ALK_HUMAN
ID ALK_HUMAN Reviewed; 1620 AA.
AC Q9UM73; A6P4T4; A6P4V4; Q4ZFX9; Q53QQ6; Q53RZ4; Q59FI3; Q9Y4K6;
DT 27-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 3.
DT 03-AUG-2022, entry version 216.
DE RecName: Full=ALK tyrosine kinase receptor {ECO:0000305};
DE EC=2.7.10.1 {ECO:0000269|PubMed:30061385, ECO:0000269|PubMed:34819673};
DE AltName: Full=Anaplastic lymphoma kinase {ECO:0000303|PubMed:9174053};
DE AltName: CD_antigen=CD246;
DE Flags: Precursor;
GN Name=ALK {ECO:0000303|PubMed:9174053, 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 NUCLEOTIDE SEQUENCE [MRNA] OF 1059-1620, VARIANTS VAL-1461; ARG-1491 AND
RP GLU-1529, AND CHROMOSOMAL TRANSLOCATION WITH EML4.
RX PubMed=17625570; DOI=10.1038/nature05945;
RA Soda M., Choi Y.L., Enomoto M., Takada S., Yamashita Y., Ishikawa S.,
RA Fujiwara S., Watanabe H., Kurashina K., Hatanaka H., Bando M., Ohno S.,
RA Ishikawa Y., Aburatani H., Niki T., Sohara Y., Sugiyama Y., Mano H.;
RT "Identification of the transforming EML4-ALK fusion gene in non-small-cell
RT lung cancer.";
RL Nature 448:561-566(2007).
RN [8]
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 [9]
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 [10]
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 [11]
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 [12]
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 [13]
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 [14]
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 [15]
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 [16]
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 [17]
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 [18]
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 [19]
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 [20]
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 [21]
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 [22]
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 [23]
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 [24]
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 [25]
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 [26]
RP ACTIVITY REGULATION, DOMAIN, AND MUTAGENESIS OF 48-ARG--LYS-52.
RX PubMed=25605972; DOI=10.1126/scisignal.2005916;
RA Murray P.B., Lax I., Reshetnyak A., Ligon G.F., Lillquist J.S.,
RA Natoli E.J. Jr., Shi X., Folta-Stogniew E., Gunel M., Alvarado D.,
RA Schlessinger J.;
RT "Heparin is an activating ligand of the orphan receptor tyrosine kinase
RT ALK.";
RL Sci. Signal. 8:ra6-ra6(2015).
RN [27]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=30061385; DOI=10.1073/pnas.1807881115;
RA Reshetnyak A.V., Mohanty J., Tome F., Puleo D.E., Plotnikov A.N., Ahmed M.,
RA Kaur N., Poliakov A., Cinnaiyan A.M., Lax I., Schlessinger J.;
RT "Identification of a biologically active fragment of ALK and LTK-Ligand 2
RT (augmentor-alpha).";
RL Proc. Natl. Acad. Sci. U.S.A. 115:8340-8345(2018).
RN [28]
RP FUNCTION.
RX PubMed=33411331; DOI=10.15252/embj.2020105784;
RA Borenaes M., Umapathy G., Lai W.Y., Lind D.E., Witek B., Guan J.,
RA Mendoza-Garcia P., Masudi T., Claeys A., Chuang T.P., El Wakil A.,
RA Arefin B., Fransson S., Koster J., Johansson M., Gaarder J.,
RA Van den Eynden J., Hallberg B., Palmer R.H.;
RT "ALK ligand ALKAL2 potentiates MYCN-driven neuroblastoma in the absence of
RT ALK mutation.";
RL EMBO J. 40:e105784-e105784(2021).
RN [29]
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 [30]
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 1072-1410 IN COMPLEX WITH ADP.
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 [31] {ECO:0007744|PDB:2XB7, ECO:0007744|PDB:2XBA}
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 [32]
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 [33]
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 [34] {ECO:0007744|PDB:3AOX}
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 [35] {ECO:0007744|PDB:4FNW, ECO:0007744|PDB:4FNX, ECO:0007744|PDB:4FNY, ECO:0007744|PDB:4FNZ}
RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 1084-1410, AND VARIANT NBLST3
RP GLN-1275.
RX PubMed=22932897; DOI=10.1074/jbc.m112.391425;
RA Epstein L.F., Chen H., Emkey R., Whittington D.A.;
RT "The R1275Q neuroblastoma mutant and certain ATP-competitive inhibitors
RT stabilize alternative activation loop conformations of anaplastic lymphoma
RT kinase.";
RL J. Biol. Chem. 287:37447-37457(2012).
RN [36]
RP STRUCTURE BY ELECTRON MICROSCOPY (4.17 ANGSTROMS) OF 648-985 IN COMPLEX
RP WITH ALKAL2, X-RAY CRYSTALLOGRAPHY (2.81 ANGSTROMS) OF 648-1030, FUNCTION,
RP ACTIVITY REGULATION, AND DOMAIN.
RX PubMed=34646012; DOI=10.1038/s41586-021-03959-5;
RA De Munck S., Provost M., Kurikawa M., Omori I., Mukohyama J., Felix J.,
RA Bloch Y., Abdel-Wahab O., Bazan J.F., Yoshimi A., Savvides S.N.;
RT "Structural basis of cytokine-mediated activation of ALK family
RT receptors.";
RL Nature 600:143-147(2021).
RN [37]
RP STRUCTURE BY ELECTRON MICROSCOPY (1.50 ANGSTROMS) OF 648-1025 IN COMPLEX
RP WITH ALKAL2, FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, SUBUNIT,
RP ACTIVITY REGULATION, AUTOPHOSPHORYLATION, DOMAIN, AND MUTAGENESIS OF
RP GLU-859; TYR-966; GLU-974 AND GLU-994.
RX PubMed=34819673; DOI=10.1038/s41586-021-04140-8;
RA Reshetnyak A.V., Rossi P., Myasnikov A.G., Sowaileh M., Mohanty J.,
RA Nourse A., Miller D.J., Lax I., Schlessinger J., Kalodimos C.G.;
RT "Mechanism for the activation of the anaplastic lymphoma kinase receptor.";
RL Nature 600:153-157(2021).
RN [38]
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 [39]
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 [40]
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 [41]
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 [42]
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 (PubMed:11121404,
CC PubMed:11387242, PubMed:16317043, PubMed:17274988, PubMed:30061385,
CC PubMed:34646012, PubMed:34819673). Also acts as a key thinness protein
CC involved in the resistance to weight gain: in hypothalamic neurons,
CC controls energy expenditure acting as a negative regulator of white
CC adipose tissue lipolysis and sympathetic tone to fine-tune energy
CC homeostasis (By similarity). Following activation by ALKAL2 ligand at
CC the cell surface, transduces an extracellular signal into an
CC intracellular response (PubMed:30061385, PubMed:33411331,
CC PubMed:34646012, PubMed:34819673). In contrast, ALKAL1 is not a potent
CC physiological ligand for ALK (PubMed:34646012). Ligand-binding to the
CC extracellular domain induces tyrosine kinase activation, leading to
CC activation of the mitogen-activated protein kinase (MAPK) pathway
CC (PubMed:34819673). Phosphorylates almost exclusively at the first
CC tyrosine of the Y-x-x-x-Y-Y motif (PubMed:15226403, PubMed:16878150).
CC Induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well
CC as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1 (PubMed:15226403,
CC PubMed:16878150). ALK activation may also be regulated by pleiotrophin
CC (PTN) and midkine (MDK) (PubMed:11278720, PubMed:11809760,
CC PubMed:12107166, PubMed:12122009). PTN-binding induces MAPK pathway
CC activation, which is important for the anti-apoptotic signaling of PTN
CC and regulation of cell proliferation (PubMed:11278720, PubMed:11809760,
CC PubMed:12107166). MDK-binding induces phosphorylation of the ALK target
CC insulin receptor substrate (IRS1), activates mitogen-activated protein
CC kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation
CC induction (PubMed:12122009). Drives NF-kappa-B activation, probably
CC through IRS1 and the activation of the AKT serine/threonine kinase
CC (PubMed:15226403, PubMed:16878150). Recruitment of IRS1 to activated
CC ALK and the activation of NF-kappa-B are essential for the autocrine
CC growth and survival signaling of MDK (PubMed:15226403,
CC PubMed:16878150). {ECO:0000250|UniProtKB:P97793,
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:16317043,
CC ECO:0000269|PubMed:16878150, ECO:0000269|PubMed:17274988,
CC ECO:0000269|PubMed:30061385, ECO:0000269|PubMed:33411331,
CC ECO:0000269|PubMed:34646012, ECO:0000269|PubMed:34819673}.
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 ECO:0000269|PubMed:30061385, ECO:0000269|PubMed:34819673};
CC -!- ACTIVITY REGULATION: Activated upon ALKAL2 ligand-binding
CC (PubMed:34646012, PubMed:34819673). ALKAL2-driven activation is coupled
CC with heparin-binding (PubMed:25605972, PubMed:34646012). Following
CC ligand-binding, homodimerizes and autophosphorylates, activating its
CC kinase activity (PubMed:16317043, PubMed:17681947, PubMed:34646012,
CC PubMed:34819673). Inactivated through dephosphorylation by receptor
CC protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) when
CC there is no stimulation by a ligand (PubMed:17681947). Staurosporine,
CC crizotinib and CH5424802 act as inhibitors of ALK kinase activity
CC (PubMed:21575866). {ECO:0000269|PubMed:16317043,
CC ECO:0000269|PubMed:17681947, ECO:0000269|PubMed:21575866,
CC ECO:0000269|PubMed:25605972, ECO:0000269|PubMed:34646012,
CC ECO:0000269|PubMed:34819673}.
CC -!- SUBUNIT: Homodimer; homodimerizes following heparin- and ligand-binding
CC (PubMed:16317043, PubMed:25605972, PubMed:34646012, PubMed:34819673).
CC Interacts with CBL, IRS1, PIK3R1 and PLCG1 (PubMed:15226403). Interacts
CC with FRS2 and SHC1 (PubMed:15226403, PubMed:16878150, PubMed:17274988).
CC Interacts with PTN and MDK (PubMed:11278720, PubMed:12122009).
CC {ECO:0000269|PubMed:11278720, ECO:0000269|PubMed:12122009,
CC ECO:0000269|PubMed:15226403, ECO:0000269|PubMed:16317043,
CC ECO:0000269|PubMed:16878150, ECO:0000269|PubMed:17274988,
CC ECO:0000269|PubMed:25605972, ECO:0000269|PubMed:34646012,
CC ECO:0000269|PubMed:34819673}.
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:34819673,
CC ECO:0000269|PubMed:9174053}; Single-pass type I membrane protein
CC {ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:9174053}.
CC Note=Membrane attachment is essential for promotion of neuron-like
CC differentiation and cell proliferation arrest through specific
CC activation of the MAP kinase pathway. {ECO:0000269|PubMed:16317043}.
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 -!- DOMAIN: The EGF-like region drives the cytokine specificity for ALKAL2.
CC {ECO:0000269|PubMed:34646012, ECO:0000269|PubMed:34819673}.
CC -!- DOMAIN: The heparin-binding region binds heparin glycosaminoglycan
CC (PubMed:25605972, PubMed:34646012). Heparin-binding is required for
CC ALKAL2-driven activation (PubMed:34646012).
CC {ECO:0000269|PubMed:25605972, ECO:0000269|PubMed:34646012}.
CC -!- PTM: Phosphorylated at tyrosine residues by autocatalysis, which
CC activates kinase activity (PubMed:11121404, PubMed:15938644,
CC PubMed:16878150, PubMed:34819673). 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 (PubMed:17681947). Phosphorylation at Tyr-1507 is critical for SHC1
CC association (PubMed:17274988). {ECO:0000269|PubMed:11121404,
CC ECO:0000269|PubMed:15938644, ECO:0000269|PubMed:16878150,
CC ECO:0000269|PubMed:17274988, ECO:0000269|PubMed:17681947,
CC ECO:0000269|PubMed:34819673}.
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 {ECO:0000269|PubMed:15938644}.
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 {ECO:0000269|PubMed:12112524, ECO:0000269|PubMed:16161041}.
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. {ECO:0000269|PubMed:12112524}.
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, ECO:0000269|PubMed:22932897}. Note=Disease
CC susceptibility is associated with variants affecting the gene
CC 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. {ECO:0000269|PubMed:15908427}.
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 -!- DISEASE: Note=A chromosomal aberration involving ALK has been
CC identified in a subset of patients with non-small-cell lung carcinoma.
CC This aberration leads to the production of a fusion protein between the
CC N-terminus of EML4 et the C-terminus of ALK. It is unclear whether the
CC fusion protein is caused by a simple inversion within 2p
CC (inv(2)(p21p23)) or whether the chromosome translocation involving 2p
CC is more complex. When tested in a heterologous system, the fusion
CC protein EML4-ALK possesses transforming activity that is dependent on
CC ALK catalytic activity, possibly due to spontaneous dimerization
CC mediated by the EML4 moiety, leading to ALK kinase activation.
CC {ECO:0000269|PubMed:17625570}.
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";
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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 EMBL; AB274722; BAF73611.1; -; mRNA.
DR EMBL; AB275889; BAF73612.1; -; mRNA.
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 PDB; 7BTT; X-ray; 1.86 A; A=1093-1410.
DR PDB; 7JY4; X-ray; 2.42 A; A=1090-1406.
DR PDB; 7JYR; X-ray; 2.32 A; A=1090-1406.
DR PDB; 7JYS; X-ray; 2.22 A; A=1090-1406.
DR PDB; 7JYT; X-ray; 2.00 A; A=1090-1406.
DR PDB; 7LRZ; X-ray; 1.91 A; A=678-986.
DR PDB; 7LS0; X-ray; 3.05 A; A/B/C/D=678-1030.
DR PDB; 7MZW; NMR; -; A=673-1025.
DR PDB; 7MZY; X-ray; 1.50 A; A/B=673-986.
DR PDB; 7N00; EM; 2.27 A; A/C=648-1025.
DR PDB; 7NWZ; X-ray; 4.17 A; A/B/E/F=648-985.
DR PDB; 7NX3; X-ray; 2.81 A; A/F=648-1030.
DR PDB; 7NX4; X-ray; 3.00 A; A=648-1030.
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 PDBsum; 7BTT; -.
DR PDBsum; 7JY4; -.
DR PDBsum; 7JYR; -.
DR PDBsum; 7JYS; -.
DR PDBsum; 7JYT; -.
DR PDBsum; 7LRZ; -.
DR PDBsum; 7LS0; -.
DR PDBsum; 7MZW; -.
DR PDBsum; 7MZY; -.
DR PDBsum; 7N00; -.
DR PDBsum; 7NWZ; -.
DR PDBsum; 7NX3; -.
DR PDBsum; 7NX4; -.
DR AlphaFoldDB; Q9UM73; -.
DR BMRB; Q9UM73; -.
DR SMR; Q9UM73; -.
DR BioGRID; 106739; 87.
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; 17 sites, 1 O-linked glycan (1 site).
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; 1350 antibodies from 41 providers.
DR DNASU; 238; -.
DR Ensembl; ENST00000389048.8; ENSP00000373700.3; ENSG00000171094.18.
DR GeneID; 238; -.
DR KEGG; hsa:238; -.
DR MANE-Select; ENST00000389048.8; ENSP00000373700.3; NM_004304.5; NP_004295.2.
DR UCSC; uc002rmy.4; human.
DR CTD; 238; -.
DR DisGeNET; 238; -.
DR GeneCards; ALK; -.
DR GeneReviews; ALK; -.
DR HGNC; HGNC:427; ALK.
DR HPA; ENSG00000171094; Tissue enriched (brain).
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 VEuPathDB; HostDB:ENSG00000171094; -.
DR eggNOG; KOG1095; Eukaryota.
DR GeneTree; ENSGT00940000159280; -.
DR InParanoid; Q9UM73; -.
DR OMA; TDRFWLQ; -.
DR OrthoDB; 40108at2759; -.
DR PhylomeDB; Q9UM73; -.
DR TreeFam; TF351636; -.
DR BRENDA; 2.7.10.1; 2681.
DR PathwayCommons; Q9UM73; -.
DR Reactome; R-HSA-201556; Signaling by ALK.
DR Reactome; R-HSA-9700645; ALK mutants bind TKIs.
DR Reactome; R-HSA-9717264; ASP-3026-resistant ALK mutants.
DR Reactome; R-HSA-9717301; NVP-TAE684-resistant ALK mutants.
DR Reactome; R-HSA-9717316; alectinib-resistant ALK mutants.
DR Reactome; R-HSA-9717319; brigatinib-resistant ALK mutants.
DR Reactome; R-HSA-9717323; ceritinib-resistant ALK mutants.
DR Reactome; R-HSA-9717326; crizotinib-resistant ALK mutants.
DR Reactome; R-HSA-9717329; lorlatinib-resistant ALK mutants.
DR Reactome; R-HSA-9725370; Signaling by ALK fusions and activated point mutants.
DR Reactome; R-HSA-9725371; Nuclear events stimulated by ALK signaling in cancer.
DR SignaLink; Q9UM73; -.
DR SIGNOR; Q9UM73; -.
DR BioGRID-ORCS; 238; 15 hits in 1108 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 154 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:0008201; F:heparin binding; IDA:UniProtKB.
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:0030298; F:receptor signaling protein tyrosine kinase activator activity; IDA:UniProtKB.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IDA:UniProtKB.
DR GO; GO:0030534; P:adult behavior; IEA:Ensembl.
DR GO; GO:0097009; P:energy homeostasis; ISS:UniProtKB.
DR GO; GO:0021766; P:hippocampus development; IEA:Ensembl.
DR GO; GO:0050995; P:negative regulation of lipid catabolic process; ISS:UniProtKB.
DR GO; GO:0048666; P:neuron development; TAS:UniProtKB.
DR GO; GO:0038083; P:peptidyl-tyrosine autophosphorylation; IDA: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:0043410; P:positive regulation of MAPK cascade; IEA:InterPro.
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; 1.
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 variant; Disulfide bond; Glycoprotein; Kinase; Membrane;
KW Nucleotide-binding; Phosphoprotein; Proto-oncogene; Receptor;
KW Reference proteome; Repeat; Signal; Transferase; Transmembrane;
KW Transmembrane helix; 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 REGION 48..70
FT /note="Heparin-binding region"
FT /evidence="ECO:0000269|PubMed:34646012"
FT REGION 650..674
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 987..1025
FT /note="EGF-like"
FT /evidence="ECO:0000269|PubMed:34646012,
FT ECO:0000269|PubMed:34819673"
FT REGION 1408..1463
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1514..1540
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1518..1532
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
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 /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 1150
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 1197..1199
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 1270
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:20632993"
FT SITE 1057..1058
FT /note="Breakpoint for translocation to form the EML4-ALK
FT fusion protein (variant 1)"
FT /evidence="ECO:0000269|PubMed:17625570"
FT SITE 1058..1059
FT /note="Breakpoint for translocation to form the EML4-ALK
FT fusion protein (variant 2)"
FT /evidence="ECO:0000269|PubMed:17625570"
FT MOD_RES 1078
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|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:0000269|PubMed:16878150,
FT ECO:0007744|PubMed:15592455"
FT MOD_RES 1131
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|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:0007744|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 DISULFID 688..701
FT /evidence="ECO:0000269|PubMed:34819673,
FT ECO:0007744|PDB:7MZW"
FT DISULFID 783..794
FT /evidence="ECO:0000269|PubMed:34819673,
FT ECO:0007744|PDB:7MZW"
FT DISULFID 906..928
FT /evidence="ECO:0000269|PubMed:34819673,
FT ECO:0007744|PDB:7MZW"
FT DISULFID 987..995
FT /evidence="ECO:0000269|PubMed:34819673,
FT ECO:0007744|PDB:7MZW"
FT DISULFID 990..1006
FT /evidence="ECO:0000269|PubMed:34819673,
FT ECO:0007744|PDB:7MZW"
FT DISULFID 1008..1021
FT /evidence="ECO:0000269|PubMed:34819673,
FT ECO:0007744|PDB:7MZW"
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, ECO:0000269|PubMed:22932897"
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:17625570,
FT ECO:0000269|PubMed:8122112, ECO:0000269|PubMed:9053841,
FT ECO:0000269|PubMed:9174053, 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:17625570, ECO:0000269|PubMed:9053841,
FT 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:17625570, ECO:0000269|PubMed:9053841,
FT ECO:0000269|Ref.4"
FT /id="VAR_031044"
FT VARIANT 1599
FT /note="P -> H (in dbSNP:rs1881423)"
FT /id="VAR_055988"
FT MUTAGEN 48..52
FT /note="RLQRK->ELQEE: Abolished heparin-binding, leading to
FT decreased ALK activation."
FT /evidence="ECO:0000269|PubMed:25605972"
FT MUTAGEN 859
FT /note="E->A: Slightly decreased autophosphorylation.
FT Decreased autophosphorylation and subsequent activation;
FT when associated with A-974."
FT /evidence="ECO:0000269|PubMed:34819673"
FT MUTAGEN 966
FT /note="Y->A: Slightly decreased autophosphorylation.
FT Strongly reduced autophosphorylation and subsequent
FT activation; when associated with A-994."
FT /evidence="ECO:0000269|PubMed:34819673"
FT MUTAGEN 974
FT /note="E->A: Slightly decreased autophosphorylation.
FT Decreased autophosphorylation and subsequent activation;
FT when associated with A-859."
FT /evidence="ECO:0000269|PubMed:34819673"
FT MUTAGEN 994
FT /note="E->A: SlStrongly reduced autophosphorylation and
FT subsequent activation; when associated with A-966."
FT /evidence="ECO:0000269|PubMed:34819673"
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 STRAND 675..677
FT /evidence="ECO:0007829|PDB:7MZW"
FT STRAND 680..685
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 692..694
FT /evidence="ECO:0007829|PDB:7LRZ"
FT HELIX 698..704
FT /evidence="ECO:0007829|PDB:7MZY"
FT TURN 705..707
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 713..715
FT /evidence="ECO:0007829|PDB:7MZY"
FT HELIX 718..720
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 724..727
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 730..739
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 747..751
FT /evidence="ECO:0007829|PDB:7LRZ"
FT STRAND 757..765
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 770..774
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 782..784
FT /evidence="ECO:0007829|PDB:7N00"
FT HELIX 788..794
FT /evidence="ECO:0007829|PDB:7MZY"
FT HELIX 800..807
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 808..810
FT /evidence="ECO:0007829|PDB:7LRZ"
FT STRAND 812..814
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 825..831
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 834..841
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 860..862
FT /evidence="ECO:0007829|PDB:7MZW"
FT STRAND 865..867
FT /evidence="ECO:0007829|PDB:7LS0"
FT STRAND 875..877
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 890..892
FT /evidence="ECO:0007829|PDB:7N00"
FT HELIX 896..898
FT /evidence="ECO:0007829|PDB:7MZY"
FT HELIX 907..913
FT /evidence="ECO:0007829|PDB:7MZY"
FT TURN 921..923
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 928..930
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 936..938
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 956..959
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 963..965
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 970..975
FT /evidence="ECO:0007829|PDB:7LRZ"
FT STRAND 978..984
FT /evidence="ECO:0007829|PDB:7MZY"
FT STRAND 990..993
FT /evidence="ECO:0007829|PDB:7N00"
FT STRAND 995..997
FT /evidence="ECO:0007829|PDB:7N00"
FT TURN 999..1001
FT /evidence="ECO:0007829|PDB:7N00"
FT STRAND 1004..1006
FT /evidence="ECO:0007829|PDB:7N00"
FT STRAND 1012..1014
FT /evidence="ECO:0007829|PDB:7MZW"
FT STRAND 1016..1022
FT /evidence="ECO:0007829|PDB:7N00"
FT HELIX 1087..1092
FT /evidence="ECO:0007829|PDB:3AOX"
FT STRAND 1096..1098
FT /evidence="ECO:0007829|PDB:4Z55"
FT STRAND 1101..1103
FT /evidence="ECO:0007829|PDB:4Z55"
FT HELIX 1105..1107
FT /evidence="ECO:0007829|PDB:4Z55"
FT HELIX 1113..1115
FT /evidence="ECO:0007829|PDB:4Z55"
FT STRAND 1116..1124
FT /evidence="ECO:0007829|PDB:4Z55"
FT STRAND 1126..1135
FT /evidence="ECO:0007829|PDB:4Z55"
FT STRAND 1137..1140
FT /evidence="ECO:0007829|PDB:3LCS"
FT STRAND 1145..1152
FT /evidence="ECO:0007829|PDB:4Z55"
FT STRAND 1154..1156
FT /evidence="ECO:0007829|PDB:5IUI"
FT HELIX 1158..1173
FT /evidence="ECO:0007829|PDB:4Z55"
FT STRAND 1182..1186
FT /evidence="ECO:0007829|PDB:4Z55"
FT STRAND 1188..1197
FT /evidence="ECO:0007829|PDB:4Z55"
FT HELIX 1204..1211
FT /evidence="ECO:0007829|PDB:4Z55"
FT STRAND 1215..1217
FT /evidence="ECO:0007829|PDB:5A9U"
FT HELIX 1223..1242
FT /evidence="ECO:0007829|PDB:4Z55"
FT HELIX 1252..1254
FT /evidence="ECO:0007829|PDB:4Z55"
FT STRAND 1255..1258
FT /evidence="ECO:0007829|PDB:4Z55"
FT STRAND 1260..1263
FT /evidence="ECO:0007829|PDB:4DCE"
FT STRAND 1266..1268
FT /evidence="ECO:0007829|PDB:4Z55"
FT HELIX 1272..1280
FT /evidence="ECO:0007829|PDB:4Z55"
FT STRAND 1284..1286
FT /evidence="ECO:0007829|PDB:7BTT"
FT HELIX 1288..1290
FT /evidence="ECO:0007829|PDB:4Z55"
FT HELIX 1293..1295
FT /evidence="ECO:0007829|PDB:4Z55"
FT HELIX 1298..1303
FT /evidence="ECO:0007829|PDB:4Z55"
FT HELIX 1308..1323
FT /evidence="ECO:0007829|PDB:4Z55"
FT HELIX 1335..1343
FT /evidence="ECO:0007829|PDB:4Z55"
FT HELIX 1356..1365
FT /evidence="ECO:0007829|PDB:4Z55"
FT HELIX 1370..1372
FT /evidence="ECO:0007829|PDB:4Z55"
FT HELIX 1376..1388
FT /evidence="ECO:0007829|PDB:4Z55"
FT HELIX 1390..1393
FT /evidence="ECO:0007829|PDB:4Z55"
FT STRAND 1574..1576
FT /evidence="ECO:0007829|PDB:2KUP"
FT STRAND 1582..1584
FT /evidence="ECO:0007829|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
