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P24062 (IGF1R_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 141. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Insulin-like growth factor 1 receptor

EC=2.7.10.1
Alternative name(s):
Insulin-like growth factor I receptor
Short name=IGF-I receptor
CD_antigen=CD221
Gene names
Name:Igf1r
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length1370 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at transcript level

General annotation (Comments)

Function

Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R By similarity. When present in a hybrid receptor with INSR, binds IGF1 By similarity. Ref.4

Catalytic activity

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

Enzyme regulation

Activated by autophosphorylation at Tyr-1162, Tyr-1166 and Tyr-1167 on the kinase activation loop; phosphorylation at all three tyrosine residues is required for optimal kinase activity. Inhibited by MSC1609119A-1, BMS-754807, PQIP, benzimidazole pyridinone, isoquinolinedione, bis-azaindole, 3-cyanoquinoline, 2,4-bis-arylamino-1,3-pyrimidine, pyrrolopyrimidine, pyrrole-5-carboxaldehyde, picropodophyllin (PPP), tyrphostin derivatives. While most inhibitors bind to the ATP binding pocket, MSC1609119A-1 functions as allosteric inhibitor and binds close to the DFG motif and the activation loop By similarity. Dephosphorylated by PTPN1 By similarity.

Subunit structure

Tetramer of 2 alpha and 2 beta chains linked by disulfide bonds. The alpha chains contribute to the formation of the ligand-binding domain, while the beta chain carries the kinase domain. Interacts with PIK3R1 and with the PTB/PID domains of IRS1 and SHC1 in vitro when autophosphorylated on tyrosine residues. Forms a hybrid receptor with INSR, the hybrid is a tetramer consisting of 1 alpha chain and 1 beta chain of INSR and 1 alpha chain and 1 beta chain of IGF1R. Interacts with ARRB1 and ARRB2. Interacts with GRB10. Interacts with GNB2L1/RACK1 By similarity. Interacts with SOCS1, SOCS2 and SOCS3 By similarity. Interacts with 14-3-3 proteins By similarity. Interacts with NMD2 By similarity. Interacts with MAP3K5 By similarity. Interacts with STAT3 By similarity.

Subcellular location

Cell membrane; Single-pass type I membrane protein By similarity.

Post-translational modification

Autophosphorylated on tyrosine residues in response to ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Autophosphorylation occurs in a sequential manner; Tyr-1166 is predominantly phosphorylated first, followed by phosphorylation of Tyr-1162 and Tyr-1167. While every single phosphorylation increases kinase activity, all three tyrosine residues in the kinase activation loop (Tyr-1162, Tyr-1166 and Tyr-1167) have to be phosphorylated for optimal activity. Can be autophosphorylated at additional tyrosine residues (in vitro). Autophosphorylated is followed by phosphorylation of juxtamembrane tyrosines and C-terminal serines. Phosphorylation of Tyr-981 is required for IRS1- and SHC1-binding. Phosphorylation of Ser-1279 by GSK-3beta restrains kinase activity and promotes cell surface expression, it requires a priming phosphorylation at Ser-1283 By similarity. Dephosphorylated by PTPN1.

Polyubiquitinated at Lys-1169 and Lys-1172 through both 'Lys-48' and 'Lys-29' linkages, promoting receptor endocytosis and subsequent degradation by the proteasome. Ubiquitination is facilitated by pre-existing phosphorylation By similarity.

Sumoylated with SUMO1 By similarity.

Controlled by regulated intramembrane proteolysis (RIP). Undergoes metalloprotease-dependent constitutive ectodomain shedding to produce a membrane-anchored 52 kDa C-Terminal fragment which is further processed by presenilin gamma-secretase to yield an intracellular 50 kDa fragment By similarity.

Sequence similarities

Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.

Contains 3 fibronectin type-III domains.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Cellular componentCell membrane
Membrane
   DomainRepeat
Signal
Transmembrane
Transmembrane helix
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Receptor
Transferase
Tyrosine-protein kinase
   PTMCleavage on pair of basic residues
Disulfide bond
Glycoprotein
Isopeptide bond
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processaxonogenesis

Inferred from mutant phenotype PubMed 16845384. Source: RGD

brain development

Inferred from electronic annotation. Source: Ensembl

establishment of cell polarity

Inferred from mutant phenotype PubMed 16845384. Source: RGD

exocrine pancreas development

Inferred from electronic annotation. Source: Ensembl

immune response

Inferred from electronic annotation. Source: Ensembl

inactivation of MAPKK activity

Inferred from sequence or structural similarity. Source: UniProtKB

insulin-like growth factor receptor signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

male sex determination

Inferred from electronic annotation. Source: Ensembl

mammary gland development

Inferred from electronic annotation. Source: Ensembl

negative regulation of apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of muscle cell apoptotic process

Inferred from mutant phenotype PubMed 19507001. Source: RGD

negative regulation of protein kinase B signaling

Inferred from electronic annotation. Source: Ensembl

neuron projection development

Inferred from direct assay PubMed 15567343. Source: RGD

peptidyl-tyrosine phosphorylation

Inferred from sequence or structural similarity. Source: GOC

phosphatidylinositol-mediated signaling

Inferred from electronic annotation. Source: Ensembl

positive regulation of DNA metabolic process

Inferred from mutant phenotype PubMed 19507001. Source: RGD

positive regulation of DNA replication

Inferred from electronic annotation. Source: Ensembl

positive regulation of MAPK cascade

Inferred from electronic annotation. Source: Ensembl

positive regulation of cell migration

Inferred from electronic annotation. Source: Ensembl

positive regulation of cytokinesis

Inferred from mutant phenotype PubMed 19507001. Source: RGD

positive regulation of protein kinase B signaling

Inferred from electronic annotation. Source: Ensembl

positive regulation of steroid hormone biosynthetic process

Inferred from mutant phenotype PubMed 17023532. Source: BHF-UCL

prostate gland epithelium morphogenesis

Inferred from electronic annotation. Source: Ensembl

protein autophosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

protein heterooligomerization

Inferred from direct assay PubMed 15272025. Source: RGD

protein tetramerization

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of JNK cascade

Inferred from sequence or structural similarity. Source: UniProtKB

response to vitamin E

Inferred from expression pattern PubMed 17447016. Source: RGD

   Cellular_componentcaveola

Inferred from direct assay PubMed 18022157. Source: RGD

integral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

intracellular membrane-bounded organelle

Inferred from electronic annotation. Source: Ensembl

neuron projection

Inferred from direct assay PubMed 16845384. Source: RGD

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

G-protein alpha-subunit binding

Inferred from physical interaction PubMed 19764351. Source: RGD

insulin binding

Inferred from electronic annotation. Source: Ensembl

insulin receptor substrate binding

Inferred from sequence or structural similarity. Source: UniProtKB

insulin-like growth factor binding

Inferred from sequence or structural similarity. Source: UniProtKB

insulin-like growth factor-activated receptor activity

Inferred from sequence or structural similarity. Source: UniProtKB

phosphatidylinositol 3-kinase binding

Inferred from sequence or structural similarity. Source: UniProtKB

protein tyrosine kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 3030 Potential
Chain31 – 737707Insulin-like growth factor 1 receptor alpha chain
PRO_0000016685
Chain742 – 1370629Insulin-like growth factor 1 receptor beta chain
PRO_0000016686

Regions

Topological domain742 – 936195Extracellular Potential
Transmembrane937 – 96024Helical; Potential
Topological domain961 – 1370410Cytoplasmic Potential
Domain490 – 610121Fibronectin type-III 1
Domain611 – 70999Fibronectin type-III 2
Domain835 – 92894Fibronectin type-III 3
Domain1000 – 1275276Protein kinase
Nucleotide binding1006 – 10149ATP By similarity
Motif978 – 9814IRS1- and SHC1-binding By similarity

Sites

Active site11361Proton acceptor By similarity
Binding site10341ATP By similarity

Amino acid modifications

Modified residue9811Phosphotyrosine By similarity
Modified residue11621Phosphotyrosine; by autocatalysis By similarity
Modified residue11661Phosphotyrosine; by autocatalysis By similarity
Modified residue11671Phosphotyrosine; by autocatalysis By similarity
Modified residue12791Phosphoserine; by GSK3-beta By similarity
Modified residue12831Phosphoserine By similarity
Glycosylation511N-linked (GlcNAc...) Potential
Glycosylation1021N-linked (GlcNAc...) Potential
Glycosylation1351N-linked (GlcNAc...) Potential
Glycosylation2451N-linked (GlcNAc...) Potential
Glycosylation3141N-linked (GlcNAc...) Potential
Glycosylation4181N-linked (GlcNAc...) Potential
Glycosylation4391N-linked (GlcNAc...) Potential
Glycosylation5351N-linked (GlcNAc...) Potential
Glycosylation6081N-linked (GlcNAc...) Potential
Glycosylation6231N-linked (GlcNAc...) Potential
Glycosylation6411N-linked (GlcNAc...) Potential
Glycosylation7481N-linked (GlcNAc...) Potential
Glycosylation7571N-linked (GlcNAc...) Potential
Glycosylation7651N-linked (GlcNAc...) Potential
Glycosylation9011N-linked (GlcNAc...) Potential
Glycosylation9141N-linked (GlcNAc...) Potential
Disulfide bond33 ↔ 52 By similarity
Disulfide bond150 ↔ 178 By similarity
Disulfide bond182 ↔ 205 By similarity
Disulfide bond192 ↔ 211 By similarity
Disulfide bond215 ↔ 224 By similarity
Disulfide bond219 ↔ 230 By similarity
Disulfide bond231 ↔ 239 By similarity
Disulfide bond235 ↔ 248 By similarity
Disulfide bond251 ↔ 260 By similarity
Disulfide bond264 ↔ 276 By similarity
Disulfide bond282 ↔ 303 By similarity
Disulfide bond307 ↔ 321 By similarity
Disulfide bond324 ↔ 328 By similarity
Disulfide bond332 ↔ 354 By similarity
Disulfide bond456 ↔ 489 By similarity
Cross-link1169Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link1172Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Experimental info

Sequence conflict985 – 9862AD → PY no nucleotide entry Ref.3

Sequences

Sequence LengthMass (Da)Tools
P24062 [UniParc].

Last modified November 1, 1997. Version 2.
Checksum: A5946897A41CB145

FASTA1,370155,396
        10         20         30         40         50         60 
MKSGSGGGSP TSLWGLVFLS AALSLWPTSG EICGPGIDIR NDYQQLKRLE NCTVIEGFLH 

        70         80         90        100        110        120 
ILLISKAEDY RSYRFPKLTV ITEYLLLFRV AGLESLGDLF PNLTVIRGWK LFYNYALVIF 

       130        140        150        160        170        180 
EMTNLKDIGL YNLRNITRGA IRIEKNADLC YLSTIDWSLI LDAVSNNYIV GNKPPKECGD 

       190        200        210        220        230        240 
LCPGTLEEKP MCEKTTINNE YNYRCWTTNR CQKMCPSVCG KRACTENNEC CHPECLGSCH 

       250        260        270        280        290        300 
TPDDNTTCVA CRHYYYKGVC VPACPPGTYR FEGWRCVDRD FCANIPNAES SDSDGFVIHD 

       310        320        330        340        350        360 
GECMQECPSG FIRNSTQSMY CIPCEGPCPK VCGDEEKKTK TIDSVTSAQM LQGCTILKGN 

       370        380        390        400        410        420 
LLINIRRGNN IASELENFMG LIEVVTGYVK IRHSHALVSL SFLKNLRLIL GEEQLEGNYS 

       430        440        450        460        470        480 
FYVLDNQNLQ QLWDWNHRNL TVRSGKMYFA FNPKLCVSEI YRMEEVTGTK GRQSKGDINT 

       490        500        510        520        530        540 
RNNGERASCE SDVLRFTSTT TWKNRIIITW HRYRPPDYRD LISFTVYYKE APFKNVTEYD 

       550        560        570        580        590        600 
GQDACGSNSW NMVDVDLPPN KEGEPGILLH GLKPWTQYAV YVKAVTLTMV ENDHIRGAKS 

       610        620        630        640        650        660 
EILYIRTNAS VPSIPLDVLS ASNSSSQLIV KWNPPTLPNG NLSYYIVRWQ RQPQDGYLFR 

       670        680        690        700        710        720 
HNYCSKDKIP IRKYADGTID VEEVTENPKT EVCGGDKGPC CACPKTEAEK QAEKEEAEYR 

       730        740        750        760        770        780 
KVFENFLHNS IFVPRPERRR RDVLQVANTT MSSRSRNTTV ADTYNITDPE EFETEYPFFE 

       790        800        810        820        830        840 
SRVDNKERTV ISNLRPFTLY RIDIHSCNHE AEKLGCSASN FVFARTMPAE GADDIPGPVT 

       850        860        870        880        890        900 
WEPRPENSIF LKWPEPENPN GLILMYEIKY GSQVEDQREC VSRQEYRKYG GAKLNRLNPG 

       910        920        930        940        950        960 
NYTARIQATS LSGNGSWTDP VFFYVPAKTT YENFMHLIIA LPVAILLIVG GLVIMLYVFH 

       970        980        990       1000       1010       1020 
RKRNNSRLGN GVLYASVNPE YFSAADVYVP DEWEVAREKI TMNRELGQGS FGMVYEGVAK 

      1030       1040       1050       1060       1070       1080 
GVVKDEPETR VAIKTVNEAA SMRERIEFLN EASVMKEFNC HHVVRLLGVV SQGQPTLVIM 

      1090       1100       1110       1120       1130       1140 
ELMTRGDLKS YLRSLRPEVE NNLVLIPPSL SKMIQMAGEI ADGMAYLNAN KFVHRDLAAR 

      1150       1160       1170       1180       1190       1200 
NCMVAEDFTV KIGDFGMTRD IYETDYYRKG GKGLLPVRWM SPESLKDGVF TTHSDVWSFG 

      1210       1220       1230       1240       1250       1260 
VVLWEIATLA EQPYQGLSNE QVLRFVMEGG LLDKPDNCPD MLFELMRMCW QYNPKMRPSF 

      1270       1280       1290       1300       1310       1320 
LEIIGSIKDE MEPSFQEVSF YYSEENKPPE PEELEMELEL EPENMESVPL DPSASSASLP 

      1330       1340       1350       1360       1370 
LPERHSGHKA ENGPGVLVLR ASFDERQPYA HMNGGRANER ALPLPQSSTC 

« Hide

References

[1]"Inhibition of vascular smooth muscle cell growth through antisense transcription of a rat insulin-like growth factor I receptor cDNA."
Du J., Delafontaine P.
Circ. Res. 76:963-972(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Brain.
[2]"Developmental regulation of the rat insulin-like growth factor I receptor gene."
Werner H., Woloschak M., Adamo M., Shen-Orr Z., Roberts C.T. Jr., Leroith D.
Proc. Natl. Acad. Sci. U.S.A. 86:7451-7455(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-364.
Strain: Sprague-Dawley.
[3]"A new member of the insulin receptor family, insulin receptor-related receptor, is expressed preferentially in the kidney."
Kurachi H., Jobo K., Ohta M., Kawasaki T., Itoh N.
Biochem. Biophys. Res. Commun. 187:934-939(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 913-1017.
[4]"Insulin and IGF-I action on insulin receptors, IGF-I receptors, and hybrid insulin/IGF-I receptors in vascular smooth muscle cells."
Johansson G.S., Arnqvist H.J.
Am. J. Physiol. 291:E1124-E1130(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, FORMATION OF A HYBRID RECEPTOR WITH INSR.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L29232 mRNA. Translation: AAA41392.1.
M27293 mRNA. Translation: AAA41384.1.
RefSeqNP_434694.1. NM_052807.2.
UniGeneRn.10957.
Rn.165078.

3D structure databases

ProteinModelPortalP24062.
SMRP24062. Positions 31-492, 978-1291.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid247747. 2 interactions.
STRING10116.ENSRNOP00000019267.

Chemistry

BindingDBP24062.
ChEMBLCHEMBL1075098.

PTM databases

PhosphoSiteP24062.

Proteomic databases

PaxDbP24062.
PRIDEP24062.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSRNOT00000019267; ENSRNOP00000019267; ENSRNOG00000014187.
GeneID25718.
KEGGrno:25718.
UCSCRGD:2869. rat.

Organism-specific databases

CTD3480.
RGD2869. Igf1r.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00750000117239.
HOGENOMHOG000038045.
HOVERGENHBG006134.
InParanoidP24062.
KOK05087.
OMARCQKMCP.
OrthoDBEOG73RB9N.
PhylomeDBP24062.

Enzyme and pathway databases

BRENDA2.7.10.1. 5301.

Gene expression databases

ArrayExpressP24062.
GenevestigatorP24062.

Family and domain databases

Gene3D2.60.40.10. 4 hits.
3.80.20.20. 2 hits.
InterProIPR000494. EGF_rcpt_L.
IPR003961. Fibronectin_type3.
IPR006211. Furin-like_Cys-rich_dom.
IPR006212. Furin_repeat.
IPR009030. Growth_fac_rcpt_N_dom.
IPR013783. Ig-like_fold.
IPR011009. Kinase-like_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.
IPR016246. Tyr_kinase_insulin-like_rcpt.
IPR002011. Tyr_kinase_rcpt_2_CS.
[Graphical view]
PfamPF00041. fn3. 1 hit.
PF00757. Furin-like. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF01030. Recep_L_domain. 2 hits.
[Graphical view]
PIRSFPIRSF000620. Insulin_receptor. 1 hit.
PRINTSPR00109. TYRKINASE.
SMARTSM00060. FN3. 3 hits.
SM00261. FU. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMSSF49265. SSF49265. 4 hits.
SSF56112. SSF56112. 1 hit.
SSF57184. SSF57184. 1 hit.
PROSITEPS50853. FN3. 3 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

NextBio607805.
PROP24062.

Entry information

Entry nameIGF1R_RAT
AccessionPrimary (citable) accession number: P24062
Entry history
Integrated into UniProtKB/Swiss-Prot: March 1, 1992
Last sequence update: November 1, 1997
Last modified: April 16, 2014
This is version 141 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families