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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   05-JUN-2019, entry version 198.
DE   RecName: Full=ALK tyrosine kinase receptor;
DE            EC=2.7.10.1;
DE   AltName: Full=Anaplastic lymphoma kinase;
DE   AltName: CD_antigen=CD246;
DE   Flags: Precursor;
GN   Name=ALK;
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], 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-
RT   Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase
RT   that is highly related to leukocyte tyrosine kinase (LTK).";
RL   Oncogene 14:2175-2188(1997).
RN   [2]
RP   ERRATUM.
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
RP   GLU-1529.
RX   PubMed=9053841; DOI=10.1038/sj.onc.1200849;
RA   Iwahara T., Fujimoto J., Wen D., Cupples R., Bucay N., Arakawa T.,
RA   Mori S., Ratzkin B., Yamamoto T.;
RT   "Molecular characterization of ALK, a receptor tyrosine kinase
RT   expressed specifically in the nervous system.";
RL   Oncogene 14:439-449(1997).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS VAL-1461;
RP   ARG-1491 AND 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.,
RA   Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA   Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA   Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA   Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA   Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA   Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA   Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA   Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA   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.,
RA   Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA   Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA   Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA   Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA   Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA   Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA   Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA   Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA   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.,
RA   Waterston R.H., Wilson R.K.;
RT   "Generation and annotation of the DNA sequences of human chromosomes 2
RT   and 4.";
RL   Nature 434:724-731(2005).
RN   [6]
RP   PARTIAL NUCLEOTIDE SEQUENCE [MRNA], CHROMOSOMAL TRANSLOCATION WITH
RP   NPM1, 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.,
RA   Shapiro D.N., Saltman D.L., Look A.T.;
RT   "Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in
RT   non-Hodgkin's lymphoma.";
RL   Science 263:1281-1284(1994).
RN   [7]
RP   FUNCTION AS AN ONCOGENE.
RX   PubMed=11387242;
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
RT   induces neuronal differentiation through the mitogen-activated protein
RT   kinase 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
RT   growth 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
RT   lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory
RT   myofibroblastic 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-
RT   limiting 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,
RT   anaplastic 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
RT   growth 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
RT   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
RT   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.,
RA   Wang M.Y., Cloughesy T.F., Nelson S.F., Mischel P.S.;
RT   "Differential induction of glioblastoma migration and growth by two
RT   forms 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
RP   AND TYR-1604, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP   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
RT   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
RT   myofibroblastic tumor.";
RL   Int. J. Cancer 118:1181-1186(2006).
RN   [20]
RP   INTERACTION WITH FRS2 AND SHC1, PHOSPHORYLATION AT TYR-1507,
RP   MUTAGENESIS OF TYR-1507, AND FUNCTION IN PHOSPHORYLATION OF FRS2;
RP   MAPK1/ERK2; MAPK3/ERK1 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
RT   phenotypic 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
RT   pleiotrophin/receptor protein-tyrosine phosphatase beta/zeta signaling
RT   pathway: an alternative mechanism of receptor tyrosine kinase
RT   activation.";
RL   J. Biol. Chem. 282:28683-28690(2007).
RN   [22]
RP   INTERACTION WITH IRS1 AND SHC, PHOSPHORYLATION AT TYR-1096, AND
RP   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-
RT   kappaB essential for midkine growth signaling through anaplastic
RT   lymphoma 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.,
RA   White E., White J., Zwirko Z., Peretz T., Nechushtan H.,
RA   Soussan-Gutman L., Kim J., Sasaki H., Kim H.R., Park S.I., Ercan D.,
RA   Sheehan C.E., Ross J.S., Cronin M.T., Jaenne P.A., Stephens P.J.;
RT   "Identification of new ALK and RET gene fusions from colorectal and
RT   lung 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.,
RA   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.,
RA   Yabuki T., Harada T., Watanabe S., Tanaka A., Shirouzu M., Kigawa T.,
RA   Yamamoto T., Yokoyama S.;
RT   "Structural basis for the recognition of nucleophosmin-anaplastic
RT   lymphoma kinase oncoprotein by the phosphotyrosine binding domain of
RT   Suc1-associated neurotrophic factor-induced tyrosine-phosphorylated
RT   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
RT   resistant gatekeeper mutant.";
RL   Cancer Cell 19:679-690(2011).
RN   [31]
RP   VARIANTS [LARGE SCALE ANALYSIS] LEU-90; LEU-163; GLN-296; ALA-476;
RP   PHE-560; ILE-680; THR-704; SER-877; MET-1012; ASP-1121; THR-1274;
RP   LEU-1328; 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.,
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).
RN   [32]
RP   VARIANTS NBLST3 ASN-1091; ALA-1128; ARG-1166; ASN-1171; ILE-1174;
RP   PRO-1192; 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.,
RA   Attiyeh E.F., Laquaglia M.J., Sennett R., Lynch J.E., Perri P.,
RA   Laureys G., Speleman F., Kim C., Hou C., Hakonarson H., Torkamani A.,
RA   Schork N.J., Brodeur G.M., Tonini G.P., Rappaport E., Devoto M.,
RA   Maris J.M.;
RT   "Identification of ALK as a major familial neuroblastoma
RT   predisposition 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.,
RA   de Pontual L., Combaret V., Raynal V., Puisieux A., Schleiermacher G.,
RA   Pierron G., Valteau-Couanet D., Frebourg T., Michon J., Lyonnet S.,
RA   Amiel J., Delattre O.;
RT   "Somatic and germline activating mutations of the ALK kinase receptor
RT   in 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.,
RA   Gregor V.E., Webb T.R., Gray N.S., Gilliland D.G., Diller L.,
RA   Greulich H., Morris S.W., 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.,
RA   Combaret V., Hallberg B., Palmer R.H., Delattre O.,
RA   Janoueix-Lerosey I., Vigny M.;
RT   "The constitutive activity of the ALK mutated at positions F1174 or
RT   R1275 impairs receptor trafficking.";
RL   Oncogene 30:2017-2025(2011).
CC   -!- FUNCTION: Neuronal receptor tyrosine kinase that is essentially
CC       and transiently expressed in specific regions of the central and
CC       peripheral nervous systems and plays an important role in the
CC       genesis and differentiation of the nervous system. Transduces
CC       signals from ligands at the cell surface, through specific
CC       activation of the mitogen-activated protein kinase (MAPK) pathway.
CC       Phosphorylates almost exclusively at the first tyrosine of the Y-
CC       x-x-x-Y-Y motif. Following activation by ligand, ALK induces
CC       tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as
CC       of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor
CC       for ligands pleiotrophin (PTN), a secreted growth factor, and
CC       midkine (MDK), a PTN-related factor, thus participating in PTN and
CC       MDK signal transduction. PTN-binding induces MAPK pathway
CC       activation, which is important for the anti-apoptotic signaling of
CC       PTN and regulation of cell proliferation. MDK-binding induces
CC       phosphorylation of the ALK target insulin receptor substrate
CC       (IRS1), activates mitogen-activated protein kinases (MAPKs) and
CC       PI3-kinase, resulting also in cell proliferation induction. Drives
CC       NF-kappa-B activation, probably through IRS1 and the activation of
CC       the AKT serine/threonine kinase. Recruitment of IRS1 to activated
CC       ALK and the activation of NF-kappa-B are essential for the
CC       autocrine growth and survival signaling of MDK.
CC       {ECO:0000269|PubMed:11121404, ECO:0000269|PubMed:11278720,
CC       ECO:0000269|PubMed:11387242, ECO:0000269|PubMed:11809760,
CC       ECO:0000269|PubMed:12107166, ECO:0000269|PubMed:12122009,
CC       ECO:0000269|PubMed:15226403, ECO:0000269|PubMed:15908427,
CC       ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:16878150,
CC       ECO:0000269|PubMed:17274988}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-
CC         tyrosyl-[protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136,
CC         Rhea:RHEA-COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216;
CC         EC=2.7.10.1; 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)
CC       when there is no stimulation by a ligand. Staurosporine,
CC       crizotinib and 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. Interacts
CC       with FRS2, IRS1, MDK, PTN and SHC1. Interacts with CBL, PIK3R1 and
CC       PLCG1 (By similarity). {ECO:0000250}.
CC   -!- INTERACTION:
CC       Self; NbExp=10; IntAct=EBI-357361, EBI-357361;
CC       Q6UXT8:ALKAL1; NbExp=7; IntAct=EBI-357361, EBI-11691642;
CC       Q6UX46:ALKAL2; NbExp=5; IntAct=EBI-357361, EBI-11691780;
CC       P08238:HSP90AB1; NbExp=2; IntAct=EBI-357361, EBI-352572;
CC       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
CC       the 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.
CC       Phosphorylation 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
CC       form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with
CC       NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the
CC       kinase becomes constitutively activated. The constitutively active
CC       fusion proteins are responsible for 5-10% of non-Hodgkin
CC       lymphomas.
CC   -!- DISEASE: Note=A chromosomal aberration involving ALK is associated
CC       with inflammatory myofibroblastic tumors (IMTs). Translocation
CC       t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with
CC       SEC31A.
CC   -!- DISEASE: Note=A chromosomal aberration involving ALK is associated
CC       with anaplastic large-cell lymphoma (ALCL). Translocation
CC       t(2;17)(p23;q25) with ALO17.
CC   -!- DISEASE: Neuroblastoma 3 (NBLST3) [MIM:613014]: A common neoplasm
CC       of early childhood arising from embryonic cells that form the
CC       primitive neural crest and give rise to the adrenal medulla and
CC       the sympathetic nervous system. {ECO:0000269|PubMed:18724359,
CC       ECO:0000269|PubMed:18923523, ECO:0000269|PubMed:18923525,
CC       ECO:0000269|PubMed:21242967}. Note=Disease susceptibility is
CC       associated with variations affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Note=The ALK signaling pathway plays an important role in
CC       glioblastoma, the most common malignant brain tumor of adults and
CC       one of the most lethal cancers. It regulates both glioblastoma
CC       migration and growth.
CC   -!- DISEASE: Note=A chromosomal aberration involving ALK is found in
CC       one subject with colorectal cancer. Translocation
CC       t(2;2)(p23.1;p23.3). A 5 million base pair tandem duplication
CC       generates an in-frame WDCP-ALK gene fusion.
CC       {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=Translation N-terminally shortened.; Evidence={ECO:0000305};
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC       and 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; 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; 6MX8; -.
DR   SMR; Q9UM73; -.
DR   BioGrid; 106739; 68.
DR   DIP; DIP-5954N; -.
DR   IntAct; Q9UM73; 12.
DR   MINT; Q9UM73; -.
DR   STRING; 9606.ENSP00000373700; -.
DR   BindingDB; Q9UM73; -.
DR   ChEMBL; CHEMBL4247; -.
DR   DrugBank; DB00171; Adenosine triphosphate.
DR   DrugBank; DB11363; Alectinib.
DR   DrugBank; DB09063; Ceritinib.
DR   DrugBank; DB08865; Crizotinib.
DR   GuidetoPHARMACOLOGY; 1839; -.
DR   iPTMnet; Q9UM73; -.
DR   PhosphoSitePlus; Q9UM73; -.
DR   BioMuta; ALK; -.
DR   DMDM; 296439447; -.
DR   EPD; Q9UM73; -.
DR   jPOST; Q9UM73; -.
DR   PaxDb; Q9UM73; -.
DR   PeptideAtlas; Q9UM73; -.
DR   PRIDE; Q9UM73; -.
DR   ProteomicsDB; 85185; -.
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   GeneCards; ALK; -.
DR   GeneReviews; ALK; -.
DR   H-InvDB; HIX0024259; -.
DR   H-InvDB; HIX0030037; -.
DR   HGNC; HGNC:427; ALK.
DR   HPA; HPA010694; -.
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   eggNOG; ENOG410XPVX; LUCA.
DR   GeneTree; ENSGT00940000159280; -.
DR   HOGENOM; HOG000231766; -.
DR   InParanoid; Q9UM73; -.
DR   KO; K05119; -.
DR   OMA; HKVQGSR; -.
DR   OrthoDB; 731388at2759; -.
DR   PhylomeDB; Q9UM73; -.
DR   TreeFam; TF351636; -.
DR   BRENDA; 2.7.10.1; 2681.
DR   SignaLink; Q9UM73; -.
DR   SIGNOR; Q9UM73; -.
DR   ChiTaRS; ALK; human.
DR   EvolutionaryTrace; Q9UM73; -.
DR   GeneWiki; Anaplastic_lymphoma_kinase; -.
DR   GenomeRNAi; 238; -.
DR   PRO; PR:Q9UM73; -.
DR   Proteomes; UP000005640; Chromosome 2.
DR   Bgee; ENSG00000171094; Expressed in 144 organ(s), highest expression level in sperm.
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:0008283; P:cell population proliferation; TAS:UniProtKB.
DR   GO; GO:0021766; P:hippocampus development; IEA:Ensembl.
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: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; Pkinase_Tyr; 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   Complete proteome; Disease mutation; Glycoprotein; Kinase; Membrane;
KW   Nucleotide-binding; Phosphoprotein; Polymorphism; Proto-oncogene;
KW   Receptor; Reference proteome; Repeat; Signal; Transferase;
KW   Transmembrane; Transmembrane helix; Tyrosine-protein kinase.
FT   SIGNAL        1     18       {ECO:0000255}.
FT   CHAIN        19   1620       ALK tyrosine kinase receptor.
FT                                /FTId=PRO_0000016740.
FT   TOPO_DOM     19   1038       Extracellular. {ECO:0000255}.
FT   TRANSMEM   1039   1059       Helical. {ECO:0000255}.
FT   TOPO_DOM   1060   1620       Cytoplasmic. {ECO:0000255}.
FT   DOMAIN      264    427       MAM 1. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00128}.
FT   DOMAIN      437    473       LDL-receptor class A.
FT   DOMAIN      478    636       MAM 2. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00128}.
FT   DOMAIN     1116   1392       Protein kinase. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159}.
FT   NP_BIND    1197   1199       ATP.
FT   REGION     1197   1199       Inhibitor binding.
FT   COMPBIAS    816    940       Gly-rich.
FT   ACT_SITE   1249   1249       Proton acceptor. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159, ECO:0000255|PROSITE-
FT                                ProRule:PRU10028}.
FT   BINDING    1124   1124       ATP; via carbonyl oxygen.
FT   BINDING    1150   1150       ATP. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159}.
FT   BINDING    1150   1150       Inhibitor. {ECO:0000269|PubMed:20695522,
FT                                ECO:0000269|PubMed:21575866}.
FT   BINDING    1199   1199       Inhibitor; via amide nitrogen.
FT                                {ECO:0000269|PubMed:20695522,
FT                                ECO:0000269|PubMed:21575866}.
FT   BINDING    1203   1203       Inhibitor. {ECO:0000269|PubMed:20695522,
FT                                ECO:0000269|PubMed:21575866}.
FT   BINDING    1210   1210       Inhibitor. {ECO:0000269|PubMed:20695522,
FT                                ECO:0000269|PubMed:21575866}.
FT   BINDING    1270   1270       ATP.
FT   MOD_RES    1078   1078       Phosphotyrosine.
FT                                {ECO:0000244|PubMed:15592455}.
FT   MOD_RES    1092   1092       Phosphotyrosine.
FT                                {ECO:0000250|UniProtKB:P97793}.
FT   MOD_RES    1096   1096       Phosphotyrosine.
FT                                {ECO:0000244|PubMed:15592455,
FT                                ECO:0000269|PubMed:16878150}.
FT   MOD_RES    1131   1131       Phosphotyrosine.
FT                                {ECO:0000244|PubMed:15592455}.
FT   MOD_RES    1278   1278       Phosphotyrosine.
FT                                {ECO:0000269|PubMed:15938644}.
FT   MOD_RES    1507   1507       Phosphotyrosine.
FT                                {ECO:0000269|PubMed:17274988}.
FT   MOD_RES    1604   1604       Phosphotyrosine.
FT                                {ECO:0000244|PubMed:15592455}.
FT   CARBOHYD    169    169       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    244    244       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    285    285       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    324    324       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    411    411       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    424    424       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    445    445       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    563    563       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    571    571       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    627    627       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    709    709       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    808    808       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    863    863       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    864    864       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    886    886       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    986    986       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   VARIANT      90     90       S -> L (in dbSNP:rs34617074).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041477.
FT   VARIANT     163    163       V -> L (in dbSNP:rs55697431).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041478.
FT   VARIANT     296    296       E -> Q (in dbSNP:rs56077855).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041479.
FT   VARIANT     476    476       V -> A (in dbSNP:rs35093491).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041480.
FT   VARIANT     560    560       L -> F (in a breast pleomorphic lobular
FT                                carcinoma sample; somatic mutation).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041481.
FT   VARIANT     680    680       T -> I (in dbSNP:rs35228363).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041482.
FT   VARIANT     704    704       A -> T (in dbSNP:rs34829159).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041483.
FT   VARIANT     868    868       L -> Q (in dbSNP:rs55941323).
FT                                /FTId=VAR_061288.
FT   VARIANT     877    877       A -> S (in an ovarian serous carcinoma
FT                                sample; somatic mutation;
FT                                dbSNP:rs746442213).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041484.
FT   VARIANT    1012   1012       T -> M (in dbSNP:rs35073634).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041485.
FT   VARIANT    1091   1091       D -> N (in NBLST3; somatic mutation;
FT                                dbSNP:rs864309584).
FT                                {ECO:0000269|PubMed:18724359}.
FT                                /FTId=VAR_063850.
FT   VARIANT    1121   1121       G -> D (in dbSNP:rs55760835).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041486.
FT   VARIANT    1128   1128       G -> A (in NBLST3; dbSNP:rs113994088).
FT                                {ECO:0000269|PubMed:18724359}.
FT                                /FTId=VAR_063851.
FT   VARIANT    1151   1151       T -> M (in NBLST3; dbSNP:rs113994091).
FT                                {ECO:0000269|PubMed:18923525}.
FT                                /FTId=VAR_063852.
FT   VARIANT    1166   1166       M -> R (in NBLST3; somatic mutation;
FT                                dbSNP:rs1057520019).
FT                                {ECO:0000269|PubMed:18724359}.
FT                                /FTId=VAR_063853.
FT   VARIANT    1171   1171       I -> N (in NBLST3; somatic mutation;
FT                                dbSNP:rs1057519698).
FT                                {ECO:0000269|PubMed:18724359}.
FT                                /FTId=VAR_063854.
FT   VARIANT    1174   1174       F -> C (in NBLST3; dbSNP:rs1057519697).
FT                                {ECO:0000269|PubMed:18923523}.
FT                                /FTId=VAR_063855.
FT   VARIANT    1174   1174       F -> I (in NBLST3; somatic mutation;
FT                                dbSNP:rs281864719).
FT                                {ECO:0000269|PubMed:18724359}.
FT                                /FTId=VAR_063856.
FT   VARIANT    1174   1174       F -> L (in NBLST3; somatic mutation;
FT                                constitutively activated; retained in the
FT                                endoplasmic reticulum and Golgi
FT                                compartments; dbSNP:rs863225281).
FT                                {ECO:0000269|PubMed:18923523,
FT                                ECO:0000269|PubMed:18923525,
FT                                ECO:0000269|PubMed:21242967}.
FT                                /FTId=VAR_063857.
FT   VARIANT    1174   1174       F -> V (in NBLST3; somatic mutation;
FT                                constitutively activated; retained in the
FT                                endoplasmic reticulum and Golgi
FT                                compartments; dbSNP:rs281864719).
FT                                {ECO:0000269|PubMed:18923523,
FT                                ECO:0000269|PubMed:21242967}.
FT                                /FTId=VAR_063858.
FT   VARIANT    1192   1192       R -> P (in NBLST3; dbSNP:rs113994089).
FT                                {ECO:0000269|PubMed:18724359,
FT                                ECO:0000269|PubMed:18923523}.
FT                                /FTId=VAR_063859.
FT   VARIANT    1234   1234       A -> T (in NBLST3; somatic mutation).
FT                                {ECO:0000269|PubMed:18923525}.
FT                                /FTId=VAR_063860.
FT   VARIANT    1245   1245       F -> C (in NBLST3; somatic mutation;
FT                                dbSNP:rs863225283).
FT                                {ECO:0000269|PubMed:18724359,
FT                                ECO:0000269|PubMed:18923525}.
FT                                /FTId=VAR_063861.
FT   VARIANT    1245   1245       F -> V (in NBLST3; somatic mutation;
FT                                dbSNP:rs281864720).
FT                                /FTId=VAR_063862.
FT   VARIANT    1250   1250       I -> T (in NBLST3; somatic mutation;
FT                                dbSNP:rs113994092).
FT                                {ECO:0000269|PubMed:18724359}.
FT                                /FTId=VAR_063863.
FT   VARIANT    1274   1274       A -> T (in dbSNP:rs45502292).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041487.
FT   VARIANT    1275   1275       R -> L (observed in neuroblastoma;
FT                                dbSNP:rs113994087).
FT                                {ECO:0000269|PubMed:18923523}.
FT                                /FTId=VAR_063864.
FT   VARIANT    1275   1275       R -> Q (in NBLST3; constitutively
FT                                activated; retained in the endoplasmic
FT                                reticulum and Golgi compartments;
FT                                dbSNP:rs113994087).
FT                                {ECO:0000269|PubMed:18724359,
FT                                ECO:0000269|PubMed:18923523,
FT                                ECO:0000269|PubMed:18923525,
FT                                ECO:0000269|PubMed:21242967}.
FT                                /FTId=VAR_063865.
FT   VARIANT    1278   1278       Y -> S (in NBLST3; somatic mutation;
FT                                dbSNP:rs863225285).
FT                                {ECO:0000269|PubMed:18923523}.
FT                                /FTId=VAR_063866.
FT   VARIANT    1328   1328       M -> L (in dbSNP:rs56160491).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041488.
FT   VARIANT    1376   1376       F -> S (in dbSNP:rs17694720).
FT                                /FTId=VAR_055987.
FT   VARIANT    1416   1416       K -> N (in dbSNP:rs55782189).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041489.
FT   VARIANT    1419   1419       E -> K (in dbSNP:rs56181542).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041490.
FT   VARIANT    1429   1429       Q -> R (in dbSNP:rs55906201).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041491.
FT   VARIANT    1461   1461       I -> V (in dbSNP:rs1670283).
FT                                {ECO:0000269|PubMed:8122112,
FT                                ECO:0000269|PubMed:9053841,
FT                                ECO:0000269|PubMed:9174053,
FT                                ECO:0000269|Ref.4}.
FT                                /FTId=VAR_031042.
FT   VARIANT    1491   1491       K -> R (in dbSNP:rs1881420).
FT                                {ECO:0000269|PubMed:17344846,
FT                                ECO:0000269|PubMed:9053841,
FT                                ECO:0000269|Ref.4}.
FT                                /FTId=VAR_031043.
FT   VARIANT    1529   1529       D -> E (in dbSNP:rs1881421).
FT                                {ECO:0000269|PubMed:17344846,
FT                                ECO:0000269|PubMed:9053841,
FT                                ECO:0000269|Ref.4}.
FT                                /FTId=VAR_031044.
FT   VARIANT    1599   1599       P -> H (in dbSNP:rs1881423).
FT                                /FTId=VAR_055988.
FT   MUTAGEN    1507   1507       Y->F: Impairs interaction with SHC1.
FT                                {ECO:0000269|PubMed:17274988}.
FT   CONFLICT     36     36       P -> S (in Ref. 1; AAB71619).
FT                                {ECO:0000305}.
FT   HELIX      1087   1092       {ECO:0000244|PDB:3AOX}.
FT   STRAND     1096   1098       {ECO:0000244|PDB:4Z55}.
FT   STRAND     1101   1103       {ECO:0000244|PDB:4Z55}.
FT   HELIX      1105   1107       {ECO:0000244|PDB:4Z55}.
FT   HELIX      1113   1115       {ECO:0000244|PDB:4Z55}.
FT   STRAND     1116   1124       {ECO:0000244|PDB:4Z55}.
FT   STRAND     1126   1135       {ECO:0000244|PDB:4Z55}.
FT   STRAND     1137   1140       {ECO:0000244|PDB:3LCS}.
FT   STRAND     1145   1152       {ECO:0000244|PDB:4Z55}.
FT   STRAND     1154   1156       {ECO:0000244|PDB:5IUI}.
FT   HELIX      1158   1173       {ECO:0000244|PDB:4Z55}.
FT   STRAND     1182   1186       {ECO:0000244|PDB:4Z55}.
FT   STRAND     1188   1197       {ECO:0000244|PDB:4Z55}.
FT   HELIX      1204   1211       {ECO:0000244|PDB:4Z55}.
FT   STRAND     1215   1217       {ECO:0000244|PDB:5A9U}.
FT   HELIX      1223   1242       {ECO:0000244|PDB:4Z55}.
FT   HELIX      1252   1254       {ECO:0000244|PDB:4Z55}.
FT   STRAND     1255   1258       {ECO:0000244|PDB:4Z55}.
FT   STRAND     1260   1263       {ECO:0000244|PDB:4DCE}.
FT   STRAND     1266   1268       {ECO:0000244|PDB:4Z55}.
FT   HELIX      1272   1280       {ECO:0000244|PDB:4Z55}.
FT   HELIX      1288   1290       {ECO:0000244|PDB:4Z55}.
FT   HELIX      1293   1295       {ECO:0000244|PDB:4Z55}.
FT   HELIX      1298   1303       {ECO:0000244|PDB:4Z55}.
FT   HELIX      1308   1323       {ECO:0000244|PDB:4Z55}.
FT   HELIX      1335   1343       {ECO:0000244|PDB:4Z55}.
FT   HELIX      1356   1365       {ECO:0000244|PDB:4Z55}.
FT   HELIX      1370   1372       {ECO:0000244|PDB:4Z55}.
FT   HELIX      1376   1388       {ECO:0000244|PDB:4Z55}.
FT   HELIX      1390   1393       {ECO:0000244|PDB:4Z55}.
FT   STRAND     1574   1576       {ECO:0000244|PDB:2KUP}.
FT   STRAND     1582   1584       {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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