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 27-MAR-2024, entry version 225. 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 Q9UM73; P07949: RET; NbExp=2; IntAct=EBI-357361, EBI-2480756; 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="https://atlasgeneticsoncology.org/gene/16/ALK"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 PDB; 7R7K; X-ray; 1.83 A; A=1093-1411. DR PDB; 7R7R; X-ray; 1.94 A; A=1093-1411. DR PDB; 8ARJ; X-ray; 1.65 A; A=1093-1411. 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 PDBsum; 7R7K; -. DR PDBsum; 7R7R; -. DR PDBsum; 8ARJ; -. DR AlphaFoldDB; Q9UM73; -. DR BMRB; Q9UM73; -. DR EMDB; EMD-24095; -. DR SMR; Q9UM73; -. DR BioGRID; 106739; 223. DR DIP; DIP-5954N; -. DR IntAct; Q9UM73; 153. 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 GlyCosmos; Q9UM73; 16 sites, No reported glycans. 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; 9606-ENSP00000373700; -. DR PeptideAtlas; Q9UM73; -. DR ProteomicsDB; 85185; -. DR Antibodypedia; 2099; 1775 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 AGR; HGNC:427; -. DR CTD; 238; -. DR DisGeNET; 238; -. DR GeneCards; ALK; -. DR GeneReviews; ALK; -. DR HGNC; HGNC:427; ALK. DR HPA; ENSG00000171094; Tissue enhanced (brain, pituitary gland, testis). 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 PharmGKB; PA24719; -. DR VEuPathDB; HostDB:ENSG00000171094; -. DR eggNOG; KOG1095; Eukaryota. DR GeneTree; ENSGT00940000159280; -. DR InParanoid; Q9UM73; -. DR OMA; NTACERQ; -. DR OrthoDB; 1614410at2759; -. 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; 17 hits in 1192 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 156 other cell types or tissues. DR ExpressionAtlas; Q9UM73; baseline and differential. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. 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: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: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; IDA:UniProt. DR CDD; cd00112; LDLa; 1. DR CDD; cd06263; MAM; 2. DR CDD; cd05036; PTKc_ALK_LTK; 1. DR Gene3D; 2.60.120.200; -; 2. DR Gene3D; 4.10.400.10; Low-density Lipoprotein Receptor; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. 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; ALK TYROSINE KINASE RECEPTOR; 1. DR PANTHER; PTHR24416; TYROSINE-PROTEIN KINASE RECEPTOR; 1. DR Pfam; PF12810; Gly_rich; 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; Concanavalin A-like lectins/glucanases; 2. DR SUPFAM; SSF57424; LDL receptor-like module; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 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. DR Genevisible; Q9UM73; HS. 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 /evidence="ECO:0000269|PubMed:18724359" 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 //