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Details on Person UniProt:P08069 IGF1R
| Class:Id | ReferenceGeneProduct:57178 |
|---|---|
| _chainChangeLog | signal peptide:1-30 added on Sat February 7 2015;chain:31-736 added on Sat February 7 2015;chain:741-1367 added on Sat February 7 2015 |
| _displayName | UniProt:P08069 IGF1R |
| _timestamp | 2025-02-21 20:10:21 |
| chain | signal peptide:1-30 chain:31-736 chain:741-1367 |
| checksum | AE8A735F87F745C8 |
| comment | 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.FUNCTION 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 L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+)ACTIVITY 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.SUBUNIT 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 RACK1. Interacts with SOCS1, SOCS2 and SOCS3. Interacts with 14-3-3 proteins. Interacts with NMD2. Interacts with MAP3K5. Interacts with STAT3. Found in a ternary complex with IGF1 and ITGAV:ITGB3 or ITGA6:ITGB4 (PubMed:19578119, PubMed:22351760). Interacts (nascent precursor form) with ZFAND2B (PubMed:26692333).SUBUNIT (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) fusion glycoprotein F1/F2 heterodimer.INTERACTION Found as a hybrid receptor with INSR in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Expressed in a variety of tissues. Overexpressed in tumors, including melanomas, cancers of the colon, pancreas prostate and kidney.PTM Autophosphorylated on tyrosine residues in response to ligand binding (PubMed:11694888, PubMed:18501599, PubMed:19041240). Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit (PubMed:11694888, PubMed:18501599, PubMed:19041240). Autophosphorylation occurs in a sequential manner; Tyr-1165 is predominantly phosphorylated first, followed by phosphorylation of Tyr-1161 and Tyr-1166 (PubMed:11694888, PubMed:18501599, PubMed:19041240). While every single phosphorylation increases kinase activity, all three tyrosine residues in the kinase activation loop (Tyr-1165, Tyr-1161 and Tyr-1166) have to be phosphorylated for optimal activity (PubMed:11694888, PubMed:18501599, PubMed:19041240). Can be autophosphorylated at additional tyrosine residues (in vitro) (PubMed:11694888, PubMed:18501599, PubMed:19041240). Autophosphorylated is followed by phosphorylation of juxtamembrane tyrosines and C-terminal serines (PubMed:11694888, PubMed:18501599, PubMed:19041240). May also be phosphorylated at Tyr-1161 and Tyr-1166 by mTORC2 (PubMed:26584640). Phosphorylation of Tyr-980 is required for IRS1- and SHC1-binding (PubMed:7541045). Phosphorylation of Ser-1278 by GSK-3beta restrains kinase activity and promotes cell surface expression, it requires a priming phosphorylation at Ser-1282 (By similarity). Dephosphorylated by PTPN1.PTM Polyubiquitinated at Lys-1168 and Lys-1171 through both 'Lys-48' and 'Lys-29' linkages, promoting receptor endocytosis and subsequent degradation by the proteasome. Ubiquitination is facilitated by pre-existing phosphorylation.PTM Sumoylated with SUMO1.PTM 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.DISEASE The disease is caused by variants affecting the gene represented in this entry.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.SEQUENCE CAUTION Extended N-terminus.ONLINE INFORMATION IGF-1 receptor entry |
| description | recommendedName: Insulin-like growth factor 1 receptor ecNumber: 2.7.10.1 alternativeName: Insulin-like growth factor I receptor shortName: IGF-I receptor cdAntigenNameCD221/cdAntigenName component recommendedName: Insulin-like growth factor 1 receptor alpha chain /component component recommendedName: Insulin-like growth factor 1 receptor beta chain /component |
| geneName | IGF1R |
| identifier | P08069 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure ATP-binding Cell membrane Cleavage on pair of basic residues Direct protein sequencing Disease variant Disulfide bond Glycoprotein Host-virus interaction Isopeptide bond Kinase Membrane Nucleotide-binding Phosphoprotein Proteomics identification Receptor Reference proteome Repeat Signal Transferase Transmembrane Transmembrane helix Tyrosine-protein kinase Ubl conjugation |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 |
| name | IGF1R |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:8993681] ENSEMBL:ENSG00000140443 IGF1R [Homo sapiens] |
| secondaryIdentifier | IGF1R_HUMAN B1B5Y2 Q14CV2 Q9UCC0 |
| sequenceLength | 1367 |
| species | [Species:48887] Homo sapiens |
| (referenceEntity) | [EntityWithAccessionedSequence:2404169] IGF1R(31-736) [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:2404172] p-Y1161,Y1165,Y1166-IGF1R(741-1367) [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:2404180] IGF1R(741-1367) [plasma membrane] [Homo sapiens] |
| (referenceSequence) | [ModifiedResidue:2404171] O4'-phospho-L-tyrosine at 1166 [ModifiedResidue:2404173] O4'-phospho-L-tyrosine at 1165 [ModifiedResidue:2404177] O4'-phospho-L-tyrosine at 1161 |
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No pathways have been reviewed or authored by UniProt:P08069 IGF1R (57178)
