Q9UM73 (ALK_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
ALK tyrosine kinase receptor
EC=2.7.10.1

Alternative name(s):
Anaplastic lymphoma kinase
CD_antigen=CD246

Gene names

Name:

ALK

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1620 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK. Ref.7 Ref.8 Ref.9 Ref.11 Ref.12 Ref.13 Ref.14 Ref.16 Ref.17 Ref.20 Ref.22
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Enzyme regulation	Activated by ligand-binding and subsequent phosphorylation. Inactivated through dephosphorylation by receptor protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) when there is no stimulation by a ligand. Staurosporine, crizotinib and CH5424802 act as inhibitors of ALK kinase activity. Ref.17 Ref.21 Ref.29
Subunit structure	Homodimer. Homodimerizes when bound to ligand. Interacts with FRS2, IRS1, MDK, PTN and SHC1. Interacts with CBL, PIK3R1 and PLCG1 By similarity. Ref.9 Ref.13 Ref.14 Ref.17 Ref.20 Ref.22
Subcellular location	Cell membrane; Single-pass type I membrane protein. Note: Membrane attachment was crucial for promotion of neuron-like differentiation and cell proliferation arrest through specific activation of the MAP kinase pathway. Ref.1 Ref.17
Tissue specificity	Expressed in brain and CNS. Also expressed in the small intestine and testis, but not in normal lymphoid cells. Ref.1
Post-translational modification	Phosphorylated at tyrosine residues by autocatalysis, which activates kinase activity. In cells not stimulated by a ligand, receptor protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) dephosphorylates ALK at the sites in ALK that are undergoing autophosphorylation through autoactivation. Ref.8 Ref.21 Ref.22 N-glycosylated. Ref.1
Involvement in disease	A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Neuroblastoma 3 (NBLST3) [MIM:613014]: A common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system. Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.31 Ref.32 Ref.33 The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily. Contains 1 LDL-receptor class A domain. Contains 2 MAM domains. Contains 1 protein kinase domain.
Sequence caution	The sequence BAD92714.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
Cellular component	Cell membrane Membrane
Coding sequence diversity	Chromosomal rearrangement Polymorphism
Disease	Disease mutation Proto-oncogene
Domain	Repeat Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Glycoprotein Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of MAPK activity Traceable author statement Ref.23. Source: UniProtKB cell proliferation Traceable author statement Ref.23. Source: UniProtKB neuron development Traceable author statement Ref.23. Source: UniProtKB positive regulation of NF-kappaB transcription factor activity Traceable author statement Ref.23. Source: UniProtKB protein autophosphorylation Inferred from direct assay Ref.1. Source: UniProtKB regulation of apoptotic process Traceable author statement Ref.23. Source: UniProtKB transmembrane receptor protein tyrosine kinase signaling pathway Inferred from electronic annotation. Source: InterPro
Cellular_component	integral to plasma membrane Inferred from direct assay Ref.1. Source: UniProtKB
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW NF-kappaB-inducing kinase activity Traceable author statement Ref.23. Source: UniProtKB transmembrane receptor protein tyrosine kinase activity Inferred from direct assay Ref.1. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
HSP90AB1	P08238	2	EBI-357361,EBI-352572

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 18

18

Potential

Chain

19 – 1620

1602

ALK tyrosine kinase receptor

PRO_0000016740

Regions

Topological domain

19 – 1038

1020

Extracellular Potential

Transmembrane

1039 – 1059

21

Helical; Potential

Topological domain

1060 – 1620

561

Cytoplasmic Potential

Domain

264 – 427

164

MAM 1

Domain

437 – 473

37

LDL-receptor class A

Domain

478 – 636

159

MAM 2

Domain

1116 – 1392

277

Protein kinase

Nucleotide binding

1197 – 1199

3

ATP

Region

1197 – 1199

3

Inhibitor binding

Compositional bias

816 – 940

125

Gly-rich

Sites

Active site

1249

1

Proton acceptor By similarity

Binding site

1124

1

ATP; via carbonyl oxygen

Binding site

1150

1

ATP By similarity

Binding site

1150

1

Inhibitor

Binding site

1199

1

Inhibitor; via amide nitrogen

Binding site

1203

1

Inhibitor

Binding site

1210

1

Inhibitor

Binding site

1270

1

ATP

Amino acid modifications

Modified residue

211

1

Phosphoserine

Modified residue

1078

1

Phosphotyrosine Ref.18

Modified residue

1092

1

Phosphotyrosine

Modified residue

1096

1

Phosphotyrosine Ref.18 Ref.22

Modified residue

1131

1

Phosphotyrosine Ref.18

Modified residue

1278

1

Phosphotyrosine

Modified residue

1282

1

Phosphotyrosine; by autocatalysis

Modified residue

1283

1

Phosphotyrosine

Modified residue

1359

1

Phosphotyrosine

Modified residue

1507

1

Phosphotyrosine

Modified residue

1584

1

Phosphotyrosine

Modified residue

1604

1

Phosphotyrosine Ref.18

Glycosylation

169

1

N-linked (GlcNAc...) Potential

Glycosylation

244

1

N-linked (GlcNAc...) Potential

Glycosylation

285

1

N-linked (GlcNAc...) Potential

Glycosylation

324

1

N-linked (GlcNAc...) Potential

Glycosylation

411

1

N-linked (GlcNAc...) Potential

Glycosylation

424

1

N-linked (GlcNAc...) Potential

Glycosylation

445

1

N-linked (GlcNAc...) Potential

Glycosylation

563

1

N-linked (GlcNAc...) Potential

Glycosylation

571

1

N-linked (GlcNAc...) Potential

Glycosylation

627

1

N-linked (GlcNAc...) Potential

Glycosylation

709

1

N-linked (GlcNAc...) Potential

Glycosylation

808

1

N-linked (GlcNAc...) Potential

Glycosylation

863

1

N-linked (GlcNAc...) Potential

Glycosylation

864

1

N-linked (GlcNAc...) Potential

Glycosylation

886

1

N-linked (GlcNAc...) Potential

Glycosylation

986

1

N-linked (GlcNAc...) Potential

Natural variations

Natural variant

90

1

S → L. Ref.30
Corresponds to variant rs34617074 [ dbSNP | Ensembl ].

VAR_041477

Natural variant

163

1

V → L. Ref.30
Corresponds to variant rs55697431 [ dbSNP | Ensembl ].

VAR_041478

Natural variant

296

1

E → Q. Ref.30
Corresponds to variant rs56077855 [ dbSNP | Ensembl ].

VAR_041479

Natural variant

476

1

V → A. Ref.30
Corresponds to variant rs35093491 [ dbSNP | Ensembl ].

VAR_041480

Natural variant

560

1

L → F in a breast pleomorphic lobular carcinoma sample; somatic mutation. Ref.30

VAR_041481

Natural variant

680

1

T → I. Ref.30
Corresponds to variant rs35228363 [ dbSNP | Ensembl ].

VAR_041482

Natural variant

704

1

A → T. Ref.30
Corresponds to variant rs34829159 [ dbSNP | Ensembl ].

VAR_041483

Natural variant

868

1

L → Q.
Corresponds to variant rs55941323 [ dbSNP | Ensembl ].

VAR_061288

Natural variant

877

1

A → S in an ovarian serous carcinoma sample; somatic mutation. Ref.30

VAR_041484

Natural variant

1012

1

T → M. Ref.30
Corresponds to variant rs35073634 [ dbSNP | Ensembl ].

VAR_041485

Natural variant

1091

1

D → N in NBLST3; somatic mutation. Ref.31

VAR_063850

Natural variant

1121

1

G → D. Ref.30
Corresponds to variant rs55760835 [ dbSNP | Ensembl ].

VAR_041486

Natural variant

1128

1

G → A in NBLST3. Ref.31

VAR_063851

Natural variant

1151

1

T → M in NBLST3. Ref.33

VAR_063852

Natural variant

1166

1

M → R in NBLST3; somatic mutation. Ref.31

VAR_063853

Natural variant

1171

1

I → N in NBLST3; somatic mutation. Ref.31

VAR_063854

Natural variant

1174

1

F → C in NBLST3. Ref.32

VAR_063855

Natural variant

1174

1

F → I in NBLST3; somatic mutation. Ref.31

VAR_063856

Natural variant

1174

1

F → L in NBLST3; somatic mutation. Ref.32 Ref.33

VAR_063857

Natural variant

1174

1

F → V in NBLST3; somatic mutation. Ref.32

VAR_063858

Natural variant

1192

1

R → P in NBLST3. Ref.31 Ref.32

VAR_063859

Natural variant

1234

1

A → T in NBLST3; somatic mutation. Ref.33

VAR_063860

Natural variant

1245

1

F → C in NBLST3; somatic mutation. Ref.31 Ref.33

VAR_063861

Natural variant

1245

1

F → V in NBLST3; somatic mutation. Ref.31

VAR_063862

Natural variant

1250

1

I → T in NBLST3; somatic mutation. Ref.31

VAR_063863

Natural variant

1274

1

A → T. Ref.30
Corresponds to variant rs45502292 [ dbSNP | Ensembl ].

VAR_041487

Natural variant

1275

1

R → L Observed in neuroblastoma. Ref.32

VAR_063864

Natural variant

1275

1

R → Q in NBLST3. Ref.31 Ref.32 Ref.33

VAR_063865

Natural variant

1278

1

Y → S in NBLST3; somatic mutation. Ref.32

VAR_063866

Natural variant

1328

1

M → L. Ref.30
Corresponds to variant rs56160491 [ dbSNP | Ensembl ].

VAR_041488

Natural variant

1376

1

F → S.
Corresponds to variant rs17694720 [ dbSNP | Ensembl ].

VAR_055987

Natural variant

1416

1

K → N. Ref.30
Corresponds to variant rs55782189 [ dbSNP | Ensembl ].

VAR_041489

Natural variant

1419

1

E → K. Ref.30
Corresponds to variant rs56181542 [ dbSNP | Ensembl ].

VAR_041490

Natural variant

1429

1

Q → R. Ref.30
Corresponds to variant rs55906201 [ dbSNP | Ensembl ].

VAR_041491

Natural variant

1461

1

I → V. Ref.1 Ref.3 Ref.4 Ref.6
Corresponds to variant rs1670283 [ dbSNP | Ensembl ].

VAR_031042

Natural variant

1491

1

K → R. Ref.3 Ref.4 Ref.30
Corresponds to variant rs1881420 [ dbSNP | Ensembl ].

VAR_031043

Natural variant

1529

1

D → E. Ref.3 Ref.4 Ref.30
Corresponds to variant rs1881421 [ dbSNP | Ensembl ].

VAR_031044

Natural variant

1599

1

P → H.
Corresponds to variant rs1881423 [ dbSNP | Ensembl ].

VAR_055988

Experimental info

Mutagenesis

1507

1

Y → F: Impairs interaction with SHC1. Ref.20

Sequence conflict

36

1

P → S in AAB71619. Ref.1

Secondary structure

1

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1620

Helix Strand Turn

Details...

Helix

1087 – 1092

6

Beta strand

1096 – 1098

3

Beta strand

1101 – 1103

3

Helix

1105 – 1107

3

Helix

1113 – 1115

3

Beta strand

1117 – 1121

5

Beta strand

1126 – 1128

3

Beta strand

1130 – 1134

5

Beta strand

1137 – 1140

4

Beta strand

1146 – 1151

6

Helix

1158 – 1173

16

Beta strand

1182 – 1186

5

Beta strand

1188 – 1191

4

Beta strand

1193 – 1197

5

Helix

1204 – 1210

7

Beta strand

1215 – 1217

3

Helix

1223 – 1242

20

Helix

1252 – 1254

3

Beta strand

1255 – 1258

4

Beta strand

1260 – 1263

4

Beta strand

1266 – 1268

3

Helix

1272 – 1278

7

Beta strand

1280 – 1282

3

Helix

1288 – 1290

3

Helix

1293 – 1295

3

Helix

1298 – 1303

6

Helix

1308 – 1323

16

Helix

1335 – 1343

9

Helix

1356 – 1365

10

Helix

1370 – 1372

3

Helix

1376 – 1388

13

Helix

1390 – 1393

4

Beta strand

1574 – 1576

3

Beta strand

1582 – 1584

3

Sequences

	Sequence		Length	Mass (Da)
	Q9UM73 [UniParc]. Last modified May 18, 2010. Version 3. Checksum: 0733D6C4FD212F41	FASTA	1,620	176,442
	10 20 30 40 50 60 MGAIGLLWLL PLLLSTAAVG SGMGTGQRAG SPAAGPPLQP REPLSYSRLQ RKSLAVDFVV 70 80 90 100 110 120 PSLFRVYARD LLLPPSSSEL KAGRPEARGS LALDCAPLLR LLGPAPGVSW TAGSPAPAEA 130 140 150 160 170 180 RTLSRVLKGG SVRKLRRAKQ LVLELGEEAI LEGCVGPPGE AAVGLLQFNL SELFSWWIRQ 190 200 210 220 230 240 GEGRLRIRLM PEKKASEVGR EGRLSAAIRA SQPRLLFQIF GTGHSSLESP TNMPSPSPDY 250 260 270 280 290 300 FTWNLTWIMK DSFPFLSHRS RYGLECSFDF PCELEYSPPL HDLRNQSWSW RRIPSEEASQ 310 320 330 340 350 360 MDLLDGPGAE RSKEMPRGSF LLLNTSADSK HTILSPWMRS SSEHCTLAVS VHRHLQPSGR 370 380 390 400 410 420 YIAQLLPHNE AAREILLMPT PGKHGWTVLQ GRIGRPDNPF RVALEYISSG NRSLSAVDFF 430 440 450 460 470 480 ALKNCSEGTS PGSKMALQSS FTCWNGTVLQ LGQACDFHQD CAQGEDESQM CRKLPVGFYC 490 500 510 520 530 540 NFEDGFCGWT QGTLSPHTPQ WQVRTLKDAR FQDHQDHALL LSTTDVPASE SATVTSATFP 550 560 570 580 590 600 APIKSSPCEL RMSWLIRGVL RGNVSLVLVE NKTGKEQGRM VWHVAAYEGL SLWQWMVLPL 610 620 630 640 650 660 LDVSDRFWLQ MVAWWGQGSR AIVAFDNISI SLDCYLTISG EDKILQNTAP KSRNLFERNP 670 680 690 700 710 720 NKELKPGENS PRQTPIFDPT VHWLFTTCGA SGPHGPTQAQ CNNAYQNSNL SVEVGSEGPL 730 740 750 760 770 780 KGIQIWKVPA TDTYSISGYG AAGGKGGKNT MMRSHGVSVL GIFNLEKDDM LYILVGQQGE 790 800 810 820 830 840 DACPSTNQLI QKVCIGENNV IEEEIRVNRS VHEWAGGGGG GGGATYVFKM KDGVPVPLII 850 860 870 880 890 900 AAGGGGRAYG AKTDTFHPER LENNSSVLGL NGNSGAAGGG GGWNDNTSLL WAGKSLQEGA 910 920 930 940 950 960 TGGHSCPQAM KKWGWETRGG FGGGGGGCSS GGGGGGYIGG NAASNNDPEM DGEDGVSFIS 970 980 990 1000 1010 1020 PLGILYTPAL KVMEGHGEVN IKHYLNCSHC EVDECHMDPE SHKVICFCDH GTVLAEDGVS 1030 1040 1050 1060 1070 1080 CIVSPTPEPH LPLSLILSVV TSALVAALVL AFSGIMIVYR RKHQELQAMQ MELQSPEYKL 1090 1100 1110 1120 1130 1140 SKLRTSTIMT DYNPNYCFAG KTSSISDLKE VPRKNITLIR GLGHGAFGEV YEGQVSGMPN 1150 1160 1170 1180 1190 1200 DPSPLQVAVK TLPEVCSEQD ELDFLMEALI ISKFNHQNIV RCIGVSLQSL PRFILLELMA 1210 1220 1230 1240 1250 1260 GGDLKSFLRE TRPRPSQPSS LAMLDLLHVA RDIACGCQYL EENHFIHRDI AARNCLLTCP 1270 1280 1290 1300 1310 1320 GPGRVAKIGD FGMARDIYRA SYYRKGGCAM LPVKWMPPEA FMEGIFTSKT DTWSFGVLLW 1330 1340 1350 1360 1370 1380 EIFSLGYMPY PSKSNQEVLE FVTSGGRMDP PKNCPGPVYR IMTQCWQHQP EDRPNFAIIL 1390 1400 1410 1420 1430 1440 ERIEYCTQDP DVINTALPIE YGPLVEEEEK VPVRPKDPEG VPPLLVSQQA KREEERSPAA 1450 1460 1470 1480 1490 1500 PPPLPTTSSG KAAKKPTAAE ISVRVPRGPA VEGGHVNMAF SQSNPPSELH KVHGSRNKPT 1510 1520 1530 1540 1550 1560 SLWNPTYGSW FTEKPTKKNN PIAKKEPHDR GNLGLEGSCT VPPNVATGRL PGASLLLEPS 1570 1580 1590 1600 1610 1620 SLTANMKEVP LFRLRHFPCG NVNYGYQQQG LPLEAATAPG AGHYEDTILK SKNSMNQPGP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK)." Morris S.W., Naeve C.W., Mathew P., James P.L., Kirstein M.N., Cui X., Witte D.P. Oncogene 14:2175-2188(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, TISSUE SPECIFICITY, GLYCOSYLATION, VARIANT VAL-1461.
[2]	Erratum Morris S.W., Naeve C.W., Mathew P., James P.L., Kirstein M.N., Cui X., Witte D.P. Oncogene 15:2883-2883(1997)
[3]	"Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system." Iwahara T., Fujimoto J., Wen D., Cupples R., Bucay N., Arakawa T., Mori S., Ratzkin B., Yamamoto T. Oncogene 14:439-449(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS VAL-1461; ARG-1491 AND GLU-1529.
[4]	Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., Ohara O., Nagase T., Kikuno R.F. Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANTS VAL-1461; ARG-1491 AND GLU-1529. Tissue: Brain.
[5]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma." Morris S.W., Kirstein M.N., Valentine M.B., Dittmer K.G., Shapiro D.N., Saltman D.L., Look A.T. Science 263:1281-1284(1994) [PubMed] [Europe PMC] [Abstract] Cited for: PARTIAL NUCLEOTIDE SEQUENCE [MRNA], CHROMOSOMAL TRANSLOCATION WITH NPM1, VARIANT VAL-1461.
[7]	"The cytoplasmic truncated receptor tyrosine kinase ALK homodimer immortalizes and cooperates with ras in cellular transformation." Simonitsch I., Polgar D., Hajek M., Duchek P., Skrzypek B., Fassl S., Lamprecht A., Schmidt G., Krupitza G., Cerni C. FASEB J. 15:1416-1418(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS AN ONCOGENE.
[8]	"Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway." Souttou B., Carvalho N.B., Raulais D., Vigny M. J. Biol. Chem. 276:9526-9531(2001) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION, FUNCTION.
[9]	"Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin." Stoica G.E., Kuo A., Aigner A., Sunitha I., Souttou B., Malerczyk C., Caughey D.J., Wen D., Karavanov A., Riegel A.T., Wellstein A. J. Biol. Chem. 276:16772-16779(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PTN, FUNCTION.
[10]	"Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor." Cools J., Wlodarska I., Somers R., Mentens N., Pedeutour F., Maes B., De Wolf-Peeters C., Pauwels P., Hagemeijer A., Marynen P. Genes Chromosomes Cancer 34:354-362(2002) [PubMed] [Europe PMC] [Abstract] Cited for: CHROMOSOMAL TRANSLOCATION WITH ALO17 AND CARS.
[11]	"Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth." Powers C., Aigner A., Stoica G.E., McDonnell K., Wellstein A. J. Biol. Chem. 277:14153-14158(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[12]	"Anti-apoptotic signaling of pleiotrophin through its receptor, anaplastic lymphoma kinase." Bowden E.T., Stoica G.E., Wellstein A. J. Biol. Chem. 277:35862-35868(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[13]	"Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types." Stoica G.E., Kuo A., Powers C., Bowden E.T., Sale E.B., Riegel A.T., Wellstein A. J. Biol. Chem. 277:35990-35998(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MDK, FUNCTION.
[14]	"ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth." Motegi A., Fujimoto J., Kotani M., Sakuraba H., Yamamoto T. J. Cell Sci. 117:3319-3329(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CBL; IRS1; PIK3R1; PLCG1 AND SHC1, FUNCTION IN PHOSPHORYLATION OF CBL; IRS1 AND SHC1.
[15]	"Unique substrate specificity of anaplastic lymphoma kinase (ALK): development of phosphoacceptor peptides for the assay of ALK activity." Donella-Deana A., Marin O., Cesaro L., Gunby R.H., Ferrarese A., Coluccia A.M., Tartari C.J., Mologni L., Scapozza L., Gambacorti-Passerini C., Pinna L.A. Biochemistry 44:8533-8542(2005) [PubMed] [Europe PMC] [Abstract] Cited for: SUBSTRATE SPECIFICITY.
[16]	"Differential induction of glioblastoma migration and growth by two forms of pleiotrophin." Lu K.V., Jong K.A., Kim G.Y., Singh J., Dia E.Q., Yoshimoto K., Wang M.Y., Cloughesy T.F., Nelson S.F., Mischel P.S. J. Biol. Chem. 280:26953-26964(2005) [PubMed] [Europe PMC] [Abstract] Cited for: ROLE IN GLIOBLASTOMA.
[17]	"Role of the subcellular localization of ALK tyrosine kinase domain in neuronal differentiation of PC12 cells." Gouzi J.Y., Moog-Lutz C., Vigny M., Brunet-de Carvalho N. J. Cell Sci. 118:5811-5823(2005) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, SUBUNIT, ENZYME REGULATION, FUNCTION.
[18]	"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells." Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J. Nat. Biotechnol. 23:94-101(2005) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-1078; TYR-1096; TYR-1131 AND TYR-1604, MASS SPECTROMETRY.
[19]	"Fusion of the SEC31L1 and ALK genes in an inflammatory myofibroblastic tumor." Panagopoulos I., Nilsson T., Domanski H.A., Isaksson M., Lindblom P., Mertens F., Mandahl N. Int. J. Cancer 118:1181-1186(2006) [PubMed] [Europe PMC] [Abstract] Cited for: CHROMOSOMAL TRANSLOCATION WITH SEC31A.
[20]	"ALK activation induces Shc and FRS2 recruitment: Signaling and phenotypic outcomes in PC12 cells differentiation." Degoutin J., Vigny M., Gouzi J.Y. FEBS Lett. 581:727-734(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FRS2 AND SHC1, MUTAGENESIS OF TYR-1507, FUNCTION IN PHOSPHORYLATION OF FRS2; MAPK1/ERK2; MAPK3/ERK1 AND SHC1.
[21]	"Anaplastic lymphoma kinase is activated through the pleiotrophin/receptor protein-tyrosine phosphatase beta/zeta signaling pathway: an alternative mechanism of receptor tyrosine kinase activation." Perez-Pinera P., Zhang W., Chang Y., Vega J.A., Deuel T.F. J. Biol. Chem. 282:28683-28690(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION, ENZYME REGULATION.
[22]	"Recruitment of insulin receptor substrate-1 and activation of NF-kappaB essential for midkine growth signaling through anaplastic lymphoma kinase." Kuo A.H., Stoica G.E., Riegel A.T., Wellstein A. Oncogene 26:859-869(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH IRS1 AND SHC, PHOSPHORYLATION AT TYR-1096, FUNCTION.
[23]	"Anaplastic lymphoma kinase: signalling in development and disease." Palmer R.H., Vernersson E., Grabbe C., Hallberg B. Biochem. J. 420:345-361(2009) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[24]	"Solution structure of the complex of the PTB domain of SNT-2 and 19-residue peptide (aa 1571-1589) of HALK." RIKEN structural genomics initiative (RSGI) Submitted (APR-2008) to the PDB data bank Cited for: STRUCTURE BY NMR OF 1571-1589.
[25]	"Crystal structure of the ALK (anaplastic lymphoma kinase) catalytic domain." Lee C.C., Jia Y., Li N., Sun X., Ng K., Ambing E., Gao M.Y., Hua S., Chen C., Kim S., Michellys P.Y., Lesley S.A., Harris J.L., Spraggon G. Biochem. J. 430:425-437(2010) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 1072-1410.
[26]	"Crystal structures of anaplastic lymphoma kinase in complex with ATP competitive inhibitors." Bossi R.T., Saccardo M.B., Ardini E., Menichincheri M., Rusconi L., Magnaghi P., Orsini P., Avanzi N., Borgia A.L., Nesi M., Bandiera T., Fogliatto G., Bertrand J.A. Biochemistry 49:6813-6825(2010) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 1094-1407 IN COMPLEX WITH INHIBITOR.
[27]	"Structural basis for the recognition of nucleophosmin-anaplastic lymphoma kinase oncoprotein by the phosphotyrosine binding domain of Suc1-associated neurotrophic factor-induced tyrosine-phosphorylated target-2." Koshiba S., Li H., Motoda Y., Tomizawa T., Kasai T., Tochio N., Yabuki T., Harada T., Watanabe S., Tanaka A., Shirouzu M., Kigawa T., Yamamoto T., Yokoyama S. J. Struct. Funct. Genomics 11:125-141(2010) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 1571-1589.
[28]	"Structure of L1196M mutant anaplastic lymphoma kinase in complex with crizotinib." Mctigue M., Deng Y., Liu W., Brooun A. Submitted (MAY-2011) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 1093-1411 IN COMPLEX WITH CRIZOTINIB.
[29]	"CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant." Sakamoto H., Tsukaguchi T., Hiroshima S., Kodama T., Kobayashi T., Fukami T.A., Oikawa N., Tsukuda T., Ishii N., Aoki Y. Cancer Cell 19:679-690(2011) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 1069-1411 IN COMPLEX WITH INHIBITOR, ENZYME REGULATION.
[30]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] LEU-90; LEU-163; GLN-296; ALA-476; PHE-560; ILE-680; THR-704; SER-877; MET-1012; ASP-1121; THR-1274; LEU-1328; ASN-1416; LYS-1419; ARG-1429; ARG-1491 AND GLU-1529.
[31]	"Identification of ALK as a major familial neuroblastoma predisposition gene." Mosse Y.P., Laudenslager M., Longo L., Cole K.A., Wood A., Attiyeh E.F., Laquaglia M.J., Sennett R., Lynch J.E., Perri P., Laureys G., Speleman F., Kim C., Hou C., Hakonarson H., Torkamani A., Schork N.J., Brodeur G.M. , Tonini G.P., Rappaport E., Devoto M., Maris J.M. Nature 455:930-935(2008) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS NBLST3 ASN-1091; ALA-1128; ARG-1166; ASN-1171; ILE-1174; PRO-1192; CYS-1245; VAL-1245 THR-1250 AND GLN-1275.
[32]	"Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma." Janoueix-Lerosey I., Lequin D., Brugieres L., Ribeiro A., de Pontual L., Combaret V., Raynal V., Puisieux A., Schleiermacher G., Pierron G., Valteau-Couanet D., Frebourg T., Michon J., Lyonnet S., Amiel J., Delattre O. Nature 455:967-970(2008) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS NBLST3 VAL-1174; LEU-1174; CYS-1174; PRO-1192; GLN-1275 AND SER-1278, VARIANT LEU-1275.
[33]	"Activating mutations in ALK provide a therapeutic target in neuroblastoma." George R.E., Sanda T., Hanna M., Froehling S., Luther W. II, Zhang J., Ahn Y., Zhou W., London W.B., McGrady P., Xue L., Zozulya S., Gregor V.E., Webb T.R., Gray N.S., Gilliland D.G., Diller L., Greulich H. , Morris S.W., Meyerson M., Look A.T. Nature 455:975-978(2008) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS NBLST3 MET-1151; LEU-1174; THR-1234; CYS-1245 AND GLN-1275.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U62540 mRNA. Translation: AAB71619.1.
U66559 mRNA. Translation: AAC51104.1.
AB209477 mRNA. Translation: BAD92714.1. Different initiation.
AC106870 Genomic DNA. Translation: AAX93126.1.
AC093756 Genomic DNA. Translation: AAX88892.1.
AC074096 Genomic DNA. Translation: AAY15027.1.

IPI

IPI00395632.

RefSeq

NP_004295.2. NM_004304.4.

UniGene

Hs.654469.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2KUP	NMR	-	B	1571-1589	[»]
2KUQ	NMR	-	A	1571-1589	[»]
2XB7	X-ray	2.50	A	1094-1407	[»]
2XBA	X-ray	1.95	A	1094-1407	[»]
2XP2	X-ray	1.90	A	1093-1411	[»]
2YFX	X-ray	1.70	A	1093-1411	[»]
2YHV	X-ray	1.90	A	1093-1411	[»]
2YJR	X-ray	1.90	A	1093-1411	[»]
2YJS	X-ray	1.90	A	1093-1411	[»]
2YS5	NMR	-	B	1571-1589	[»]
2YT2	NMR	-	A	1571-1589	[»]
3AOX	X-ray	1.75	A	1069-1411	[»]
3L9P	X-ray	1.80	A	1072-1410	[»]
3LCS	X-ray	1.95	A	1072-1410	[»]
3LCT	X-ray	2.10	A	1072-1410	[»]
4DCE	X-ray	2.03	A/B	1078-1410	[»]
4FNW	X-ray	1.75	A	1084-1410	[»]
4FNX	X-ray	1.70	A	1084-1410	[»]
4FNY	X-ray	2.45	A	1084-1410	[»]
4FNZ	X-ray	2.60	A	1084-1410	[»]
4FOB	X-ray	1.90	A	1058-1410	[»]
4FOC	X-ray	1.70	A	1058-1410	[»]
4FOD	X-ray	2.00	A	1078-1410	[»]

ProteinModelPortal

Q9UM73.

SMR

Q9UM73. Positions 435-474, 1096-1399.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-5954N.

IntAct

Q9UM73. 4 interactions.

MINT

MINT-1133857.

STRING

9606.ENSP00000373700.

PTM databases

PhosphoSite

Q9UM73.

Polymorphism databases

DMDM

296439447.

Proteomic databases

PaxDb

Q9UM73.

PRIDE

Q9UM73.

Protocols and materials databases

DNASU

238.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000389048; ENSP00000373700; ENSG00000171094.

GeneID

238.

KEGG

hsa:238.

UCSC

uc002rmy.3. human.

Organism-specific databases

CTD

238.

GeneCards

GC02M029327.

H-InvDB

HIX0024259.
HIX0030037.

HGNC

HGNC:427. ALK.

HPA

HPA010694.

MIM

105590. gene.
613014. phenotype.

neXtProt

NX_Q9UM73.

Orphanet

98841. Anaplastic large cell lymphoma.
635. Neuroblastoma.

PharmGKB

PA24719.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000231766.

HOVERGEN

HBG018726.

InParanoid

Q9UM73.

KO

K05119.

OMA

LIQKVCI.

OrthoDB

EOG4DR9BP.

Enzyme and pathway databases

BRENDA

2.7.10.1. 2681.

Gene expression databases

ArrayExpress

Q9UM73.

Bgee

Q9UM73.

CleanEx

HS_ALK.

Genevestigator

Q9UM73.

GermOnline

ENSG00000171094. Homo sapiens.

Family and domain databases

Gene3D

4.10.400.10. 1 hit.

InterPro

IPR026830. ALK.
IPR008985. ConA-like_lec_gl_sf.
IPR011009. Kinase-like_dom.
IPR002172. LDrepeatLR_classA_rpt.
IPR000998. MAM_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR002011. Tyr_kinase_rcpt_2_CS.
[Graphical view]

PANTHER

PTHR24416:SF139. PTHR24416:SF139. 1 hit.

Pfam

PF00629. MAM. 2 hits.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]

PRINTS

PR00109. TYRKINASE.

SMART

SM00192. LDLa. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]

SUPFAM

SSF49899. ConA_like_lec_gl. 2 hits.
SSF56112. Kinase_like. 1 hit.

PROSITE

PS01209. LDLRA_1. False negative.
PS50068. LDLRA_2. False negative.
PS00740. MAM_1. False negative.
PS50060. MAM_2. 2 hits.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS00239. RECEPTOR_TYR_KIN_II. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q9UM73.

ChEMBL

CHEMBL4247.

ChiTaRS

ALK. human.

DrugBank

DB00171. Adenosine triphosphate.

EvolutionaryTrace

Q9UM73.

GenomeRNAi

238.

NextBio

948.

SOURCE

Search...

Entry information

Entry name

ALK_HUMAN

Accession

Primary (citable) accession number: Q9UM73
Secondary accession number(s): Q4ZFX9 , Q53QQ6, Q53RZ4, Q59FI3, Q9Y4K6

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 27, 2002
Last sequence update:	May 18, 2010
Last modified:	May 1, 2013
This is version 134 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.