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Protein

ALK tyrosine kinase receptor

Gene

Alk

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Neuronal 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.4 Publications

Catalytic activityi

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

Enzyme regulationi

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).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei1128ATP; via carbonyl oxygenPROSITE-ProRule annotation1
Binding sitei1154ATPPROSITE-ProRule annotation1
Binding sitei1154InhibitorBy similarity1
Binding sitei1203Inhibitor; via amide nitrogenBy similarity1
Binding sitei1207InhibitorBy similarity1
Binding sitei1214InhibitorBy similarity1
Active sitei1253Proton acceptorPROSITE-ProRule annotation1
Binding sitei1274ATPPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi1126 – 1134ATPPROSITE-ProRule annotation9
Nucleotide bindingi1201 – 1203ATPPROSITE-ProRule annotation3

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Receptor, Transferase, Tyrosine-protein kinase

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.1. 3474.

Names & Taxonomyi

Protein namesi
Recommended name:
ALK tyrosine kinase receptor (EC:2.7.10.1)
Alternative name(s):
Anaplastic lymphoma kinase
CD_antigen: CD246
Gene namesi
Name:Alk
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 17

Organism-specific databases

MGIiMGI:103305. Alk.

Subcellular locationi

  • Cell membrane By similarity; 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

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini19 – 1042ExtracellularSequence analysisAdd BLAST1024
Transmembranei1043 – 1063HelicalSequence analysisAdd BLAST21
Topological domaini1064 – 1621CytoplasmicSequence analysisAdd BLAST558

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Chemistry databases

ChEMBLiCHEMBL5771.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 18Sequence analysisAdd BLAST18
ChainiPRO_000001674119 – 1621ALK tyrosine kinase receptorAdd BLAST1603

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi174N-linked (GlcNAc...)Sequence analysis1
Glycosylationi248N-linked (GlcNAc...)Sequence analysis1
Glycosylationi289N-linked (GlcNAc...)Sequence analysis1
Glycosylationi328N-linked (GlcNAc...)Sequence analysis1
Glycosylationi415N-linked (GlcNAc...)Sequence analysis1
Glycosylationi428N-linked (GlcNAc...)Sequence analysis1
Glycosylationi449N-linked (GlcNAc...)Sequence analysis1
Glycosylationi567N-linked (GlcNAc...)Sequence analysis1
Glycosylationi575N-linked (GlcNAc...)Sequence analysis1
Glycosylationi631N-linked (GlcNAc...)Sequence analysis1
Glycosylationi673N-linked (GlcNAc...)Sequence analysis1
Glycosylationi713N-linked (GlcNAc...)Sequence analysis1
Glycosylationi812N-linked (GlcNAc...)Sequence analysis1
Glycosylationi868N-linked (GlcNAc...)Sequence analysis1
Glycosylationi890N-linked (GlcNAc...)Sequence analysis1
Glycosylationi990N-linked (GlcNAc...)Sequence analysis1
Modified residuei1082PhosphotyrosineBy similarity1
Modified residuei1096Phosphotyrosine1 Publication1
Modified residuei1100PhosphotyrosineBy similarity1
Modified residuei1135PhosphotyrosineBy similarity1
Modified residuei1282PhosphotyrosineBy similarity1
Modified residuei1516PhosphotyrosineBy similarity1

Post-translational modificationi

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.By similarity
N-glycosylated.By similarity

Keywords - PTMi

Glycoprotein, Phosphoprotein

Proteomic databases

MaxQBiP97793.
PaxDbiP97793.
PRIDEiP97793.

PTM databases

iPTMnetiP97793.
PhosphoSitePlusiP97793.

Expressioni

Tissue specificityi

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.1 Publication

Gene expression databases

BgeeiENSMUSG00000055471.
CleanExiMM_ALK.
GenevisibleiP97793. MM.

Interactioni

Subunit structurei

Homodimer. Homodimerizes when bound to ligand (By similarity). Interacts with CBL, IRS1, PIK3R1, PLCG1 and SHC1. Interacts with FRS2, PTN and MDK.By similarity2 Publications

Protein-protein interaction databases

BioGridi198070. 1 interactor.
STRINGi10090.ENSMUSP00000083840.

Chemistry databases

BindingDBiP97793.

Structurei

3D structure databases

ProteinModelPortaliP97793.
SMRiP97793.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini268 – 431MAM 1PROSITE-ProRule annotationAdd BLAST164
Domaini441 – 477LDL-receptor class AAdd BLAST37
Domaini482 – 640MAM 2PROSITE-ProRule annotationAdd BLAST159
Domaini1120 – 1396Protein kinasePROSITE-ProRule annotationAdd BLAST277

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1201 – 1203Inhibitor bindingBy similarity3

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi820 – 944Gly-richAdd BLAST125

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.PROSITE-ProRule annotation
Contains 1 LDL-receptor class A domain.Curated
Contains 2 MAM domains.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1095. Eukaryota.
ENOG410XPVX. LUCA.
GeneTreeiENSGT00760000118818.
HOGENOMiHOG000231766.
HOVERGENiHBG018726.
InParanoidiP97793.
KOiK05119.
OMAiNAIMLSK.
OrthoDBiEOG091G003T.
TreeFamiTF351636.

Family and domain databases

CDDicd06263. MAM. 2 hits.
Gene3Di4.10.400.10. 1 hit.
InterProiIPR026830. ALK.
IPR013320. ConA-like_dom.
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]
PANTHERiPTHR24416:SF276. PTHR24416:SF276. 1 hit.
PfamiPF00629. MAM. 2 hits.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PRINTSiPR00109. TYRKINASE.
SMARTiSM00192. LDLa. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF49899. SSF49899. 2 hits.
SSF56112. SSF56112. 1 hit.
SSF57424. SSF57424. 1 hit.
PROSITEiPS50060. 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]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P97793-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGAAGFLWLL PPLLLAAASY SGAATDQRAG SPASGPPLQP REPLSYSRLQ
60 70 80 90 100
RKSLAVDFVV PSLFRVYARD LLLPQPRSPS EPEAGGLEAR GSLALDCEPL
110 120 130 140 150
LRLLGPLPGI SWADGASSPS PEAGPTLSRV LKGGSVRKLR RAKQLVLELG
160 170 180 190 200
EETILEGCIG PPEEVAAVGI LQFNLSELFS WWILHGEGRL RIRLMPEKKA
210 220 230 240 250
SEVGREGRLS SAIRASQPRL LFQIFGTGHS SMESPSETPS PPGTFMWNLT
260 270 280 290 300
WTMKDSFPFL SHRSRYGLEC SFDFPCELEY SPPLHNHGNQ SWSWRHVPSE
310 320 330 340 350
EASRMNLLDG PEAEHSQEMP RGSFLLLNTS ADSKHTILSP WMRSSSDHCT
360 370 380 390 400
LAVSVHRHLQ PSGRYVAQLL PHNEAGREIL LVPTPGKHGW TVLQGRVGRP
410 420 430 440 450
ANPFRVALEY ISSGNRSLSA VDFFALKNCS EGTSPGSKMA LQSSFTCWNG
460 470 480 490 500
TVLQLGQACD FHQDCAQGED EGQLCSKLPA GFYCNFENGF CGWTQSPLSP
510 520 530 540 550
HMPRWQVRTL RDAHSQGHQG RALLLSTTDI LASEGATVTS ATFPAPMKNS
560 570 580 590 600
PCELRMSWLI RGVLRGNVSL VLVENKTGKE QSRTVWHVAT DEGLSLWQHT
610 620 630 640 650
VLSLLDVTDR FWLQIVTWWG PGSRATVGFD NISISLDCYL TISGEEKMSL
660 670 680 690 700
NSVPKSRNLF EKNPNKESKS WANISGPTPI FDPTVHWLFT TCGASGPHGP
710 720 730 740 750
TQAQCNNAYQ NSNLSVVVGS EGPLKGVQIW KVPATDTYSI SGYGAAGGKG
760 770 780 790 800
GKNTMMRSHG VSVLGIFNLE KGDTLYILVG QQGEDACPRA NQLIQKVCVG
810 820 830 840 850
ENNVIEEEIR VNRSVHEWAG GGGGGGGATY VFKMKDGVPV PLIIAAGGGG
860 870 880 890 900
RAYGAKTETF HPERLESNSS VLGLNGNSGA AGGGGGWNDN TSLLWAGKSL
910 920 930 940 950
LEGAAGGHSC PQAMKKWGWE TRGGFGGGGG GCSSGGGGGG YIGGNAASNN
960 970 980 990 1000
DPEMDGEDGV SFISPLGILY TPALKVMEGH GEVNIKHYLN CSHCEVDECH
1010 1020 1030 1040 1050
MDPESHKVIC FCDHGTVLAD DGVSCIVSPT PEPHLPLSLI LSVVTSALVA
1060 1070 1080 1090 1100
ALVLAFSGIM IVYRRKHQEL QAMQMELQSP EYKLSKLRTS TIMTDYNPNY
1110 1120 1130 1140 1150
CFAGKTSSIS DLKEVPRKNI TLIRGLGHGA FGEVYEGQVS GMPNDPSPLQ
1160 1170 1180 1190 1200
VAVKTLPEVC SEQDELDFLM EALIISKFNH QNIVRCIGVS LQALPRFILL
1210 1220 1230 1240 1250
ELMAGGDLKS FLRETRPRPN QPTSLAMLDL LHVARDIACG CQYLEENHFI
1260 1270 1280 1290 1300
HRDIAARNCL LTCPGAGRIA KIGDFGMARD IYRASYYRKG GCAMLPVKWM
1310 1320 1330 1340 1350
PPEAFMEGIF TSKTDTWSFG VLLWEIFSLG YMPYPSKSNQ EVLEFVTSGG
1360 1370 1380 1390 1400
RMDPPKNCPG PVYRIMTQCW QHQPEDRPNF AIILERIEYC TQDPDVINTA
1410 1420 1430 1440 1450
LPIEYGPVVE EEEKVPMRPK DPEGMPPLLV SPQPAKHEEA SAAPQPAALT
1460 1470 1480 1490 1500
APGPSVKKPP GAGAGAGAGA GAGPVPRGAA DRGHVNMAFS QPNPPPELHK
1510 1520 1530 1540 1550
GPGSRNKPTS LWNPTYGSWF TEKPAKKTHP PPGAEPQARA GAAEGGWTGP
1560 1570 1580 1590 1600
GAGPRRAEAA LLLEPSALSA TMKEVPLFRL RHFPCGNVNY GYQQQGLPLE
1610 1620
ATAAPGDTML KSKNKVTQPG P
Length:1,621
Mass (Da):174,948
Last modified:July 27, 2011 - v2
Checksum:i72D1022E117F303E
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti138 – 139KL → NV in BAA11673 (PubMed:9053841).Curated2
Sequence conflicti232M → L in BAA11673 (PubMed:9053841).Curated1
Sequence conflicti857T → R in BAA11673 (PubMed:9053841).Curated1
Sequence conflicti1075 – 1076ME → IQ in BAA11673 (PubMed:9053841).Curated2
Sequence conflicti1522E → A in BAA11673 (PubMed:9053841).Curated1
Sequence conflicti1586G → P in BAA11673 (PubMed:9053841).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS37688.1.
PIRiT30200.
RefSeqiNP_031465.2. NM_007439.2.
UniGeneiMm.311854.

Genome annotation databases

EnsembliENSMUST00000086639; ENSMUSP00000083840; ENSMUSG00000055471.
GeneIDi11682.
KEGGimmu:11682.
UCSCiuc008dnb.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS37688.1.
PIRiT30200.
RefSeqiNP_031465.2. NM_007439.2.
UniGeneiMm.311854.

3D structure databases

ProteinModelPortaliP97793.
SMRiP97793.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi198070. 1 interactor.
STRINGi10090.ENSMUSP00000083840.

Chemistry databases

BindingDBiP97793.
ChEMBLiCHEMBL5771.

PTM databases

iPTMnetiP97793.
PhosphoSitePlusiP97793.

Proteomic databases

MaxQBiP97793.
PaxDbiP97793.
PRIDEiP97793.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000086639; ENSMUSP00000083840; ENSMUSG00000055471.
GeneIDi11682.
KEGGimmu:11682.
UCSCiuc008dnb.1. mouse.

Organism-specific databases

CTDi238.
MGIiMGI:103305. Alk.

Phylogenomic databases

eggNOGiKOG1095. Eukaryota.
ENOG410XPVX. LUCA.
GeneTreeiENSGT00760000118818.
HOGENOMiHOG000231766.
HOVERGENiHBG018726.
InParanoidiP97793.
KOiK05119.
OMAiNAIMLSK.
OrthoDBiEOG091G003T.
TreeFamiTF351636.

Enzyme and pathway databases

BRENDAi2.7.10.1. 3474.

Miscellaneous databases

PROiP97793.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000055471.
CleanExiMM_ALK.
GenevisibleiP97793. MM.

Family and domain databases

CDDicd06263. MAM. 2 hits.
Gene3Di4.10.400.10. 1 hit.
InterProiIPR026830. ALK.
IPR013320. ConA-like_dom.
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]
PANTHERiPTHR24416:SF276. PTHR24416:SF276. 1 hit.
PfamiPF00629. MAM. 2 hits.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PRINTSiPR00109. TYRKINASE.
SMARTiSM00192. LDLa. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF49899. SSF49899. 2 hits.
SSF56112. SSF56112. 1 hit.
SSF57424. SSF57424. 1 hit.
PROSITEiPS50060. 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]
ProtoNetiSearch...

Entry informationi

Entry nameiALK_MOUSE
AccessioniPrimary (citable) accession number: P97793
Secondary accession number(s): E9QKV3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 27, 2002
Last sequence update: July 27, 2011
Last modified: November 30, 2016
This is version 150 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.