P24062 (IGF1R_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Cleaved into the following 2 chains:

1. Insulin-like growth factor 1 receptor alpha chain
2. Insulin-like growth factor 1 receptor beta chain

Gene names

Name:

Igf1r

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	1370 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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	Membrane; Single-pass type I membrane protein.
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 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.
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 component	Membrane
Domain	Repeat Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Cleavage on pair of basic residues Disulfide bond Glycoprotein Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	axonogenesis Inferred from mutant phenotype PubMed 16845384. Source: RGD brain development Inferred from electronic annotation. Source: Compara establishment of cell polarity Inferred from mutant phenotype PubMed 16845384. Source: RGD exocrine pancreas development Inferred from electronic annotation. Source: Compara immune response Inferred from electronic annotation. Source: Compara inactivation of MAPKK activity Inferred from sequence or structural similarity. Source: UniProtKB male sex determination Inferred from electronic annotation. Source: Compara mammary gland development Inferred from electronic annotation. Source: Compara negative regulation of muscle cell apoptotic process Inferred from mutant phenotype PubMed 19507001. Source: RGD negative regulation of protein kinase B signaling cascade Inferred from electronic annotation. Source: Compara phosphatidylinositol-mediated signaling Inferred from electronic annotation. Source: Compara positive regulation of DNA metabolic process Inferred from mutant phenotype PubMed 19507001. Source: RGD positive regulation of DNA replication Inferred from electronic annotation. Source: Compara positive regulation of MAPK cascade Inferred from electronic annotation. Source: Compara positive regulation of cell migration Inferred from electronic annotation. Source: Compara positive regulation of cytokinesis Inferred from mutant phenotype PubMed 19507001. Source: RGD positive regulation of protein kinase B signaling cascade Inferred from electronic annotation. Source: Compara 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: Compara 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_component	caveola Inferred from direct assay PubMed 18022157. Source: RGD integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW intracellular membrane-bounded organelle Inferred from electronic annotation. Source: Compara neuron projection Inferred from direct assay PubMed 16845384. Source: RGD
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW insulin binding Inferred from electronic annotation. Source: Compara 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
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 30	30	Potential
	Chain	31 – 737	707	Insulin-like growth factor 1 receptor alpha chain		PRO_0000016685
	Chain	742 – 1370	629	Insulin-like growth factor 1 receptor beta chain		PRO_0000016686
Regions
	Topological domain	742 – 936	195	Extracellular Potential
	Transmembrane	937 – 960	24	Helical; Potential
	Topological domain	961 – 1370	410	Cytoplasmic Potential
	Domain	489 – 607	119	Fibronectin type-III 1
	Domain	612 – 690	79	Fibronectin type-III 2
	Domain	832 – 927	96	Fibronectin type-III 3
	Domain	1000 – 1275	276	Protein kinase
	Nucleotide binding	1006 – 1014	9	ATP By similarity
	Motif	978 – 981	4	IRS1- and SHC1-binding By similarity
Sites
	Active site	1136	1	Proton acceptor By similarity
	Binding site	1034	1	ATP By similarity
Amino acid modifications
	Modified residue	981	1	Phosphotyrosine By similarity
	Modified residue	1162	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1166	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1167	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1342	1	Phosphoserine By similarity
	Glycosylation	51	1	N-linked (GlcNAc...) Potential
	Glycosylation	102	1	N-linked (GlcNAc...) Potential
	Glycosylation	135	1	N-linked (GlcNAc...) Potential
	Glycosylation	245	1	N-linked (GlcNAc...) Potential
	Glycosylation	314	1	N-linked (GlcNAc...) Potential
	Glycosylation	418	1	N-linked (GlcNAc...) Potential
	Glycosylation	439	1	N-linked (GlcNAc...) Potential
	Glycosylation	535	1	N-linked (GlcNAc...) Potential
	Glycosylation	608	1	N-linked (GlcNAc...) Potential
	Glycosylation	623	1	N-linked (GlcNAc...) Potential
	Glycosylation	641	1	N-linked (GlcNAc...) Potential
	Glycosylation	748	1	N-linked (GlcNAc...) Potential
	Glycosylation	757	1	N-linked (GlcNAc...) Potential
	Glycosylation	765	1	N-linked (GlcNAc...) Potential
	Glycosylation	901	1	N-linked (GlcNAc...) Potential
	Glycosylation	914	1	N-linked (GlcNAc...) Potential
	Disulfide bond	33 ↔ 52		By similarity
	Disulfide bond	150 ↔ 178		By similarity
	Disulfide bond	182 ↔ 205		By similarity
	Disulfide bond	192 ↔ 211		By similarity
	Disulfide bond	215 ↔ 224		By similarity
	Disulfide bond	219 ↔ 230		By similarity
	Disulfide bond	231 ↔ 239		By similarity
	Disulfide bond	235 ↔ 248		By similarity
	Disulfide bond	251 ↔ 260		By similarity
	Disulfide bond	264 ↔ 276		By similarity
	Disulfide bond	282 ↔ 303		By similarity
	Disulfide bond	307 ↔ 321		By similarity
	Disulfide bond	324 ↔ 328		By similarity
	Disulfide bond	332 ↔ 354		By similarity
	Disulfide bond	456 ↔ 489		By similarity
	Cross-link	1169		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
	Cross-link	1172		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Experimental info
	Sequence conflict	985 – 986	2	AD → PY no nucleotide entry Ref.3

Sequences

	Sequence		Length	Mass (Da)
	P24062 [UniParc]. Last modified November 1, 1997. Version 2. Checksum: A5946897A41CB145	FASTA	1,370	155,396
	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

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.
IPI	IPI00211005.
RefSeq	NP_434694.1. NM_052807.2.
UniGene	Rn.10957.
3D structure databases
ProteinModelPortal	P24062.
SMR	P24062. Positions 31-492, 978-1291.
ModBase	Search...
Protein-protein interaction databases
STRING	10116.ENSRNOP00000019267.
PTM databases
PhosphoSite	P24062.
Proteomic databases
PaxDb	P24062.
PRIDE	P24062.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSRNOT00000019267; ENSRNOP00000019267; ENSRNOG00000014187.
GeneID	25718.
KEGG	rno:25718.
UCSC	RGD:2869. rat.
Organism-specific databases
CTD	3480.
RGD	2869. Igf1r.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00690000101688.
HOGENOM	HOG000038045.
HOVERGEN	HBG006134.
InParanoid	P24062.
KO	K05087.
OrthoDB	EOG4Z62MR.
Enzyme and pathway databases
BRENDA	2.7.10.1. 5301.
Gene expression databases
Genevestigator	P24062.
GermOnline	ENSRNOG00000014187. Rattus norvegicus.
Family and domain databases
Gene3D	2.60.40.10. 4 hits.
InterPro	IPR000494. EGF_rcpt_L. IPR003961. Fibronectin_type3. IPR006211. Furin-like_Cys-rich_dom. IPR006212. Furin_repeat. IPR009030. Growth_fac_rcpt. IPR013783. Ig-like_fold. IPR011009. Kinase-like_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. IPR016246. Tyr_kinase_insulin-like_rcpt. IPR002011. Tyr_kinase_rcpt_2_CS. [Graphical view]
Pfam	PF00041. fn3. 1 hit. PF00757. Furin-like. 1 hit. PF07714. Pkinase_Tyr. 1 hit. PF01030. Recep_L_domain. 2 hits. [Graphical view]
PIRSF	PIRSF000620. Insulin_receptor. 1 hit.
PRINTS	PR00109. TYRKINASE.
SMART	SM00060. FN3. 3 hits. SM00261. FU. 1 hit. SM00219. TyrKc. 1 hit. [Graphical view]
SUPFAM	SSF49265. FN_III-like. 3 hits. SSF57184. Grow_fac_recept. 1 hit. SSF56112. Kinase_like. 1 hit.
PROSITE	PS50853. 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]
ProtoNet	Search...
Other
BindingDB	P24062.
ChEMBL	CHEMBL1075098.
NextBio	607805.

Entry information

Entry name

IGF1R_RAT

Accession

Primary (citable) accession number: P24062

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 1, 1992
Last sequence update:	November 1, 1997
Last modified:	April 3, 2013
This is version 131 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program