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P97793 (ALK_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified May 1, 2013. Version 119. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
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to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·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
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length1621 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.3 Ref.4 Ref.5 Ref.6

Catalytic activity

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

Enzyme regulation

Activated by ligand-binding and subsequent phosphorylation By similarity. 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 By similarity.

Subunit structure

Homodimer. Homodimerizes when bound to ligand By similarity. Interacts with CBL, IRS1, PIK3R1, PLCG1 and SHC1. Interacts with FRS2, PTN and MDK. Ref.3 Ref.5

Subcellular location

Cell membrane; Single-pass type I membrane protein By similarity. Note: Membrane attachment was crucial for promotion of neuron-like differentiation and cell proliferation arrest through specific activation of the MAP kinase pathway By similarity.

Tissue specificity

Mainly expressed in central nervous system (CNS) and other parts of the brain. Expression is also found in peripheral nervous systems, eye, nasal epithelium, olfactory nerve, tongue, skin, tissue surrounding the esophagus, stomach, midgut, as well as testis and ovary. Ref.4

Post-translational modification

Phosphorylated at tyrosine residues by autocatalysis, which activates kinase activity By similarity. 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 By similarity. Ref.3 Ref.5

N-glycosylated By similarity.

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 annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 1818 Potential
Chain19 – 16211603ALK tyrosine kinase receptor
PRO_0000016741

Regions

Topological domain19 – 10421024Extracellular Potential
Transmembrane1043 – 106321Helical; Potential
Topological domain1064 – 1621558Cytoplasmic Potential
Domain268 – 431164MAM 1
Domain441 – 47737LDL-receptor class A
Domain482 – 640159MAM 2
Domain1120 – 1396277Protein kinase
Nucleotide binding1126 – 11349ATP By similarity
Nucleotide binding1201 – 12033ATP By similarity
Region1201 – 12033Inhibitor binding By similarity
Compositional bias820 – 944125Gly-rich

Sites

Active site12531Proton acceptor By similarity
Binding site11281ATP; via carbonyl oxygen By similarity
Binding site11541ATP By similarity
Binding site11541Inhibitor By similarity
Binding site12031Inhibitor; via amide nitrogen By similarity
Binding site12071Inhibitor By similarity
Binding site12141Inhibitor By similarity
Binding site12741ATP By similarity

Amino acid modifications

Modified residue2161Phosphoserine By similarity
Modified residue10821Phosphotyrosine By similarity
Modified residue10961Phosphotyrosine By similarity
Modified residue11001Phosphotyrosine By similarity
Modified residue11351Phosphotyrosine By similarity
Modified residue12821Phosphotyrosine By similarity
Modified residue12861Phosphotyrosine; by autocatalysis By similarity
Modified residue12871Phosphotyrosine By similarity
Modified residue13631Phosphotyrosine By similarity
Modified residue15161Phosphotyrosine By similarity
Modified residue15901Phosphotyrosine By similarity
Glycosylation1741N-linked (GlcNAc...) Potential
Glycosylation2481N-linked (GlcNAc...) Potential
Glycosylation2891N-linked (GlcNAc...) Potential
Glycosylation3281N-linked (GlcNAc...) Potential
Glycosylation4151N-linked (GlcNAc...) Potential
Glycosylation4281N-linked (GlcNAc...) Potential
Glycosylation4491N-linked (GlcNAc...) Potential
Glycosylation5671N-linked (GlcNAc...) Potential
Glycosylation5751N-linked (GlcNAc...) Potential
Glycosylation6311N-linked (GlcNAc...) Potential
Glycosylation6731N-linked (GlcNAc...) Potential
Glycosylation7131N-linked (GlcNAc...) Potential
Glycosylation8121N-linked (GlcNAc...) Potential
Glycosylation8681N-linked (GlcNAc...) Potential
Glycosylation8901N-linked (GlcNAc...) Potential
Glycosylation9901N-linked (GlcNAc...) Potential

Experimental info

Sequence conflict138 – 1392KL → NV in BAA11673. Ref.1
Sequence conflict2321M → L in BAA11673. Ref.1
Sequence conflict8571T → R in BAA11673. Ref.1
Sequence conflict1075 – 10762ME → IQ in BAA11673. Ref.1
Sequence conflict15221E → A in BAA11673. Ref.1
Sequence conflict15861G → P in BAA11673. Ref.1

Sequences

Sequence LengthMass (Da)Tools
P97793 [UniParc].

Last modified July 27, 2011. Version 2.
Checksum: 72D1022E117F303E

FASTA1,621174,948
        10         20         30         40         50         60 
MGAAGFLWLL PPLLLAAASY SGAATDQRAG SPASGPPLQP REPLSYSRLQ RKSLAVDFVV 

        70         80         90        100        110        120 
PSLFRVYARD LLLPQPRSPS EPEAGGLEAR GSLALDCEPL LRLLGPLPGI SWADGASSPS 

       130        140        150        160        170        180 
PEAGPTLSRV LKGGSVRKLR RAKQLVLELG EETILEGCIG PPEEVAAVGI LQFNLSELFS 

       190        200        210        220        230        240 
WWILHGEGRL RIRLMPEKKA SEVGREGRLS SAIRASQPRL LFQIFGTGHS SMESPSETPS 

       250        260        270        280        290        300 
PPGTFMWNLT WTMKDSFPFL SHRSRYGLEC SFDFPCELEY SPPLHNHGNQ SWSWRHVPSE 

       310        320        330        340        350        360 
EASRMNLLDG PEAEHSQEMP RGSFLLLNTS ADSKHTILSP WMRSSSDHCT LAVSVHRHLQ 

       370        380        390        400        410        420 
PSGRYVAQLL PHNEAGREIL LVPTPGKHGW TVLQGRVGRP ANPFRVALEY ISSGNRSLSA 

       430        440        450        460        470        480 
VDFFALKNCS EGTSPGSKMA LQSSFTCWNG TVLQLGQACD FHQDCAQGED EGQLCSKLPA 

       490        500        510        520        530        540 
GFYCNFENGF CGWTQSPLSP HMPRWQVRTL RDAHSQGHQG RALLLSTTDI LASEGATVTS 

       550        560        570        580        590        600 
ATFPAPMKNS PCELRMSWLI RGVLRGNVSL VLVENKTGKE QSRTVWHVAT DEGLSLWQHT 

       610        620        630        640        650        660 
VLSLLDVTDR FWLQIVTWWG PGSRATVGFD NISISLDCYL TISGEEKMSL NSVPKSRNLF 

       670        680        690        700        710        720 
EKNPNKESKS WANISGPTPI FDPTVHWLFT TCGASGPHGP TQAQCNNAYQ NSNLSVVVGS 

       730        740        750        760        770        780 
EGPLKGVQIW KVPATDTYSI SGYGAAGGKG GKNTMMRSHG VSVLGIFNLE KGDTLYILVG 

       790        800        810        820        830        840 
QQGEDACPRA NQLIQKVCVG ENNVIEEEIR VNRSVHEWAG GGGGGGGATY VFKMKDGVPV 

       850        860        870        880        890        900 
PLIIAAGGGG RAYGAKTETF HPERLESNSS VLGLNGNSGA AGGGGGWNDN TSLLWAGKSL 

       910        920        930        940        950        960 
LEGAAGGHSC PQAMKKWGWE TRGGFGGGGG GCSSGGGGGG YIGGNAASNN DPEMDGEDGV 

       970        980        990       1000       1010       1020 
SFISPLGILY TPALKVMEGH GEVNIKHYLN CSHCEVDECH MDPESHKVIC FCDHGTVLAD 

      1030       1040       1050       1060       1070       1080 
DGVSCIVSPT PEPHLPLSLI LSVVTSALVA ALVLAFSGIM IVYRRKHQEL QAMQMELQSP 

      1090       1100       1110       1120       1130       1140 
EYKLSKLRTS TIMTDYNPNY CFAGKTSSIS DLKEVPRKNI TLIRGLGHGA FGEVYEGQVS 

      1150       1160       1170       1180       1190       1200 
GMPNDPSPLQ VAVKTLPEVC SEQDELDFLM EALIISKFNH QNIVRCIGVS LQALPRFILL 

      1210       1220       1230       1240       1250       1260 
ELMAGGDLKS FLRETRPRPN QPTSLAMLDL LHVARDIACG CQYLEENHFI HRDIAARNCL 

      1270       1280       1290       1300       1310       1320 
LTCPGAGRIA KIGDFGMARD IYRASYYRKG GCAMLPVKWM PPEAFMEGIF TSKTDTWSFG 

      1330       1340       1350       1360       1370       1380 
VLLWEIFSLG YMPYPSKSNQ EVLEFVTSGG RMDPPKNCPG PVYRIMTQCW QHQPEDRPNF 

      1390       1400       1410       1420       1430       1440 
AIILERIEYC TQDPDVINTA LPIEYGPVVE EEEKVPMRPK DPEGMPPLLV SPQPAKHEEA 

      1450       1460       1470       1480       1490       1500 
SAAPQPAALT APGPSVKKPP GAGAGAGAGA GAGPVPRGAA DRGHVNMAFS QPNPPPELHK 

      1510       1520       1530       1540       1550       1560 
GPGSRNKPTS LWNPTYGSWF TEKPAKKTHP PPGAEPQARA GAAEGGWTGP GAGPRRAEAA 

      1570       1580       1590       1600       1610       1620 
LLLEPSALSA TMKEVPLFRL RHFPCGNVNY GYQQQGLPLE ATAAPGDTML KSKNKVTQPG 


P

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References

« Hide 'large scale' references
[1]"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].
Tissue: Brain and Testis.
[2]"Lineage-specific biology revealed by a finished genome assembly of the mouse."
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. expand/collapse author list , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: C57BL/6J.
[3]"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: PHOSPHORYLATION, INTERACTION WITH CBL; IRS1; PIK3R1; PLCG1 AND SHC1, FUNCTION IN PHOSPHORYLATION OF CBL; IRS1 AND SHC1.
[4]"Characterization of the expression of the ALK receptor tyrosine kinase in mice."
Vernersson E., Khoo N.K., Henriksson M.L., Roos G., Palmer R.H., Hallberg B.
Gene Expr. Patterns 6:448-461(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY, FUNCTION.
[5]"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.
[6]"ALK (Anaplastic Lymphoma Kinase) expression in DRG neurons and its involvement in neuron-Schwann cells interaction."
Degoutin J., Brunet-de Carvalho N., Cifuentes-Diaz C., Vigny M.
Eur. J. Neurosci. 29:275-286(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[7]"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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ		D83002 mRNA. Translation: BAA11673.1.
AC122746 Genomic DNA. No translation available.
AC151265 Genomic DNA. No translation available.
AC154458 Genomic DNA. No translation available.
AC154602 Genomic DNA. No translation available.
AC154659 Genomic DNA. No translation available.
AC155242 Genomic DNA. No translation available.
IPIIPI00620900.
PIRT30200.
RefSeqNP_031465.2. NM_007439.2.
UniGeneMm.311854.

3D structure databases

ProteinModelPortalP97793.
SMRP97793. Positions 1100-1403.
ModBaseSearch...

Protein-protein interaction databases

STRING10090.ENSMUSP00000083840.

PTM databases

PhosphoSiteP97793.

Proteomic databases

PaxDbP97793.
PRIDEP97793.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000086639; ENSMUSP00000083840; ENSMUSG00000055471.
GeneID11682.
KEGGmmu:11682.
UCSCuc008dnb.1. mouse.

Organism-specific databases

CTD238.
MGIMGI:103305. Alk.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00700000104172.
HOGENOMHOG000231766.
HOVERGENHBG018726.
InParanoidP97793.
KOK05119.
OMALIQKVCI.
OrthoDBEOG4DR9BP.

Enzyme and pathway databases

BRENDA2.7.10.1. 3474.

Gene expression databases

BgeeP97793.
CleanExMM_ALK.
GenevestigatorP97793.
GermOnlineENSMUSG00000055471. Mus musculus.

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_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]
PANTHERPTHR24416:SF139. PTHR24416:SF139. 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. ConA_like_lec_gl. 2 hits.
SSF56112. Kinase_like. 1 hit.
PROSITEPS01209. 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]
ProtoNetSearch...

Other

BindingDBP97793.
ChEMBLCHEMBL5771.
NextBio279315.
SOURCESearch...

Entry information

Entry nameALK_MOUSE
AccessionPrimary (citable) accession number: P97793
Secondary accession number(s): E9QKV3
Entry history
Integrated into UniProtKB/Swiss-Prot: March 27, 2002
Last sequence update: July 27, 2011
Last modified: May 1, 2013
This is version 119 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot

SIMILARITY comments

Index of protein domains and families

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