ID IGF1R_BOVIN Reviewed; 640 AA.
AC Q05688;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 24-JAN-2024, entry version 170.
DE RecName: Full=Insulin-like growth factor 1 receptor;
DE EC=2.7.10.1;
DE AltName: Full=Insulin-like growth factor I receptor;
DE Short=IGF-I receptor;
DE AltName: CD_antigen=CD221;
DE Contains:
DE RecName: Full=Insulin-like growth factor 1 receptor alpha chain;
DE Contains:
DE RecName: Full=Insulin-like growth factor 1 receptor beta chain;
DE Flags: Precursor; Fragment;
GN Name=IGF1R;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Kidney;
RX PubMed=1662995; DOI=10.3109/10425179109020797;
RA Sneyers M., Kettmann R., Massart S., Renaville R., Burny A., Portetelle D.;
RT "Cloning and characterization of a cDNA encoding the beta-subunit of the
RT bovine insulin-like growth factor-1 receptor.";
RL DNA Seq. 1:405-406(1991).
CC -!- FUNCTION: Receptor tyrosine kinase which mediates actions of insulin-
CC like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and
CC insulin (INS) with a lower affinity. The activated IGF1R is involved in
CC cell growth and survival control. IGF1R is crucial for tumor
CC transformation and survival of malignant cell. Ligand binding activates
CC the receptor kinase, leading to receptor autophosphorylation, and
CC tyrosines phosphorylation of multiple substrates, that function as
CC signaling adapter proteins including, the insulin-receptor substrates
CC (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins
CC lead to the activation of two main signaling pathways: the PI3K-AKT/PKB
CC pathway and the Ras-MAPK pathway. The result of activating the MAPK
CC pathway is increased cellular proliferation, whereas activating the
CC PI3K pathway inhibits apoptosis and stimulates protein synthesis.
CC Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K
CC (PIK3R1), leading to activation of several downstream substrates,
CC including protein AKT/PKB. AKT phosphorylation, in turn, enhances
CC protein synthesis through mTOR activation and triggers the
CC antiapoptotic effects of IGFIR through phosphorylation and inactivation
CC of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS
CC by phosphorylated IRS1 or Shc leads to recruitment of Ras and
CC activation of the ras-MAPK pathway. In addition to these two main
CC signaling pathways IGF1R signals also through the Janus kinase/signal
CC transducer and activator of transcription pathway (JAK/STAT).
CC Phosphorylation of JAK proteins can lead to phosphorylation/activation
CC of signal transducers and activators of transcription (STAT) proteins.
CC In particular activation of STAT3, may be essential for the
CC transforming activity of IGF1R. The JAK/STAT pathway activates gene
CC transcription and may be responsible for the transforming activity. JNK
CC kinases can also be activated by the IGF1R. IGF1 exerts inhibiting
CC activities on JNK activation via phosphorylation and inhibition of
CC MAP3K5/ASK1, which is able to directly associate with the IGF1R (By
CC similarity). When present in a hybrid receptor with INSR, binds IGF1
CC (By similarity). {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
CC -!- ACTIVITY REGULATION: Activated by autophosphorylation at Tyr-434, Tyr-
CC 438 and Tyr-439 on the kinase activation loop; phosphorylation at all
CC three tyrosine residues is required for optimal kinase activity.
CC Inhibited by MSC1609119A-1, BMS-754807, PQIP, benzimidazole pyridinone,
CC isoquinolinedione, bis-azaindole, 3-cyanoquinoline, 2,4-bis-arylamino-
CC 1,3-pyrimidine, pyrrolopyrimidine, pyrrole-5-carboxaldehyde,
CC picropodophyllin (PPP), tyrphostin derivatives. While most inhibitors
CC bind to the ATP binding pocket, MSC1609119A-1 functions as allosteric
CC inhibitor and binds close to the DFG motif and the activation loop (By
CC similarity). {ECO:0000250}.
CC -!- SUBUNIT: Tetramer of 2 alpha and 2 beta chains linked by disulfide
CC bonds. The alpha chains contribute to the formation of the ligand-
CC binding domain, while the beta chain carries the kinase domain.
CC Interacts with PIK3R1 and with the PTB/PID domains of IRS1 and SHC1 in
CC vitro when autophosphorylated on tyrosine residues. Forms a hybrid
CC receptor with INSR, the hybrid is a tetramer consisting of 1 alpha
CC chain and 1 beta chain of INSR and 1 alpha chain and 1 beta chain of
CC IGF1R. Interacts with ARRB1 and ARRB2. Interacts with GRB10. Interacts
CC with RACK1 (By similarity). Interacts with SOCS1, SOCS2 and SOCS3 (By
CC similarity). Interacts with 14-3-3 proteins (By similarity). Interacts
CC with NMD2 (By similarity). Interacts with MAP3K5 (By similarity).
CC Interacts with STAT3 (By similarity). Interacts (nascent precursor
CC form) with ZFAND2B (By similarity). {ECO:0000250,
CC ECO:0000250|UniProtKB:P08069}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass type I
CC membrane protein {ECO:0000250}.
CC -!- PTM: Autophosphorylated on tyrosine residues in response to ligand
CC binding. Autophosphorylation occurs in trans, i.e. one subunit of the
CC dimeric receptor phosphorylates tyrosine residues on the other subunit.
CC Autophosphorylation occurs in a sequential manner; Tyr-438 is
CC predominantly phosphorylated first, followed by phosphorylation of Tyr-
CC 434 and Tyr-439. While every single phosphorylation increases kinase
CC activity, all three tyrosine residues in the kinase activation loop
CC (Tyr-438, Tyr-434 and Tyr-439) have to be phosphorylated for optimal
CC activity. Can be autophosphorylated at additional tyrosine residues (in
CC vitro). Autophosphorylated is followed by phosphorylation of
CC juxtamembrane tyrosines and C-terminal serines. Phosphorylation of Tyr-
CC 253 is required for IRS1- and SHC1-binding (By similarity).
CC Phosphorylation of Ser-551 by GSK-3beta restrains kinase activity and
CC promotes cell surface expression, it requires a priming phosphorylation
CC at Ser-555. Dephosphorylated by PTPN1 (By similarity). {ECO:0000250}.
CC -!- PTM: Polyubiquitinated at Lys-441 and Lys-444 through both 'Lys-48' and
CC 'Lys-29' linkages, promoting receptor endocytosis and subsequent
CC degradation by the proteasome. Ubiquitination is facilitated by pre-
CC existing phosphorylation (By similarity). {ECO:0000250}.
CC -!- PTM: Sumoylated with SUMO1. {ECO:0000250}.
CC -!- PTM: Controlled by regulated intramembrane proteolysis (RIP). Undergoes
CC metalloprotease-dependent constitutive ectodomain shedding to produce a
CC membrane-anchored 52 kDa C-Terminal fragment which is further processed
CC by presenilin gamma-secretase to yield an intracellular 50 kDa fragment
CC (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. Insulin receptor subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
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DR EMBL; X54980; CAA38724.1; -; mRNA.
DR PIR; S23008; S23008.
DR RefSeq; NP_001231541.1; NM_001244612.1.
DR AlphaFoldDB; Q05688; -.
DR SMR; Q05688; -.
DR STRING; 9913.ENSBTAP00000028690; -.
DR GlyCosmos; Q05688; 5 sites, No reported glycans.
DR PaxDb; 9913-ENSBTAP00000028690; -.
DR GeneID; 281848; -.
DR KEGG; bta:281848; -.
DR CTD; 3480; -.
DR eggNOG; KOG4258; Eukaryota.
DR HOGENOM; CLU_000288_166_0_1; -.
DR InParanoid; Q05688; -.
DR OrthoDB; 1614410at2759; -.
DR Proteomes; UP000009136; Unplaced.
DR GO; GO:0030424; C:axon; IBA:GO_Central.
DR GO; GO:0005737; C:cytoplasm; IDA:AgBase.
DR GO; GO:0005899; C:insulin receptor complex; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:AgBase.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005009; F:insulin receptor activity; IBA:GO_Central.
DR GO; GO:0043560; F:insulin receptor substrate binding; ISS:UniProtKB.
DR GO; GO:0005520; F:insulin-like growth factor binding; IMP:AgBase.
DR GO; GO:0005010; F:insulin-like growth factor receptor activity; ISS:UniProtKB.
DR GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; ISS:UniProtKB.
DR GO; GO:0004713; F:protein tyrosine kinase activity; ISS:UniProtKB.
DR GO; GO:0005198; F:structural molecule activity; ISS:UniProtKB.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IBA:GO_Central.
DR GO; GO:0048009; P:insulin-like growth factor receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0043409; P:negative regulation of MAPK cascade; ISS:UniProtKB.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IBA:GO_Central.
DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IBA:GO_Central.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0046328; P:regulation of JNK cascade; ISS:UniProtKB.
DR CDD; cd00063; FN3; 1.
DR CDD; cd05032; PTKc_InsR_like; 1.
DR Gene3D; 2.60.40.10; Immunoglobulins; 2.
DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR InterPro; IPR003961; FN3_dom.
DR InterPro; IPR036116; FN3_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR002011; Tyr_kinase_rcpt_2_CS.
DR PANTHER; PTHR24416:SF106; INSULIN-LIKE GROWTH FACTOR 1 RECEPTOR; 1.
DR PANTHER; PTHR24416; TYROSINE-PROTEIN KINASE RECEPTOR; 1.
DR Pfam; PF00041; fn3; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00060; FN3; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF49265; Fibronectin type III; 1.
DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR PROSITE; PS50853; FN3; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS00239; RECEPTOR_TYR_KIN_II; 1.
PE 2: Evidence at transcript level;
KW ATP-binding; Cell membrane; Cleavage on pair of basic residues;
KW Disulfide bond; Glycoprotein; Isopeptide bond; Kinase; Membrane;
KW Nucleotide-binding; Phosphoprotein; Receptor; Reference proteome; Repeat;
KW Transferase; Transmembrane; Transmembrane helix; Tyrosine-protein kinase;
KW Ubl conjugation.
FT CHAIN <1..9
FT /note="Insulin-like growth factor 1 receptor alpha chain"
FT /id="PRO_0000016679"
FT CHAIN 14..640
FT /note="Insulin-like growth factor 1 receptor beta chain"
FT /id="PRO_0000016680"
FT TOPO_DOM 14..208
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 209..232
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 233..640
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 5..101
FT /note="Fibronectin type-III 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 107..200
FT /note="Fibronectin type-III 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 272..547
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 555..640
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 250..253
FT /note="IRS1- and SHC1-binding"
FT /evidence="ECO:0000250"
FT ACT_SITE 408
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 278..286
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 306
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 253
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P08069"
FT MOD_RES 434
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P08069"
FT MOD_RES 438
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P08069"
FT MOD_RES 439
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P08069"
FT MOD_RES 551
FT /note="Phosphoserine; by GSK3-beta"
FT /evidence="ECO:0000250|UniProtKB:Q60751"
FT MOD_RES 555
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q60751"
FT CARBOHYD 20
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 29
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 37
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 173
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 186
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CROSSLNK 441
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P08069"
FT CROSSLNK 444
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P08069"
FT NON_TER 1
SQ SEQUENCE 640 AA; 72511 MW; 1E645258BDC6FF29 CRC64;
NAIFVPRPER KRREVMQIAN TTMSSRSRNT TVLDTYNITD PEELETEYPF FESRVDNKER
TVISNLRPFT LYRIDIHSCN HEAEKLGCSA SNFVFARTMP AEGADDIPGP VTWEPRPENS
IFLKWPEPEN PNGLILMYEI KYGSQVEDQR ECVSRQEYRK YGGAKLNRLN PGNYTARIQA
TSLSGNGSWT DPVFFYVQAK TTYENFIHLM IALPIAVLLI VGGLVIMLYV FHRKRNSSRL
GNGVLYASVN PEYFSAADVY VPDEWEVARE KITMSRELGQ GSFGMVYEGV AKGVVKDEPE
TRVAIKTVNE AASMRERIEF LNEASVMKEF NCHHVVRLLG VVSQGQPTLV IMELMTRGDL
KSYLRSLRPE MENNPVLAPP SLSKMIQMAG EIADGMAYLN ANKFVHRDLA ARNCMVAEDF
TVKIGDFGMT RDIYETDYYR KGGKGLLPVR WMSPESLKDG VFTTHSDVWS FGVVLWEIAT
LAEQPYQGLS NEQVLRFVME GGLLDKPDNC PDMLFELMRM CWQYNPKMRP SFLEIISSVK
DEMEAGFREV SFYYSEENKP PEPEELDLEP ENMESVPLDP SASSASLPLP DRHSGHKAEN
GPGPGVLVLR ASFDERQPYA HMNGGRKNER ALPLPQSSTC
//
