ALK genes in an inflammatory myofibroblastic
RT   tumor.";
RL   Int. J. Cancer 118:1181-1186(2006).
RN   [20]
RP   INTERACTION WITH FRS2 AND SHC1, PHOSPHORYLATION AT TYR-1507, MUTAGENESIS OF
RP   TYR-1507, AND FUNCTION IN PHOSPHORYLATION OF FRS2; MAPK1/ERK2; MAPK3/ERK1
RP   AND SHC1.
RX   PubMed=17274988; DOI=10.1016/j.febslet.2007.01.039;
RA   Degoutin J., Vigny M., Gouzi J.Y.;
RT   "ALK activation induces Shc and FRS2 recruitment: Signaling and phenotypic
RT   outcomes in PC12 cells differentiation.";
RL   FEBS Lett. 581:727-734(2007).
RN   [21]
RP   PHOSPHORYLATION, AND ACTIVITY REGULATION.
RX   PubMed=17681947; DOI=10.1074/jbc.m704505200;
RA   Perez-Pinera P., Zhang W., Chang Y., Vega J.A., Deuel T.F.;
RT   "Anaplastic lymphoma kinase is activated through the pleiotrophin/receptor
RT   protein-tyrosine phosphatase beta/zeta signaling pathway: an alternative
RT   mechanism of receptor tyrosine kinase activation.";
RL   J. Biol. Chem. 282:28683-28690(2007).
RN   [22]
RP   INTERACTION WITH IRS1 AND SHC, PHOSPHORYLATION AT TYR-1096, AND FUNCTION.
RX   PubMed=16878150; DOI=10.1038/sj.onc.1209840;
RA   Kuo A.H., Stoica G.E., Riegel A.T., Wellstein A.;
RT   "Recruitment of insulin receptor substrate-1 and activation of NF-kappaB
RT   essential for midkine growth signaling through anaplastic lymphoma
RT   kinase.";
RL   Oncogene 26:859-869(2007).
RN   [23]
RP   REVIEW ON FUNCTION.
RX   PubMed=19459784; DOI=10.1042/bj20090387;
RA   Palmer R.H., Vernersson E., Grabbe C., Hallberg B.;
RT   "Anaplastic lymphoma kinase: signalling in development and disease.";
RL   Biochem. J. 420:345-361(2009).
RN   [24]
RP   CHROMOSOMAL TRANSLOCATION WITH WDCP.
RX   PubMed=22327622; DOI=10.1038/nm.2673;
RA   Lipson D., Capelletti M., Yelensky R., Otto G., Parker A., Jarosz M.,
RA   Curran J.A., Balasubramanian S., Bloom T., Brennan K.W., Donahue A.,
RA   Downing S.R., Frampton G.M., Garcia L., Juhn F., Mitchell K.C., White E.,
RA   White J., Zwirko Z., Peretz T., Nechushtan H., Soussan-Gutman L., Kim J.,
RA   Sasaki H., Kim H.R., Park S.I., Ercan D., Sheehan C.E., Ross J.S.,
RA   Cronin M.T., Jaenne P.A., Stephens P.J.;
RT   "Identification of new ALK and RET gene fusions from colorectal and lung
RT   cancer biopsies.";
RL   Nat. Med. 18:382-384(2012).
RN   [25]
RP   STRUCTURE BY NMR OF 1571-1589.
RG   RIKEN structural genomics initiative (RSGI);
RT   "Solution structure of the complex of the PTB domain of SNT-2 and 19-
RT   residue peptide (aa 1571-1589) of HALK.";
RL   Submitted (APR-2008) to the PDB data bank.
RN   [26]
RP   X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 1072-1410.
RX   PubMed=20632993; DOI=10.1042/bj20100609;
RA   Lee C.C., Jia Y., Li N., Sun X., Ng K., Ambing E., Gao M.Y., Hua S.,
RA   Chen C., Kim S., Michellys P.Y., Lesley S.A., Harris J.L., Spraggon G.;
RT   "Crystal structure of the ALK (anaplastic lymphoma kinase) catalytic
RT   domain.";
RL   Biochem. J. 430:425-437(2010).
RN   [27]
RP   X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 1094-1407 IN COMPLEX WITH
RP   INHIBITOR.
RX   PubMed=20695522; DOI=10.1021/bi1005514;
RA   Bossi R.T., Saccardo M.B., Ardini E., Menichincheri M., Rusconi L.,
RA   Magnaghi P., Orsini P., Avanzi N., Borgia A.L., Nesi M., Bandiera T.,
RA   Fogliatto G., Bertrand J.A.;
RT   "Crystal structures of anaplastic lymphoma kinase in complex with ATP
RT   competitive inhibitors.";
RL   Biochemistry 49:6813-6825(2010).
RN   [28]
RP   STRUCTURE BY NMR OF 1571-1589.
RX   PubMed=20454865; DOI=10.1007/s10969-010-9091-x;
RA   Koshiba S., Li H., Motoda Y., Tomizawa T., Kasai T., Tochio N., Yabuki T.,
RA   Harada T., Watanabe S., Tanaka A., Shirouzu M., Kigawa T., Yamamoto T.,
RA   Yokoyama S.;
RT   "Structural basis for the recognition of nucleophosmin-anaplastic lymphoma
RT   kinase oncoprotein by the phosphotyrosine binding domain of Suc1-associated
RT   neurotrophic factor-induced tyrosine-phosphorylated target-2.";
RL   J. Struct. Funct. Genomics 11:125-141(2010).
RN   [29]
RP   X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 1093-1411 IN COMPLEX WITH
RP   CRIZOTINIB.
RA   Mctigue M., Deng Y., Liu W., Brooun A.;
RT   "Structure of L1196M mutant anaplastic lymphoma kinase in complex with
RT   crizotinib.";
RL   Submitted (MAY-2011) to the PDB data bank.
RN   [30]
RP   X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 1069-1411 IN COMPLEX WITH
RP   INHIBITOR, AND ACTIVITY REGULATION.
RX   PubMed=21575866; DOI=10.1016/j.ccr.2011.04.004;
RA   Sakamoto H., Tsukaguchi T., Hiroshima S., Kodama T., Kobayashi T.,
RA   Fukami T.A., Oikawa N., Tsukuda T., Ishii N., Aoki Y.;
RT   "CH5424802, a selective ALK inhibitor capable of blocking the resistant
RT   gatekeeper mutant.";
RL   Cancer Cell 19:679-690(2011).
RN   [31]
RP   VARIANTS [LARGE SCALE ANALYSIS] LEU-90; LEU-163; GLN-296; ALA-476; PHE-560;
RP   ILE-680; THR-704; SER-877; MET-1012; ASP-1121; THR-1274; LEU-1328;
RP   ASN-1416; LYS-1419; ARG-1429; ARG-1491 AND GLU-1529.
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).
RN   [32]
RP   VARIANTS NBLST3 ASN-1091; ALA-1128; ARG-1166; ASN-1171; ILE-1174; PRO-1192;
RP   CYS-1245; VAL-1245 THR-1250 AND GLN-1275.
RX   PubMed=18724359; DOI=10.1038/nature07261;
RA   Mosse Y.P., Laudenslager M., Longo L., Cole K.A., Wood A., Attiyeh E.F.,
RA   Laquaglia M.J., Sennett R., Lynch J.E., Perri P., Laureys G., Speleman F.,
RA   Kim C., Hou C., Hakonarson H., Torkamani A., Schork N.J., Brodeur G.M.,
RA   Tonini G.P., Rappaport E., Devoto M., Maris J.M.;
RT   "Identification of ALK as a major familial neuroblastoma predisposition
RT   gene.";
RL   Nature 455:930-935(2008).
RN   [33]
RP   VARIANTS NBLST3 VAL-1174; LEU-1174; CYS-1174; PRO-1192; GLN-1275 AND
RP   SER-1278, AND VARIANT LEU-1275.
RX   PubMed=18923523; DOI=10.1038/nature07398;
RA   Janoueix-Lerosey I., Lequin D., Brugieres L., Ribeiro A., de Pontual L.,
RA   Combaret V., Raynal V., Puisieux A., Schleiermacher G., Pierron G.,
RA   Valteau-Couanet D., Frebourg T., Michon J., Lyonnet S., Amiel J.,
RA   Delattre O.;
RT   "Somatic and germline activating mutations of the ALK kinase receptor in
RT   neuroblastoma.";
RL   Nature 455:967-970(2008).
RN   [34]
RP   VARIANTS NBLST3 MET-1151; LEU-1174; THR-1234; CYS-1245 AND GLN-1275.
RX   PubMed=18923525; DOI=10.1038/nature07397;
RA   George R.E., Sanda T., Hanna M., Froehling S., Luther W. II, Zhang J.,
RA   Ahn Y., Zhou W., London W.B., McGrady P., Xue L., Zozulya S., Gregor V.E.,
RA   Webb T.R., Gray N.S., Gilliland D.G., Diller L., Greulich H., Morris S.W.,
RA   Meyerson M., Look A.T.;
RT   "Activating mutations in ALK provide a therapeutic target in
RT   neuroblastoma.";
RL   Nature 455:975-978(2008).
RN   [35]
RP   CHARACTERIZATION OF VARIANTS NBLST3 LEU-1174; VAL-1174 AND GLN-1275.
RX   PubMed=21242967; DOI=10.1038/onc.2010.595;
RA   Mazot P., Cazes A., Boutterin M.C., Figueiredo A., Raynal V., Combaret V.,
RA   Hallberg B., Palmer R.H., Delattre O., Janoueix-Lerosey I., Vigny M.;
RT   "The constitutive activity of the ALK mutated at positions F1174 or R1275
RT   impairs receptor trafficking.";
RL   Oncogene 30:2017-2025(2011).
CC   -!- FUNCTION: Neuronal receptor tyrosine kinase that is essentially and
CC       transiently expressed in specific regions of the central and peripheral
CC       nervous systems and plays an important role in the genesis and
CC       differentiation of the nervous system. Transduces signals from ligands
CC       at the cell surface, through specific activation of the mitogen-
CC       activated protein kinase (MAPK) pathway. Phosphorylates almost
CC       exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following
CC       activation by ligand, ALK induces tyrosine phosphorylation of CBL,
CC       FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and
CC       MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a
CC       secreted growth factor, and midkine (MDK), a PTN-related factor, thus
CC       participating in PTN and MDK signal transduction. PTN-binding induces
CC       MAPK pathway activation, which is important for the anti-apoptotic
CC       signaling of PTN and regulation of cell proliferation. MDK-binding
CC       induces phosphorylation of the ALK target insulin receptor substrate
CC       (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-
CC       kinase, resulting also in cell proliferation induction. Drives NF-
CC       kappa-B activation, probably through IRS1 and the activation of the AKT
CC       serine/threonine kinase. Recruitment of IRS1 to activated ALK and the
CC       activation of NF-kappa-B are essential for the autocrine growth and
CC       survival signaling of MDK. Thinness gene involved in the resistance to
CC       weight gain: in hypothalamic neurons, controls energy expenditure
CC       acting as a negative regulator of white adipose tissue lipolysis and
CC       sympathetic tone to fine-tune energy homeostasis (By similarity).
CC       {ECO:0000250|UniProtKB:P97793, ECO:0000269|PubMed:11121404,
CC       ECO:0000269|PubMed:11278720, ECO:0000269|PubMed:11387242,
CC       ECO:0000269|PubMed:11809760, ECO:0000269|PubMed:12107166,
CC       ECO:0000269|PubMed:12122009, ECO:0000269|PubMed:15226403,
CC       ECO:0000269|PubMed:15908427, ECO:0000269|PubMed:16317043,
CC       ECO:0000269|PubMed:16878150, ECO:0000269|PubMed:17274988}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC         [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC         COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC         ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC         Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
CC   -!- ACTIVITY REGULATION: Activated by ligand-binding and subsequent
CC       phosphorylation. Inactivated through dephosphorylation by receptor
CC       protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) when
CC       there is no stimulation by a ligand. Staurosporine, crizotinib and
CC       CH5424802 act as inhibitors of ALK kinase activity.
CC       {ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:17681947,
CC       ECO:0000269|PubMed:21575866}.
CC   -!- SUBUNIT: Homodimer. Homodimerizes when bound to ligand
CC       (PubMed:16317043). Interacts with CBL, IRS1, PIK3R1 and PLCG1
CC       (PubMed:15226403). Interacts with FRS2 and SHC1 (PubMed:17274988,
CC       PubMed:16878150, PubMed:15226403). Interacts with PTN and MDK
CC       (PubMed:12122009, PubMed:11278720). {ECO:0000269|PubMed:11278720,
CC       ECO:0000269|PubMed:12122009, ECO:0000269|PubMed:15226403,
CC       ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:16878150,
CC       ECO:0000269|PubMed:17274988}.
CC   -!- INTERACTION:
CC       Q9UM73; Q9UM73: ALK; NbExp=10; IntAct=EBI-357361, EBI-357361;
CC       Q9UM73; Q6UXT8: ALKAL1; NbExp=7; IntAct=EBI-357361, EBI-11691642;
CC       Q9UM73; Q6UX46: ALKAL2; NbExp=5; IntAct=EBI-357361, EBI-11691780;
CC       Q9UM73; P08238: HSP90AB1; NbExp=2; IntAct=EBI-357361, EBI-352572;
CC       Q9UM73; P23471: PTPRZ1; NbExp=2; IntAct=EBI-357361, EBI-2263175;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:16317043,
CC       ECO:0000269|PubMed:9174053}; Single-pass type I membrane protein
CC       {ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:9174053}.
CC       Note=Membrane attachment was crucial for promotion of neuron-like
CC       differentiation and cell proliferation arrest through specific
CC       activation of the MAP kinase pathway.
CC   -!- TISSUE SPECIFICITY: Expressed in brain and CNS. Also expressed in the
CC       small intestine and testis, but not in normal lymphoid cells.
CC       {ECO:0000269|PubMed:9174053}.
CC   -!- PTM: Phosphorylated at tyrosine residues by autocatalysis, which
CC       activates kinase activity. In cells not stimulated by a ligand,
CC       receptor protein tyrosine phosphatase beta and zeta complex
CC       (PTPRB/PTPRZ1) dephosphorylates ALK at the sites in ALK that are
CC       undergoing autophosphorylation through autoactivation. Phosphorylation
CC       at Tyr-1507 is critical for SHC1 association.
CC       {ECO:0000269|PubMed:11121404, ECO:0000269|PubMed:15938644,
CC       ECO:0000269|PubMed:16878150, ECO:0000269|PubMed:17274988,
CC       ECO:0000269|PubMed:17681947}.
CC   -!- PTM: N-glycosylated. {ECO:0000269|PubMed:9174053}.
CC   -!- DISEASE: Note=A chromosomal aberration involving ALK is found in a form
CC       of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The
CC       resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes
CC       constitutively activated. The constitutively active fusion proteins are
CC       responsible for 5-10% of non-Hodgkin lymphomas.
CC   -!- DISEASE: Note=A chromosomal aberration involving ALK is associated with
CC       inflammatory myofibroblastic tumors (IMTs). Translocation
CC       t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A.
CC   -!- DISEASE: Note=A chromosomal aberration involving ALK is associated with
CC       anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25)
CC       with ALO17.
CC   -!- DISEASE: Neuroblastoma 3 (NBLST3) [MIM:613014]: A common neoplasm of
CC       early childhood arising from embryonic cells that form the primitive
CC       neural crest and give rise to the adrenal medulla and the sympathetic
CC       nervous system. {ECO:0000269|PubMed:18724359,
CC       ECO:0000269|PubMed:18923523, ECO:0000269|PubMed:18923525,
CC       ECO:0000269|PubMed:21242967}. Note=Disease susceptibility is associated
CC       with variations affecting the gene represented in this entry.
CC   -!- DISEASE: Note=The ALK signaling pathway plays an important role in
CC       glioblastoma, the most common malignant brain tumor of adults and one
CC       of the most lethal cancers. It regulates both glioblastoma migration
CC       and growth.
CC   -!- DISEASE: Note=A chromosomal aberration involving ALK is found in one
CC       subject with colorectal cancer. Translocation t(2;2)(p23.1;p23.3). A 5
CC       million base pair tandem duplication generates an in-frame WDCP-ALK
CC       gene fusion. {ECO:0000269|PubMed:22327622}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC       kinase family. Insulin receptor subfamily. {ECO:0000255|PROSITE-
CC       ProRule:PRU00159}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAD92714.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="http://atlasgeneticsoncology.org/Genes/ALKID16.html";
DR   EMBL; U62540; AAB71619.1; -; mRNA.
DR   EMBL; U66559; AAC51104.1; -; mRNA.
DR   EMBL; AB209477; BAD92714.1; ALT_INIT; mRNA.
DR   EMBL; AC106870; AAX93126.1; -; Genomic_DNA.
DR   EMBL; AC093756; AAX88892.1; -; Genomic_DNA.
DR   EMBL; AC074096; AAY15027.1; -; Genomic_DNA.
DR   CCDS; CCDS33172.1; -.
DR   RefSeq; NP_004295.2; NM_004304.4.
DR   PDB; 2KUP; NMR; -; B=1571-1589.
DR   PDB; 2KUQ; NMR; -; A=1571-1589.
DR   PDB; 2XB7; X-ray; 2.50 A; A=1094-1407.
DR   PDB; 2XBA; X-ray; 1.95 A; A=1094-1407.
DR   PDB; 2XP2; X-ray; 1.90 A; A=1093-1411.
DR   PDB; 2YFX; X-ray; 1.70 A; A=1093-1411.
DR   PDB; 2YHV; X-ray; 1.90 A; A=1093-1411.
DR   PDB; 2YJR; X-ray; 1.90 A; A=1093-1411.
DR   PDB; 2YJS; X-ray; 1.90 A; A=1093-1411.
DR   PDB; 2YS5; NMR; -; B=1571-1589.
DR   PDB; 2YT2; NMR; -; A=1571-1589.
DR   PDB; 3AOX; X-ray; 1.75 A; A=1069-1411.
DR   PDB; 3L9P; X-ray; 1.80 A; A=1072-1410.
DR   PDB; 3LCS; X-ray; 1.95 A; A=1072-1410.
DR   PDB; 3LCT; X-ray; 2.10 A; A=1072-1410.
DR   PDB; 4ANL; X-ray; 1.70 A; A=1093-1411.
DR   PDB; 4ANQ; X-ray; 1.76 A; A=1093-1411.
DR   PDB; 4ANS; X-ray; 1.85 A; A=1093-1411.
DR   PDB; 4CCB; X-ray; 2.03 A; A=1093-1411.
DR   PDB; 4CCU; X-ray; 2.00 A; A=1093-1411.
DR   PDB; 4CD0; X-ray; 2.23 A; A=1093-1411.
DR   PDB; 4CLI; X-ray; 2.05 A; A=1093-1411.
DR   PDB; 4CLJ; X-ray; 1.66 A; A=1093-1411.
DR   PDB; 4CMO; X-ray; 2.05 A; A=1093-1411.
DR   PDB; 4CMT; X-ray; 1.73 A; A=1093-1411.
DR   PDB; 4CMU; X-ray; 1.80 A; A=1093-1411.
DR   PDB; 4CNH; X-ray; 1.90 A; A/B=1093-1411.
DR   PDB; 4CTB; X-ray; 1.79 A; A=1093-1411.
DR   PDB; 4CTC; X-ray; 2.03 A; A=1093-1411.
DR   PDB; 4DCE; X-ray; 2.03 A; A/B=1078-1410.
DR   PDB; 4FNW; X-ray; 1.75 A; A=1084-1410.
DR   PDB; 4FNX; X-ray; 1.70 A; A=1084-1410.
DR   PDB; 4FNY; X-ray; 2.45 A; A=1084-1410.
DR   PDB; 4FNZ; X-ray; 2.60 A; A=1084-1410.
DR   PDB; 4FOB; X-ray; 1.90 A; A=1058-1410.
DR   PDB; 4FOC; X-ray; 1.70 A; A=1058-1410.
DR   PDB; 4FOD; X-ray; 2.00 A; A=1078-1410.
DR   PDB; 4JOA; X-ray; 2.70 A; A=1072-1410.
DR   PDB; 4MKC; X-ray; 2.01 A; A=1072-1410.
DR   PDB; 4TT7; X-ray; 2.10 A; A=1095-1410.
DR   PDB; 4Z55; X-ray; 1.55 A; A=1072-1410.
DR   PDB; 5A9U; X-ray; 1.60 A; A=1093-1411.
DR   PDB; 5AA8; X-ray; 1.86 A; A=1093-1411.
DR   PDB; 5AA9; X-ray; 1.93 A; A=1093-1411.
DR   PDB; 5AAA; X-ray; 1.73 A; A=1093-1411.
DR   PDB; 5AAB; X-ray; 2.20 A; A=1093-1411.
DR   PDB; 5AAC; X-ray; 1.70 A; A=1093-1411.
DR   PDB; 5FTO; X-ray; 2.22 A; A=1094-1407.
DR   PDB; 5FTQ; X-ray; 1.70 A; A=1094-1407.
DR   PDB; 5IMX; X-ray; 2.12 A; A=1093-1411.
DR   PDB; 5IUG; X-ray; 1.93 A; A=1084-1410.
DR   PDB; 5IUH; X-ray; 2.10 A; A=1084-1410.
DR   PDB; 5IUI; X-ray; 1.88 A; A=1084-1410.
DR   PDB; 5KZ0; X-ray; 2.30 A; A=1093-1411.
DR   PDB; 5VZ5; X-ray; 2.59 A; C=1274-1283.
DR   PDB; 6AT9; X-ray; 2.95 A; C=1274-1283.
DR   PDB; 6CDT; X-ray; 1.80 A; A=1093-1411.
DR   PDB; 6E0R; X-ray; 2.30 A; A=1090-1406.
DR   PDB; 6EBW; X-ray; 2.46 A; A=1090-1406.
DR   PDB; 6EDL; X-ray; 2.80 A; A=1090-1406.
DR   PDB; 6MX8; X-ray; 1.96 A; A=1094-1400.
DR   PDBsum; 2KUP; -.
DR   PDBsum; 2KUQ; -.
DR   PDBsum; 2XB7; -.
DR   PDBsum; 2XBA; -.
DR   PDBsum; 2XP2; -.
DR   PDBsum; 2YFX; -.
DR   PDBsum; 2YHV; -.
DR   PDBsum; 2YJR; -.
DR   PDBsum; 2YJS; -.
DR   PDBsum; 2YS5; -.
DR   PDBsum; 2YT2; -.
DR   PDBsum; 3AOX; -.
DR   PDBsum; 3L9P; -.
DR   PDBsum; 3LCS; -.
DR   PDBsum; 3LCT; -.
DR   PDBsum; 4ANL; -.
DR   PDBsum; 4ANQ; -.
DR   PDBsum; 4ANS; -.
DR   PDBsum; 4CCB; -.
DR   PDBsum; 4CCU; -.
DR   PDBsum; 4CD0; -.
DR   PDBsum; 4CLI; -.
DR   PDBsum; 4CLJ; -.
DR   PDBsum; 4CMO; -.
DR   PDBsum; 4CMT; -.
DR   PDBsum; 4CMU; -.
DR   PDBsum; 4CNH; -.
DR   PDBsum; 4CTB; -.
DR   PDBsum; 4CTC; -.
DR   PDBsum; 4DCE; -.
DR   PDBsum; 4FNW; -.
DR   PDBsum; 4FNX; -.
DR   PDBsum; 4FNY; -.
DR   PDBsum; 4FNZ; -.
DR   PDBsum; 4FOB; -.
DR   PDBsum; 4FOC; -.
DR   PDBsum; 4FOD; -.
DR   PDBsum; 4JOA; -.
DR   PDBsum; 4MKC; -.
DR   PDBsum; 4TT7; -.
DR   PDBsum; 4Z55; -.
DR   PDBsum; 5A9U; -.
DR   PDBsum; 5AA8; -.
DR   PDBsum; 5AA9; -.
DR   PDBsum; 5AAA; -.
DR   PDBsum; 5AAB; -.
DR   PDBsum; 5AAC; -.
DR   PDBsum; 5FTO; -.
DR   PDBsum; 5FTQ; -.
DR   PDBsum; 5IMX; -.
DR   PDBsum; 5IUG; -.
DR   PDBsum; 5IUH; -.
DR   PDBsum; 5IUI; -.
DR   PDBsum; 5KZ0; -.
DR   PDBsum; 5VZ5; -.
DR   PDBsum; 6AT9; -.
DR   PDBsum; 6CDT; -.
DR   PDBsum; 6E0R; -.
DR   PDBsum; 6EBW; -.
DR   PDBsum; 6EDL; -.
DR   PDBsum; 6MX8; -.
DR   BMRB; Q9UM73; -.
DR   SMR; Q9UM73; -.
DR   BioGRID; 106739; 71.
DR   DIP; DIP-5954N; -.
DR   IntAct; Q9UM73; 14.
DR   MINT; Q9UM73; -.
DR   STRING; 9606.ENSP00000373700; -.
DR   BindingDB; Q9UM73; -.
DR   ChEMBL; CHEMBL4247; -.
DR   DrugBank; DB11363; Alectinib.
DR   DrugBank; DB00171; ATP.
DR   DrugBank; DB12267; Brigatinib.
DR   DrugBank; DB09063; Ceritinib.
DR   DrugBank; DB08865; Crizotinib.
DR   DrugBank; DB12010; Fostamatinib.
DR   DrugBank; DB12141; Gilteritinib.
DR   DrugBank; DB12130; Lorlatinib.
DR   DrugCentral; Q9UM73; -.
DR   GuidetoPHARMACOLOGY; 1839; -.
DR   GlyGen; Q9UM73; 16 sites.
DR   iPTMnet; Q9UM73; -.
DR   PhosphoSitePlus; Q9UM73; -.
DR   BioMuta; ALK; -.
DR   DMDM; 296439447; -.
DR   EPD; Q9UM73; -.
DR   MassIVE; Q9UM73; -.
DR   PaxDb; Q9UM73; -.
DR   PeptideAtlas; Q9UM73; -.
DR   PRIDE; Q9UM73; -.
DR   ProteomicsDB; 85185; -.
DR   Antibodypedia; 2099; 1185 antibodies.
DR   DNASU; 238; -.
DR   Ensembl; ENST00000389048; ENSP00000373700; ENSG00000171094.
DR   GeneID; 238; -.
DR   KEGG; hsa:238; -.
DR   UCSC; uc002rmy.4; human.
DR   CTD; 238; -.
DR   DisGeNET; 238; -.
DR   EuPathDB; HostDB:ENSG00000171094.15; -.
DR   GeneCards; ALK; -.
DR   GeneReviews; ALK; -.
DR   HGNC; HGNC:427; ALK.
DR   HPA; ENSG00000171094; Tissue enhanced (brain, pituitary gland).
DR   MalaCards; ALK; -.
DR   MIM; 105590; gene.
DR   MIM; 613014; phenotype.
DR   neXtProt; NX_Q9UM73; -.
DR   OpenTargets; ENSG00000171094; -.
DR   Orphanet; 300895; ALK-positive anaplastic large cell lymphoma.
DR   Orphanet; 364043; ALK-positive large B-cell lymphoma.
DR   Orphanet; 146; Differentiated thyroid carcinoma.
DR   Orphanet; 178342; Inflammatory myofibroblastic tumor.
DR   Orphanet; 635; Neuroblastoma.
DR   Orphanet; 357191; Selection of therapeutic option in non-small cell lung carcinoma.
DR   PharmGKB; PA24719; -.
DR   eggNOG; KOG1095; Eukaryota.
DR   GeneTree; ENSGT00940000159280; -.
DR   InParanoid; Q9UM73; -.
DR   KO; K05119; -.
DR   OMA; TDRFWLQ; -.
DR   OrthoDB; 40108at2759; -.
DR   PhylomeDB; Q9UM73; -.
DR   TreeFam; TF351636; -.
DR   BRENDA; 2.7.10.1; 2681.
DR   PathwayCommons; Q9UM73; -.
DR   SignaLink; Q9UM73; -.
DR   SIGNOR; Q9UM73; -.
DR   BioGRID-ORCS; 238; 8 hits in 903 CRISPR screens.
DR   ChiTaRS; ALK; human.
DR   EvolutionaryTrace; Q9UM73; -.
DR   GeneWiki; Anaplastic_lymphoma_kinase; -.
DR   GenomeRNAi; 238; -.
DR   Pharos; Q9UM73; Tclin.
DR   PRO; PR:Q9UM73; -.
DR   Proteomes; UP000005640; Chromosome 2.
DR   RNAct; Q9UM73; protein.
DR   Bgee; ENSG00000171094; Expressed in sperm and 166 other tissues.
DR   ExpressionAtlas; Q9UM73; baseline and differential.
DR   Genevisible; Q9UM73; HS.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0032991; C:protein-containing complex; IDA:MGI.
DR   GO; GO:0043235; C:receptor complex; IBA:GO_Central.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0004704; F:NF-kappaB-inducing kinase activity; TAS:UniProtKB.
DR   GO; GO:0004713; F:protein tyrosine kinase activity; IDA:MGI.
DR   GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IDA:UniProtKB.
DR   GO; GO:0000187; P:activation of MAPK activity; TAS:UniProtKB.
DR   GO; GO:0030534; P:adult behavior; IEA:Ensembl.
DR   GO; GO:0021766; P:hippocampus development; IEA:Ensembl.
DR   GO; GO:0007275; P:multicellular organism development; IBA:GO_Central.
DR   GO; GO:0048666; P:neuron development; TAS:UniProtKB.
DR   GO; GO:0016310; P:phosphorylation; IDA:UniProtKB.
DR   GO; GO:1900006; P:positive regulation of dendrite development; ISS:UniProtKB.
DR   GO; GO:0033674; P:positive regulation of kinase activity; IBA:GO_Central.
DR   GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; TAS:UniProtKB.
DR   GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR   GO; GO:0042981; P:regulation of apoptotic process; TAS:UniProtKB.
DR   GO; GO:0042127; P:regulation of cell population proliferation; IBA:GO_Central.
DR   GO; GO:0060159; P:regulation of dopamine receptor signaling pathway; IEA:Ensembl.
DR   GO; GO:0045664; P:regulation of neuron differentiation; IBA:GO_Central.
DR   GO; GO:0090648; P:response to environmental enrichment; IEA:Ensembl.
DR   GO; GO:0007165; P:signal transduction; TAS:UniProtKB.
DR   GO; GO:0036269; P:swimming behavior; IEA:Ensembl.
DR   GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR   CDD; cd00112; LDLa; 1.
DR   CDD; cd06263; MAM; 2.
DR   Gene3D; 4.10.400.10; -; 1.
DR   InterPro; IPR026830; ALK.
DR   InterPro; IPR013320; ConA-like_dom_sf.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR036055; LDL_receptor-like_sf.
DR   InterPro; IPR002172; LDrepeatLR_classA_rpt.
DR   InterPro; IPR000998; MAM_dom.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR   InterPro; IPR008266; Tyr_kinase_AS.
DR   InterPro; IPR020635; Tyr_kinase_cat_dom.
DR   InterPro; IPR002011; Tyr_kinase_rcpt_2_CS.
DR   PANTHER; PTHR24416:SF276; PTHR24416:SF276; 1.
DR   Pfam; PF00629; MAM; 2.
DR   Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR   PRINTS; PR00109; TYRKINASE.
DR   SMART; SM00192; LDLa; 1.
DR   SMART; SM00219; TyrKc; 1.
DR   SUPFAM; SSF49899; SSF49899; 2.
DR   SUPFAM; SSF56112; SSF56112; 1.
DR   SUPFAM; SSF57424; SSF57424; 1.
DR   PROSITE; PS50060; MAM_2; 2.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR   PROSITE; PS00239; RECEPTOR_TYR_KIN_II; 1.
PE   1: Evidence at protein level;
KW   3D-structure; ATP-binding; Cell membrane; Chromosomal rearrangement;
KW   Disease mutation; Glycoprotein; Kinase; Membrane; Nucleotide-binding;
KW   Phosphoprotein; Polymorphism; Proto-oncogene; Receptor; Reference proteome;
KW   Repeat; Signal; Transferase; Transmembrane; Transmembrane helix;
KW   Tyrosine-protein kinase.
FT   SIGNAL          1..18
FT                   /evidence="ECO:0000255"
FT   CHAIN           19..1620
FT                   /note="ALK tyrosine kinase receptor"
FT                   /id="PRO_0000016740"
FT   TOPO_DOM        19..1038
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1039..1059
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        1060..1620
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          264..427
FT                   /note="MAM 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00128"
FT   DOMAIN          437..473
FT                   /note="LDL-receptor class A"
FT   DOMAIN          478..636
FT                   /note="MAM 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00128"
FT   DOMAIN          1116..1392
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   NP_BIND         1197..1199
FT                   /note="ATP"
FT   REGION          1197..1199
FT                   /note="Inhibitor binding"
FT   COMPBIAS        816..940
FT                   /note="Gly-rich"
FT   ACT_SITE        1249
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10028"
FT   BINDING         1124
FT                   /note="ATP; via carbonyl oxygen"
FT   BINDING         1150
FT                   /note="ATP"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         1150
FT                   /note="Inhibitor"
FT                   /evidence="ECO:0000269|PubMed:20695522,
FT                   ECO:0000269|PubMed:21575866"
FT   BINDING         1199
FT                   /note="Inhibitor; via amide nitrogen"
FT                   /evidence="ECO:0000269|PubMed:20695522,
FT                   ECO:0000269|PubMed:21575866"
FT   BINDING         1203
FT                   /note="Inhibitor"
FT                   /evidence="ECO:0000269|PubMed:20695522,
FT                   ECO:0000269|PubMed:21575866"
FT   BINDING         1210
FT                   /note="Inhibitor"
FT                   /evidence="ECO:0000269|PubMed:20695522,
FT                   ECO:0000269|PubMed:21575866"
FT   BINDING         1270
FT                   /note="ATP"
FT   MOD_RES         1078
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000244|PubMed:15592455"
FT   MOD_RES         1092
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:P97793"
FT   MOD_RES         1096
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000244|PubMed:15592455,
FT                   ECO:0000269|PubMed:16878150"
FT   MOD_RES         1131
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000244|PubMed:15592455"
FT   MOD_RES         1278
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000269|PubMed:15938644"
FT   MOD_RES         1507
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000269|PubMed:17274988"
FT   MOD_RES         1604
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000244|PubMed:15592455"
FT   CARBOHYD        169
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        244
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        285
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        324
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        411
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        424
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        445
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        563
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        571
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        627
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        709
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        808
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        863
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        864
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        886
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        986
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   VARIANT         90
FT                   /note="S -> L (in dbSNP:rs34617074)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041477"
FT   VARIANT         163
FT                   /note="V -> L (in dbSNP:rs55697431)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041478"
FT   VARIANT         296
FT                   /note="E -> Q (in dbSNP:rs56077855)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041479"
FT   VARIANT         476
FT                   /note="V -> A (in dbSNP:rs35093491)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041480"
FT   VARIANT         560
FT                   /note="L -> F (in a breast pleomorphic lobular carcinoma
FT                   sample; somatic mutation)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041481"
FT   VARIANT         680
FT                   /note="T -> I (in dbSNP:rs35228363)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041482"
FT   VARIANT         704
FT                   /note="A -> T (in dbSNP:rs34829159)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041483"
FT   VARIANT         868
FT                   /note="L -> Q (in dbSNP:rs55941323)"
FT                   /id="VAR_061288"
FT   VARIANT         877
FT                   /note="A -> S (in an ovarian serous carcinoma sample;
FT                   somatic mutation; dbSNP:rs746442213)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041484"
FT   VARIANT         1012
FT                   /note="T -> M (in dbSNP:rs35073634)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041485"
FT   VARIANT         1091
FT                   /note="D -> N (in NBLST3; somatic mutation;
FT                   dbSNP:rs864309584)"
FT                   /evidence="ECO:0000269|PubMed:18724359"
FT                   /id="VAR_063850"
FT   VARIANT         1121
FT                   /note="G -> D (in dbSNP:rs55760835)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041486"
FT   VARIANT         1128
FT                   /note="G -> A (in NBLST3; dbSNP:rs113994088)"
FT                   /evidence="ECO:0000269|PubMed:18724359"
FT                   /id="VAR_063851"
FT   VARIANT         1151
FT                   /note="T -> M (in NBLST3; dbSNP:rs113994091)"
FT                   /evidence="ECO:0000269|PubMed:18923525"
FT                   /id="VAR_063852"
FT   VARIANT         1166
FT                   /note="M -> R (in NBLST3; somatic mutation;
FT                   dbSNP:rs1057520019)"
FT                   /evidence="ECO:0000269|PubMed:18724359"
FT                   /id="VAR_063853"
FT   VARIANT         1171
FT                   /note="I -> N (in NBLST3; somatic mutation;
FT                   dbSNP:rs1057519698)"
FT                   /evidence="ECO:0000269|PubMed:18724359"
FT                   /id="VAR_063854"
FT   VARIANT         1174
FT                   /note="F -> C (in NBLST3; dbSNP:rs1057519697)"
FT                   /evidence="ECO:0000269|PubMed:18923523"
FT                   /id="VAR_063855"
FT   VARIANT         1174
FT                   /note="F -> I (in NBLST3; somatic mutation;
FT                   dbSNP:rs281864719)"
FT                   /evidence="ECO:0000269|PubMed:18724359"
FT                   /id="VAR_063856"
FT   VARIANT         1174
FT                   /note="F -> L (in NBLST3; somatic mutation; constitutively
FT                   activated; retained in the endoplasmic reticulum and Golgi
FT                   compartments; dbSNP:rs863225281)"
FT                   /evidence="ECO:0000269|PubMed:18923523,
FT                   ECO:0000269|PubMed:18923525, ECO:0000269|PubMed:21242967"
FT                   /id="VAR_063857"
FT   VARIANT         1174
FT                   /note="F -> V (in NBLST3; somatic mutation; constitutively
FT                   activated; retained in the endoplasmic reticulum and Golgi
FT                   compartments; dbSNP:rs281864719)"
FT                   /evidence="ECO:0000269|PubMed:18923523,
FT                   ECO:0000269|PubMed:21242967"
FT                   /id="VAR_063858"
FT   VARIANT         1192
FT                   /note="R -> P (in NBLST3; dbSNP:rs113994089)"
FT                   /evidence="ECO:0000269|PubMed:18724359,
FT                   ECO:0000269|PubMed:18923523"
FT                   /id="VAR_063859"
FT   VARIANT         1234
FT                   /note="A -> T (in NBLST3; somatic mutation)"
FT                   /evidence="ECO:0000269|PubMed:18923525"
FT                   /id="VAR_063860"
FT   VARIANT         1245
FT                   /note="F -> C (in NBLST3; somatic mutation;
FT                   dbSNP:rs863225283)"
FT                   /evidence="ECO:0000269|PubMed:18724359,
FT                   ECO:0000269|PubMed:18923525"
FT                   /id="VAR_063861"
FT   VARIANT         1245
FT                   /note="F -> V (in NBLST3; somatic mutation;
FT                   dbSNP:rs281864720)"
FT                   /id="VAR_063862"
FT   VARIANT         1250
FT                   /note="I -> T (in NBLST3; somatic mutation;
FT                   dbSNP:rs113994092)"
FT                   /evidence="ECO:0000269|PubMed:18724359"
FT                   /id="VAR_063863"
FT   VARIANT         1274
FT                   /note="A -> T (in dbSNP:rs45502292)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041487"
FT   VARIANT         1275
FT                   /note="R -> L (observed in neuroblastoma;
FT                   dbSNP:rs113994087)"
FT                   /evidence="ECO:0000269|PubMed:18923523"
FT                   /id="VAR_063864"
FT   VARIANT         1275
FT                   /note="R -> Q (in NBLST3; constitutively activated;
FT                   retained in the endoplasmic reticulum and Golgi
FT                   compartments; dbSNP:rs113994087)"
FT                   /evidence="ECO:0000269|PubMed:18724359,
FT                   ECO:0000269|PubMed:18923523, ECO:0000269|PubMed:18923525,
FT                   ECO:0000269|PubMed:21242967"
FT                   /id="VAR_063865"
FT   VARIANT         1278
FT                   /note="Y -> S (in NBLST3; somatic mutation;
FT                   dbSNP:rs863225285)"
FT                   /evidence="ECO:0000269|PubMed:18923523"
FT                   /id="VAR_063866"
FT   VARIANT         1328
FT                   /note="M -> L (in dbSNP:rs56160491)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041488"
FT   VARIANT         1376
FT                   /note="F -> S (in dbSNP:rs17694720)"
FT                   /id="VAR_055987"
FT   VARIANT         1416
FT                   /note="K -> N (in dbSNP:rs55782189)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041489"
FT   VARIANT         1419
FT                   /note="E -> K (in dbSNP:rs56181542)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041490"
FT   VARIANT         1429
FT                   /note="Q -> R (in dbSNP:rs55906201)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041491"
FT   VARIANT         1461
FT                   /note="I -> V (in dbSNP:rs1670283)"
FT                   /evidence="ECO:0000269|PubMed:8122112,
FT                   ECO:0000269|PubMed:9053841, ECO:0000269|PubMed:9174053,
FT                   ECO:0000269|Ref.4"
FT                   /id="VAR_031042"
FT   VARIANT         1491
FT                   /note="K -> R (in dbSNP:rs1881420)"
FT                   /evidence="ECO:0000269|PubMed:17344846,
FT                   ECO:0000269|PubMed:9053841, ECO:0000269|Ref.4"
FT                   /id="VAR_031043"
FT   VARIANT         1529
FT                   /note="D -> E (in dbSNP:rs1881421)"
FT                   /evidence="ECO:0000269|PubMed:17344846,
FT                   ECO:0000269|PubMed:9053841, ECO:0000269|Ref.4"
FT                   /id="VAR_031044"
FT   VARIANT         1599
FT                   /note="P -> H (in dbSNP:rs1881423)"
FT                   /id="VAR_055988"
FT   MUTAGEN         1507
FT                   /note="Y->F: Impairs interaction with SHC1."
FT                   /evidence="ECO:0000269|PubMed:17274988"
FT   CONFLICT        36
FT                   /note="P -> S (in Ref. 1; AAB71619)"
FT                   /evidence="ECO:0000305"
FT   HELIX           1087..1092
FT                   /evidence="ECO:0000244|PDB:3AOX"
FT   STRAND          1096..1098
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   STRAND          1101..1103
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   HELIX           1105..1107
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   HELIX           1113..1115
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   STRAND          1116..1124
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   STRAND          1126..1135
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   STRAND          1137..1140
FT                   /evidence="ECO:0000244|PDB:3LCS"
FT   STRAND          1145..1152
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   STRAND          1154..1156
FT                   /evidence="ECO:0000244|PDB:5IUI"
FT   HELIX           1158..1173
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   STRAND          1182..1186
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   STRAND          1188..1197
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   HELIX           1204..1211
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   STRAND          1215..1217
FT                   /evidence="ECO:0000244|PDB:5A9U"
FT   HELIX           1223..1242
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   HELIX           1252..1254
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   STRAND          1255..1258
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   STRAND          1260..1263
FT                   /evidence="ECO:0000244|PDB:4DCE"
FT   STRAND          1266..1268
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   HELIX           1272..1280
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   HELIX           1288..1290
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   HELIX           1293..1295
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   HELIX           1298..1303
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   HELIX           1308..1323
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   HELIX           1335..1343
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   HELIX           1356..1365
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   HELIX           1370..1372
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   HELIX           1376..1388
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   HELIX           1390..1393
FT                   /evidence="ECO:0000244|PDB:4Z55"
FT   STRAND          1574..1576
FT                   /evidence="ECO:0000244|PDB:2KUP"
FT   STRAND          1582..1584
FT                   /evidence="ECO:0000244|PDB:2YT2"
SQ   SEQUENCE   1620 AA;  176442 MW;  0733D6C4FD212F41 CRC64;
     MGAIGLLWLL PLLLSTAAVG SGMGTGQRAG SPAAGPPLQP REPLSYSRLQ RKSLAVDFVV
     PSLFRVYARD LLLPPSSSEL KAGRPEARGS LALDCAPLLR LLGPAPGVSW TAGSPAPAEA
     RTLSRVLKGG SVRKLRRAKQ LVLELGEEAI LEGCVGPPGE AAVGLLQFNL SELFSWWIRQ
     GEGRLRIRLM PEKKASEVGR EGRLSAAIRA SQPRLLFQIF GTGHSSLESP TNMPSPSPDY
     FTWNLTWIMK DSFPFLSHRS RYGLECSFDF PCELEYSPPL HDLRNQSWSW RRIPSEEASQ
     MDLLDGPGAE RSKEMPRGSF LLLNTSADSK HTILSPWMRS SSEHCTLAVS VHRHLQPSGR
     YIAQLLPHNE AAREILLMPT PGKHGWTVLQ GRIGRPDNPF RVALEYISSG NRSLSAVDFF
     ALKNCSEGTS PGSKMALQSS FTCWNGTVLQ LGQACDFHQD CAQGEDESQM CRKLPVGFYC
     NFEDGFCGWT QGTLSPHTPQ WQVRTLKDAR FQDHQDHALL LSTTDVPASE SATVTSATFP
     APIKSSPCEL RMSWLIRGVL RGNVSLVLVE NKTGKEQGRM VWHVAAYEGL SLWQWMVLPL
     LDVSDRFWLQ MVAWWGQGSR AIVAFDNISI SLDCYLTISG EDKILQNTAP KSRNLFERNP
     NKELKPGENS PRQTPIFDPT VHWLFTTCGA SGPHGPTQAQ CNNAYQNSNL SVEVGSEGPL
     KGIQIWKVPA TDTYSISGYG AAGGKGGKNT MMRSHGVSVL GIFNLEKDDM LYILVGQQGE
     DACPSTNQLI QKVCIGENNV IEEEIRVNRS VHEWAGGGGG GGGATYVFKM KDGVPVPLII
     AAGGGGRAYG AKTDTFHPER LENNSSVLGL NGNSGAAGGG GGWNDNTSLL WAGKSLQEGA
     TGGHSCPQAM KKWGWETRGG FGGGGGGCSS GGGGGGYIGG NAASNNDPEM DGEDGVSFIS
     PLGILYTPAL KVMEGHGEVN IKHYLNCSHC EVDECHMDPE SHKVICFCDH GTVLAEDGVS
     CIVSPTPEPH LPLSLILSVV TSALVAALVL AFSGIMIVYR RKHQELQAMQ MELQSPEYKL
     SKLRTSTIMT DYNPNYCFAG KTSSISDLKE VPRKNITLIR GLGHGAFGEV YEGQVSGMPN
     DPSPLQVAVK TLPEVCSEQD ELDFLMEALI ISKFNHQNIV RCIGVSLQSL PRFILLELMA
     GGDLKSFLRE TRPRPSQPSS LAMLDLLHVA RDIACGCQYL EENHFIHRDI AARNCLLTCP
     GPGRVAKIGD FGMARDIYRA SYYRKGGCAM LPVKWMPPEA FMEGIFTSKT DTWSFGVLLW
     EIFSLGYMPY PSKSNQEVLE FVTSGGRMDP PKNCPGPVYR IMTQCWQHQP EDRPNFAIIL
     ERIEYCTQDP DVINTALPIE YGPLVEEEEK VPVRPKDPEG VPPLLVSQQA KREEERSPAA
     PPPLPTTSSG KAAKKPTAAE ISVRVPRGPA VEGGHVNMAF SQSNPPSELH KVHGSRNKPT
     SLWNPTYGSW FTEKPTKKNN PIAKKEPHDR GNLGLEGSCT VPPNVATGRL PGASLLLEPS
     SLTANMKEVP LFRLRHFPCG NVNYGYQQQG LPLEAATAPG AGHYEDTILK SKNSMNQPGP
//
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