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Names & Taxonomy

Uniprot ID:: P08069
Entry Name:: IGF1R_HUMAN
Status:: reviewed
Protein Names:: Insulin-like growth factor 1 receptor (EC 2.7.10.1) (Insulin-like growth factor I receptor) (IGF-I receptor) (CD antigen CD221) [Cleaved into: Insulin-like growth factor 1 receptor alpha chain; Insulin-like growth factor 1 receptor beta chain]
Gene Names:: IGF1R
Gene Names Primary:: IGF1R
Organism:: Homo sapiens (Human)

Structure

Length:: 1367
Sequence:: MKSGSGGGSPTSLWGLLFLSAALSLWPTSGEICGPGIDIRNDYQQLKRLENCTVIEGYLHILLISKAEDYRSYRFPKLTVITEYLLLFRVAGLESLGDLFPNLTVIRGWKLFYNYALVIFEMTNLKDIGLYNLRNITRGAIRIEKNADLCYLSTVDWSLILDAVSNNYIVGNKPPKECGDLCPGTMEEKPMCEKTTINNEYNYRCWTTNRCQKMCPSTCGKRACTENNECCHPECLGSCSAPDNDTACVACRHYYYAGVCVPACPPNTYRFEGWRCVDRDFCANILSAESSDSEGFVIHDGECMQECPSGFIRNGSQSMYCIPCEGPCPKVCEEEKKTKTIDSVTSAQMLQGCTIFKGNLLINIRRGNNIASELENFMGLIEVVTGYVKIRHSHALVSLSFLKNLRLILGEEQLEGNYSFYVLDNQNLQQLWDWDHRNLTIKAGKMYFAFNPKLCVSEIYRMEEVTGTKGRQSKGDINTRNNGERASCESDVLHFTSTTTSKNRIIITWHRYRPPDYRDLISFTVYYKEAPFKNVTEYDGQDACGSNSWNMVDVDLPPNKDVEPGILLHGLKPWTQYAVYVKAVTLTMVENDHIRGAKSEILYIRTNASVPSIPLDVLSASNSSSQLIVKWNPPSLPNGNLSYYIVRWQRQPQDGYLYRHNYCSKDKIPIRKYADGTIDIEEVTENPKTEVCGGEKGPCCACPKTEAEKQAEKEEAEYRKVFENFLHNSIFVPRPERKRRDVMQVANTTMSSRSRNTTAADTYNITDPEELETEYPFFESRVDNKERTVISNLRPFTLYRIDIHSCNHEAEKLGCSASNFVFARTMPAEGADDIPGPVTWEPRPENSIFLKWPEPENPNGLILMYEIKYGSQVEDQRECVSRQEYRKYGGAKLNRLNPGNYTARIQATSLSGNGSWTDPVFFYVQAKTGYENFIHLIIALPVAVLLIVGGLVIMLYVFHRKRNNSRLGNGVLYASVNPEYFSAADVYVPDEWEVAREKITMSRELGQGSFGMVYEGVAKGVVKDEPETRVAIKTVNEAASMRERIEFLNEASVMKEFNCHHVVRLLGVVSQGQPTLVIMELMTRGDLKSYLRSLRPEMENNPVLAPPSLSKMIQMAGEIADGMAYLNANKFVHRDLAARNCMVAEDFTVKIGDFGMTRDIYETDYYRKGGKGLLPVRWMSPESLKDGVFTTYSDVWSFGVVLWEIATLAEQPYQGLSNEQVLRFVMEGGLLDKPDNCPDMLFELMRMCWQYNPKMRPSFLEIISSIKEEMEPGFREVSFYYSEENKLPEPEELDLEPENMESVPLDPSASSSSLPLPDRHSGHKAENGPGPGVLVLRASFDERQPYAHMNGGRKNERALPLPQSSTC
Proteomes:: UP000005640

Subcellular location

Subcellular Location:: Cell membrane

Function

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.; When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.
Catalytic Activity:: ATP + a -L-tyrosine = ADP + a -L-tyrosine phosphate.
Enzyme Regulation:: ENZYME REGULATION: Activated by autophosphorylation at Tyr-1165, Tyr-1161 and Tyr-1166 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.
Active Site:: ACT_SITE 1135 1135 Proton acceptor.
Cross Reference Drug Bank:: DB00047 DB00046 DB00030 DB01277
Gene Ontology Go:: integral component of plasma membrane
intracellular membrane-bounded organelle
membrane
plasma membrane
receptor complex
ATP binding
identical protein binding
insulin binding
insulin receptor binding
insulin receptor substrate binding
insulin-like growth factor binding
insulin-like growth factor I binding
insulin-like growth factor-activated receptor activity
phosphatidylinositol 3-kinase binding
protein tyrosine kinase activity
immune response
inactivation of MAPKK activity
insulin receptor signaling pathway
insulin-like growth factor receptor signaling pathway
negative regulation of apoptotic process
peptidyl-tyrosine autophosphorylation
phosphatidylinositol 3-kinase signaling
phosphatidylinositol-mediated signaling
positive regulation of cell migration
positive regulation of cell proliferation
positive regulation of DNA replication
protein autophosphorylation
protein tetramerization
regulation of JNK cascade
signal transduction
Gene Ontology Biological Process:: immune response
inactivation of MAPKK activity
insulin-like growth factor receptor signaling pathway
insulin receptor signaling pathway
negative regulation of apoptotic process
peptidyl-tyrosine autophosphorylation
phosphatidylinositol 3-kinase signaling
phosphatidylinositol-mediated signaling
positive regulation of cell migration
positive regulation of cell proliferation
positive regulation of DNA replication
protein autophosphorylation
protein tetramerization
regulation of JNK cascade
signal transduction
Gene Ontology Molecular Function:: ATP binding
identical protein binding
insulin binding
insulin-like growth factor-activated receptor activity
insulin-like growth factor binding
insulin-like growth factor I binding
insulin receptor binding
insulin receptor substrate binding
phosphatidylinositol 3-kinase binding
protein tyrosine kinase activity
Gene Ontology Cellular Component:: integral component of plasma membrane
intracellular membrane-bounded organelle
membrane
plasma membrane
receptor complex
Keywords:: 3D-structure
ATP-binding
Cell membrane
Cleavage on pair of basic residues
Complete proteome
Direct protein sequencing
Disease mutation
Disulfide bond
Glycoprotein
Isopeptide bond
Kinase
Membrane
Nucleotide-binding
Phosphoprotein
Polymorphism
Receptor
Reference proteome
Repeat
Signal
Transferase
Transmembrane
Transmembrane helix
Tyrosine-protein kinase
Ubl conjugation
Interacts With:: Itself; Q9NZN5; P49913; Q64010; P41240; P35222; P05019; P01317; Q9Y2W7; Q9UJU2; Q00987; P27986; P18031; Q06124; P29353-2; Q01995

Names & Taxonomy

Structure

Subcellular location

Function

Publication