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Q9UM73 (ALK_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 147. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (8) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
ALK tyrosine kinase receptor

EC=2.7.10.1
Alternative name(s):
Anaplastic lymphoma kinase
CD_antigen=CD246
Gene names
Name:ALK
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1620 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence 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. Phosphorylation at Tyr-1507 is critical for SHC1 association. Ref.8 Ref.15 Ref.20 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 Ref.34

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 componentCell membrane
Membrane
   Coding sequence diversityChromosomal rearrangement
Polymorphism
   DiseaseDisease mutation
Proto-oncogene
   DomainRepeat
Signal
Transmembrane
Transmembrane helix
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Receptor
Transferase
Tyrosine-protein kinase
   PTMGlycoprotein
Phosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processNIK/NF-kappaB signaling

Traceable author statement Ref.23. Source: GOC

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

peptidyl-tyrosine phosphorylation

Inferred from direct assay Ref.1. Source: GOC

phosphorylation

Inferred from direct assay Ref.1. 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

signal transduction

Traceable author statement Ref.23. Source: UniProtKB

transmembrane receptor protein tyrosine kinase signaling pathway

Inferred from electronic annotation. Source: InterPro

   Cellular_componentextracellular vesicular exosome

Inferred from direct assay PubMed 19056867. Source: UniProt

integral component of plasma membrane

Inferred from direct assay Ref.1. Source: UniProtKB

protein complex

Inferred from direct assay PubMed 23382219. Source: MGI

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

NF-kappaB-inducing kinase activity

Traceable author statement Ref.23. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.21PubMed 22939624. Source: IntAct

protein tyrosine kinase activity

Inferred from direct assay Ref.1. Source: MGI

transmembrane receptor protein tyrosine kinase activity

Inferred from direct assay Ref.1. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

HSP90AB1P082382EBI-357361,EBI-352572
PTPRZ1P234712EBI-357361,EBI-2263175

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 1818 Potential
Chain19 – 16201602ALK tyrosine kinase receptor
PRO_0000016740

Regions

Topological domain19 – 10381020Extracellular Potential
Transmembrane1039 – 105921Helical; Potential
Topological domain1060 – 1620561Cytoplasmic Potential
Domain264 – 427164MAM 1
Domain437 – 47337LDL-receptor class A
Domain478 – 636159MAM 2
Domain1116 – 1392277Protein kinase
Nucleotide binding1197 – 11993ATP
Region1197 – 11993Inhibitor binding
Compositional bias816 – 940125Gly-rich

Sites

Active site12491Proton acceptor By similarity
Binding site11241ATP; via carbonyl oxygen
Binding site11501ATP By similarity
Binding site11501Inhibitor
Binding site11991Inhibitor; via amide nitrogen
Binding site12031Inhibitor
Binding site12101Inhibitor
Binding site12701ATP

Amino acid modifications

Modified residue2111Phosphoserine
Modified residue10781Phosphotyrosine Ref.18
Modified residue10921Phosphotyrosine
Modified residue10961Phosphotyrosine Ref.18 Ref.22
Modified residue11311Phosphotyrosine Ref.18
Modified residue12781Phosphotyrosine Ref.15
Modified residue12821Phosphotyrosine; by autocatalysis
Modified residue12831Phosphotyrosine
Modified residue13591Phosphotyrosine
Modified residue15071Phosphotyrosine Ref.20
Modified residue15841Phosphotyrosine
Modified residue16041Phosphotyrosine Ref.18
Glycosylation1691N-linked (GlcNAc...) Potential
Glycosylation2441N-linked (GlcNAc...) Potential
Glycosylation2851N-linked (GlcNAc...) Potential
Glycosylation3241N-linked (GlcNAc...) Potential
Glycosylation4111N-linked (GlcNAc...) Potential
Glycosylation4241N-linked (GlcNAc...) Potential
Glycosylation4451N-linked (GlcNAc...) Potential
Glycosylation5631N-linked (GlcNAc...) Potential
Glycosylation5711N-linked (GlcNAc...) Potential
Glycosylation6271N-linked (GlcNAc...) Potential
Glycosylation7091N-linked (GlcNAc...) Potential
Glycosylation8081N-linked (GlcNAc...) Potential
Glycosylation8631N-linked (GlcNAc...) Potential
Glycosylation8641N-linked (GlcNAc...) Potential
Glycosylation8861N-linked (GlcNAc...) Potential
Glycosylation9861N-linked (GlcNAc...) Potential

Natural variations

Natural variant901S → L. Ref.30
Corresponds to variant rs34617074 [ dbSNP | Ensembl ].
VAR_041477
Natural variant1631V → L. Ref.30
Corresponds to variant rs55697431 [ dbSNP | Ensembl ].
VAR_041478
Natural variant2961E → Q. Ref.30
Corresponds to variant rs56077855 [ dbSNP | Ensembl ].
VAR_041479
Natural variant4761V → A. Ref.30
Corresponds to variant rs35093491 [ dbSNP | Ensembl ].
VAR_041480
Natural variant5601L → F in a breast pleomorphic lobular carcinoma sample; somatic mutation. Ref.30
VAR_041481
Natural variant6801T → I. Ref.30
Corresponds to variant rs35228363 [ dbSNP | Ensembl ].
VAR_041482
Natural variant7041A → T. Ref.30
Corresponds to variant rs34829159 [ dbSNP | Ensembl ].
VAR_041483
Natural variant8681L → Q.
Corresponds to variant rs55941323 [ dbSNP | Ensembl ].
VAR_061288
Natural variant8771A → S in an ovarian serous carcinoma sample; somatic mutation. Ref.30
VAR_041484
Natural variant10121T → M. Ref.30
Corresponds to variant rs35073634 [ dbSNP | Ensembl ].
VAR_041485
Natural variant10911D → N in NBLST3; somatic mutation. Ref.31
VAR_063850
Natural variant11211G → D. Ref.30
Corresponds to variant rs55760835 [ dbSNP | Ensembl ].
VAR_041486
Natural variant11281G → A in NBLST3. Ref.31
VAR_063851
Natural variant11511T → M in NBLST3. Ref.33
VAR_063852
Natural variant11661M → R in NBLST3; somatic mutation. Ref.31
VAR_063853
Natural variant11711I → N in NBLST3; somatic mutation. Ref.31
VAR_063854
Natural variant11741F → C in NBLST3. Ref.32
VAR_063855
Natural variant11741F → I in NBLST3; somatic mutation. Ref.31
VAR_063856
Natural variant11741F → L in NBLST3; somatic mutation; constitutively activated; retained in the endoplasmic reticulum and Golgi compartments. Ref.32 Ref.33 Ref.34
VAR_063857
Natural variant11741F → V in NBLST3; somatic mutation; constitutively activated; retained in the endoplasmic reticulum and Golgi compartments. Ref.32 Ref.34
VAR_063858
Natural variant11921R → P in NBLST3. Ref.31 Ref.32
VAR_063859
Natural variant12341A → T in NBLST3; somatic mutation. Ref.33
VAR_063860
Natural variant12451F → C in NBLST3; somatic mutation. Ref.31 Ref.33
VAR_063861
Natural variant12451F → V in NBLST3; somatic mutation. Ref.31
VAR_063862
Natural variant12501I → T in NBLST3; somatic mutation. Ref.31
VAR_063863
Natural variant12741A → T. Ref.30
Corresponds to variant rs45502292 [ dbSNP | Ensembl ].
VAR_041487
Natural variant12751R → L Observed in neuroblastoma. Ref.32
VAR_063864
Natural variant12751R → Q in NBLST3; constitutively activated; retained in the endoplasmic reticulum and Golgi compartments. Ref.31 Ref.32 Ref.33 Ref.34
VAR_063865
Natural variant12781Y → S in NBLST3; somatic mutation. Ref.32
VAR_063866
Natural variant13281M → L. Ref.30
Corresponds to variant rs56160491 [ dbSNP | Ensembl ].
VAR_041488
Natural variant13761F → S.
Corresponds to variant rs17694720 [ dbSNP | Ensembl ].
VAR_055987
Natural variant14161K → N. Ref.30
Corresponds to variant rs55782189 [ dbSNP | Ensembl ].
VAR_041489
Natural variant14191E → K. Ref.30
Corresponds to variant rs56181542 [ dbSNP | Ensembl ].
VAR_041490
Natural variant14291Q → R. Ref.30
Corresponds to variant rs55906201 [ dbSNP | Ensembl ].
VAR_041491
Natural variant14611I → V. Ref.1 Ref.3 Ref.4 Ref.6
Corresponds to variant rs1670283 [ dbSNP | Ensembl ].
VAR_031042
Natural variant14911K → R. Ref.3 Ref.4 Ref.30
Corresponds to variant rs1881420 [ dbSNP | Ensembl ].
VAR_031043
Natural variant15291D → E. Ref.3 Ref.4 Ref.30
Corresponds to variant rs1881421 [ dbSNP | Ensembl ].
VAR_031044
Natural variant15991P → H.
Corresponds to variant rs1881423 [ dbSNP | Ensembl ].
VAR_055988

Experimental info

Mutagenesis15071Y → F: Impairs interaction with SHC1. Ref.20
Sequence conflict361P → S in AAB71619. Ref.1

Secondary structure

.................................................................... 1620
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q9UM73 [UniParc].

Last modified May 18, 2010. Version 3.
Checksum: 0733D6C4FD212F41

FASTA1,620176,442
        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 

« Hide

References

« Hide '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. expand/collapse author list , 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, PHOSPHORYLATION AT TYR-1278.
[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, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[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, PHOSPHORYLATION AT TYR-1507, 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. expand/collapse author list , 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. expand/collapse author list , 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. expand/collapse author list , 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.
[34]"The constitutive activity of the ALK mutated at positions F1174 or R1275 impairs receptor trafficking."
Mazot P., Cazes A., Boutterin M.C., Figueiredo A., Raynal V., Combaret V., Hallberg B., Palmer R.H., Delattre O., Janoueix-Lerosey I., Vigny M.
Oncogene 30:2017-2025(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION OF VARIANTS NBLST3 LEU-1174; VAL-1174 AND GLN-1275.
+Additional computationally mapped references.

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.
CCDSCCDS33172.1.
RefSeqNP_004295.2. NM_004304.4.
UniGeneHs.654469.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2KUPNMR-B1571-1589[»]
2KUQNMR-A1571-1589[»]
2XB7X-ray2.50A1094-1407[»]
2XBAX-ray1.95A1094-1407[»]
2XP2X-ray1.90A1093-1411[»]
2YFXX-ray1.70A1093-1411[»]
2YHVX-ray1.90A1093-1411[»]
2YJRX-ray1.90A1093-1411[»]
2YJSX-ray1.90A1093-1411[»]
2YS5NMR-B1571-1589[»]
2YT2NMR-A1571-1589[»]
3AOXX-ray1.75A1069-1411[»]
3L9PX-ray1.80A1072-1410[»]
3LCSX-ray1.95A1072-1410[»]
3LCTX-ray2.10A1072-1410[»]
4ANLX-ray1.70A1093-1411[»]
4ANQX-ray1.76A1093-1411[»]
4ANSX-ray1.85A1093-1411[»]
4CCBX-ray2.03A1093-1411[»]
4CCUX-ray2.00A1093-1411[»]
4CD0X-ray2.23A1093-1411[»]
4DCEX-ray2.03A/B1078-1410[»]
4FNWX-ray1.75A1084-1410[»]
4FNXX-ray1.70A1084-1410[»]
4FNYX-ray2.45A1084-1410[»]
4FNZX-ray2.60A1084-1410[»]
4FOBX-ray1.90A1058-1410[»]
4FOCX-ray1.70A1058-1410[»]
4FODX-ray2.00A1078-1410[»]
4JOAX-ray2.70A1072-1410[»]
4MKCX-ray2.01A1072-1410[»]
ProteinModelPortalQ9UM73.
SMRQ9UM73. Positions 1096-1480.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid106739. 48 interactions.
DIPDIP-5954N.
IntActQ9UM73. 6 interactions.
MINTMINT-1133857.
STRING9606.ENSP00000373700.

Chemistry

BindingDBQ9UM73.
ChEMBLCHEMBL4247.
DrugBankDB00171. Adenosine triphosphate.
GuidetoPHARMACOLOGY1839.

PTM databases

PhosphoSiteQ9UM73.

Polymorphism databases

DMDM296439447.

Proteomic databases

PaxDbQ9UM73.
PRIDEQ9UM73.

Protocols and materials databases

DNASU238.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000389048; ENSP00000373700; ENSG00000171094.
GeneID238.
KEGGhsa:238.
UCSCuc002rmy.3. human.

Organism-specific databases

CTD238.
GeneCardsGC02M029327.
GeneReviewsALK.
H-InvDBHIX0024259.
HIX0030037.
HGNCHGNC:427. ALK.
HPAHPA010694.
MIM105590. gene.
613014. phenotype.
neXtProtNX_Q9UM73.
Orphanet300895. ALK-positive anaplastic large cell lymphoma.
364043. ALK-positive large B-cell lymphoma.
178342. Inflammatory myofibroblastic tumor.
635. Neuroblastoma.
357191. Selection of therapeutic option in non-small cell lung carcinoma.
PharmGKBPA24719.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000231766.
HOVERGENHBG018726.
InParanoidQ9UM73.
KOK05119.
OMALIQKVCI.
OrthoDBEOG7GN2KT.
PhylomeDBQ9UM73.
TreeFamTF351636.

Enzyme and pathway databases

BRENDA2.7.10.1. 2681.
SignaLinkQ9UM73.

Gene expression databases

ArrayExpressQ9UM73.
BgeeQ9UM73.
CleanExHS_ALK.
GenevestigatorQ9UM73.

Family and domain databases

Gene3D4.10.400.10. 1 hit.
InterProIPR026830. ALK.
IPR008985. ConA-like_lec_gl_sf.
IPR011009. Kinase-like_dom.
IPR002172. LDrepeatLR_classA_rpt.
IPR000998. MAM_dom.
IPR000719. Prot_kinase_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]
PANTHERPTHR24416:SF276. PTHR24416:SF276. 1 hit.
PfamPF00629. MAM. 2 hits.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PRINTSPR00109. TYRKINASE.
SMARTSM00192. LDLa. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMSSF49899. SSF49899. 2 hits.
SSF56112. SSF56112. 1 hit.
SSF57424. SSF57424. 1 hit.
PROSITEPS50060. 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]
ProtoNetSearch...

Other

ChiTaRSALK. human.
EvolutionaryTraceQ9UM73.
GeneWikiAnaplastic_lymphoma_kinase.
GenomeRNAi238.
NextBio948.
PROQ9UM73.
SOURCESearch...

Entry information

Entry nameALK_HUMAN
AccessionPrimary (citable) accession number: Q9UM73
Secondary accession number(s): Q4ZFX9 expand/collapse secondary AC list , Q53QQ6, Q53RZ4, Q59FI3, Q9Y4K6
Entry history
Integrated into UniProtKB/Swiss-Prot: March 27, 2002
Last sequence update: May 18, 2010
Last modified: July 9, 2014
This is version 147 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM

Human cell differentiation molecules

CD nomenclature of surface proteins of human leucocytes and list of entries