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P97793

- ALK_MOUSE

UniProt

P97793 - ALK_MOUSE

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Protein
ALK tyrosine kinase receptor
Gene
Alk
Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

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.4 Publications

Catalytic activityi

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

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.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei1128 – 11281ATP; via carbonyl oxygen By similarity
Binding sitei1154 – 11541ATP By similarity
Binding sitei1154 – 11541Inhibitor By similarity
Binding sitei1203 – 12031Inhibitor; via amide nitrogen By similarity
Binding sitei1207 – 12071Inhibitor By similarity
Binding sitei1214 – 12141Inhibitor By similarity
Active sitei1253 – 12531Proton acceptor By similarity
Binding sitei1274 – 12741ATP By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi1126 – 11349ATP By similarity
Nucleotide bindingi1201 – 12033ATP By similarity

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. transmembrane receptor protein tyrosine kinase activity Source: MGI

GO - Biological processi

  1. activation of MAPK activity Source: InterPro
  2. neuron development Source: InterPro
  3. transmembrane receptor protein tyrosine kinase signaling pathway Source: InterPro
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
ProteomesiUP000000589: Chromosome 17

Organism-specific databases

MGIiMGI:103305. Alk.

Subcellular locationi

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.

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini19 – 10421024Extracellular Reviewed prediction
Add
BLAST
Transmembranei1043 – 106321Helical; Reviewed prediction
Add
BLAST
Topological domaini1064 – 1621558Cytoplasmic Reviewed prediction
Add
BLAST

GO - Cellular componenti

  1. integral component of plasma membrane Source: MGI
  2. protein complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 1818 Reviewed prediction
Add
BLAST
Chaini19 – 16211603ALK tyrosine kinase receptor
PRO_0000016741Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi174 – 1741N-linked (GlcNAc...) Reviewed prediction
Modified residuei216 – 2161Phosphoserine By similarity
Glycosylationi248 – 2481N-linked (GlcNAc...) Reviewed prediction
Glycosylationi289 – 2891N-linked (GlcNAc...) Reviewed prediction
Glycosylationi328 – 3281N-linked (GlcNAc...) Reviewed prediction
Glycosylationi415 – 4151N-linked (GlcNAc...) Reviewed prediction
Glycosylationi428 – 4281N-linked (GlcNAc...) Reviewed prediction
Glycosylationi449 – 4491N-linked (GlcNAc...) Reviewed prediction
Glycosylationi567 – 5671N-linked (GlcNAc...) Reviewed prediction
Glycosylationi575 – 5751N-linked (GlcNAc...) Reviewed prediction
Glycosylationi631 – 6311N-linked (GlcNAc...) Reviewed prediction
Glycosylationi673 – 6731N-linked (GlcNAc...) Reviewed prediction
Glycosylationi713 – 7131N-linked (GlcNAc...) Reviewed prediction
Glycosylationi812 – 8121N-linked (GlcNAc...) Reviewed prediction
Glycosylationi868 – 8681N-linked (GlcNAc...) Reviewed prediction
Glycosylationi890 – 8901N-linked (GlcNAc...) Reviewed prediction
Glycosylationi990 – 9901N-linked (GlcNAc...) Reviewed prediction
Modified residuei1082 – 10821Phosphotyrosine By similarity
Modified residuei1096 – 10961Phosphotyrosine By similarity
Modified residuei1100 – 11001Phosphotyrosine By similarity
Modified residuei1135 – 11351Phosphotyrosine By similarity
Modified residuei1282 – 12821Phosphotyrosine By similarity
Modified residuei1286 – 12861Phosphotyrosine; by autocatalysis By similarity
Modified residuei1287 – 12871Phosphotyrosine By similarity
Modified residuei1363 – 13631Phosphotyrosine By similarity
Modified residuei1516 – 15161Phosphotyrosine By similarity
Modified residuei1590 – 15901Phosphotyrosine By similarity

Post-translational modificationi

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.2 Publications
N-glycosylated By similarity.

Keywords - PTMi

Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiP97793.
PRIDEiP97793.

PTM databases

PhosphoSiteiP97793.

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

BgeeiP97793.
CleanExiMM_ALK.
GenevestigatoriP97793.

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.2 Publications

Protein-protein interaction databases

BioGridi198070. 1 interaction.
STRINGi10090.ENSMUSP00000083840.

Structurei

3D structure databases

ProteinModelPortaliP97793.
SMRiP97793. Positions 1100-1403.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini268 – 431164MAM 1
Add
BLAST
Domaini441 – 47737LDL-receptor class A
Add
BLAST
Domaini482 – 640159MAM 2
Add
BLAST
Domaini1120 – 1396277Protein kinase
Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni1201 – 12033Inhibitor binding By similarity

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi820 – 944125Gly-rich
Add
BLAST

Sequence similaritiesi

Contains 2 MAM domains.

Keywords - Domaini

Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00750000117362.
HOGENOMiHOG000231766.
HOVERGENiHBG018726.
InParanoidiP97793.
KOiK05119.
OMAiLIQKVCI.
OrthoDBiEOG7GN2KT.
TreeFamiTF351636.

Family and domain databases

Gene3Di4.10.400.10. 1 hit.
InterProiIPR026830. 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]
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

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MGAAGFLWLL PPLLLAAASY SGAATDQRAG SPASGPPLQP REPLSYSRLQ     50
RKSLAVDFVV PSLFRVYARD LLLPQPRSPS EPEAGGLEAR GSLALDCEPL 100
LRLLGPLPGI SWADGASSPS PEAGPTLSRV LKGGSVRKLR RAKQLVLELG 150
EETILEGCIG PPEEVAAVGI LQFNLSELFS WWILHGEGRL RIRLMPEKKA 200
SEVGREGRLS SAIRASQPRL LFQIFGTGHS SMESPSETPS PPGTFMWNLT 250
WTMKDSFPFL SHRSRYGLEC SFDFPCELEY SPPLHNHGNQ SWSWRHVPSE 300
EASRMNLLDG PEAEHSQEMP RGSFLLLNTS ADSKHTILSP WMRSSSDHCT 350
LAVSVHRHLQ PSGRYVAQLL PHNEAGREIL LVPTPGKHGW TVLQGRVGRP 400
ANPFRVALEY ISSGNRSLSA VDFFALKNCS EGTSPGSKMA LQSSFTCWNG 450
TVLQLGQACD FHQDCAQGED EGQLCSKLPA GFYCNFENGF CGWTQSPLSP 500
HMPRWQVRTL RDAHSQGHQG RALLLSTTDI LASEGATVTS ATFPAPMKNS 550
PCELRMSWLI RGVLRGNVSL VLVENKTGKE QSRTVWHVAT DEGLSLWQHT 600
VLSLLDVTDR FWLQIVTWWG PGSRATVGFD NISISLDCYL TISGEEKMSL 650
NSVPKSRNLF EKNPNKESKS WANISGPTPI FDPTVHWLFT TCGASGPHGP 700
TQAQCNNAYQ NSNLSVVVGS EGPLKGVQIW KVPATDTYSI SGYGAAGGKG 750
GKNTMMRSHG VSVLGIFNLE KGDTLYILVG QQGEDACPRA NQLIQKVCVG 800
ENNVIEEEIR VNRSVHEWAG GGGGGGGATY VFKMKDGVPV PLIIAAGGGG 850
RAYGAKTETF HPERLESNSS VLGLNGNSGA AGGGGGWNDN TSLLWAGKSL 900
LEGAAGGHSC PQAMKKWGWE TRGGFGGGGG GCSSGGGGGG YIGGNAASNN 950
DPEMDGEDGV SFISPLGILY TPALKVMEGH GEVNIKHYLN CSHCEVDECH 1000
MDPESHKVIC FCDHGTVLAD DGVSCIVSPT PEPHLPLSLI LSVVTSALVA 1050
ALVLAFSGIM IVYRRKHQEL QAMQMELQSP EYKLSKLRTS TIMTDYNPNY 1100
CFAGKTSSIS DLKEVPRKNI TLIRGLGHGA FGEVYEGQVS GMPNDPSPLQ 1150
VAVKTLPEVC SEQDELDFLM EALIISKFNH QNIVRCIGVS LQALPRFILL 1200
ELMAGGDLKS FLRETRPRPN QPTSLAMLDL LHVARDIACG CQYLEENHFI 1250
HRDIAARNCL LTCPGAGRIA KIGDFGMARD IYRASYYRKG GCAMLPVKWM 1300
PPEAFMEGIF TSKTDTWSFG VLLWEIFSLG YMPYPSKSNQ EVLEFVTSGG 1350
RMDPPKNCPG PVYRIMTQCW QHQPEDRPNF AIILERIEYC TQDPDVINTA 1400
LPIEYGPVVE EEEKVPMRPK DPEGMPPLLV SPQPAKHEEA SAAPQPAALT 1450
APGPSVKKPP GAGAGAGAGA GAGPVPRGAA DRGHVNMAFS QPNPPPELHK 1500
GPGSRNKPTS LWNPTYGSWF TEKPAKKTHP PPGAEPQARA GAAEGGWTGP 1550
GAGPRRAEAA LLLEPSALSA TMKEVPLFRL RHFPCGNVNY GYQQQGLPLE 1600
ATAAPGDTML KSKNKVTQPG P 1621
Length:1,621
Mass (Da):174,948
Last modified:July 27, 2011 - v2
Checksum:i72D1022E117F303E
GO

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti138 – 1392KL → NV in BAA11673. 1 Publication
Sequence conflicti232 – 2321M → L in BAA11673. 1 Publication
Sequence conflicti857 – 8571T → R in BAA11673. 1 Publication
Sequence conflicti1075 – 10762ME → IQ in BAA11673. 1 Publication
Sequence conflicti1522 – 15221E → A in BAA11673. 1 Publication
Sequence conflicti1586 – 15861G → P in BAA11673. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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:
EMBL
GenBank
DDBJ
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.
CCDSi CCDS37688.1.
PIRi T30200.
RefSeqi NP_031465.2. NM_007439.2.
UniGenei Mm.311854.

3D structure databases

ProteinModelPortali P97793.
SMRi P97793. Positions 1100-1403.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 198070. 1 interaction.
STRINGi 10090.ENSMUSP00000083840.

Chemistry

BindingDBi P97793.
ChEMBLi CHEMBL5771.

PTM databases

PhosphoSitei P97793.

Proteomic databases

PaxDbi P97793.
PRIDEi P97793.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000086639 ; ENSMUSP00000083840 ; ENSMUSG00000055471 .
GeneIDi 11682.
KEGGi mmu:11682.
UCSCi uc008dnb.1. mouse.

Organism-specific databases

CTDi 238.
MGIi MGI:103305. Alk.

Phylogenomic databases

eggNOGi COG0515.
GeneTreei ENSGT00750000117362.
HOGENOMi HOG000231766.
HOVERGENi HBG018726.
InParanoidi P97793.
KOi K05119.
OMAi LIQKVCI.
OrthoDBi EOG7GN2KT.
TreeFami TF351636.

Enzyme and pathway databases

BRENDAi 2.7.10.1. 3474.

Miscellaneous databases

NextBioi 279315.
PROi P97793.
SOURCEi Search...

Gene expression databases

Bgeei P97793.
CleanExi MM_ALK.
Genevestigatori P97793.

Family and domain databases

Gene3Di 4.10.400.10. 1 hit.
InterProi IPR026830. 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 ]
PANTHERi PTHR24416:SF276. PTHR24416:SF276. 1 hit.
Pfami PF00629. MAM. 2 hits.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view ]
PRINTSi PR00109. TYRKINASE.
SMARTi SM00192. LDLa. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view ]
SUPFAMi SSF49899. SSF49899. 2 hits.
SSF56112. SSF56112. 1 hit.
SSF57424. SSF57424. 1 hit.
PROSITEi 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 ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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. 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.

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: September 3, 2014
This is version 132 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

External Data

Dasty 3

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