IGF1R_HUMAN » Insulin-like growth factor 1 receptor

IGF1R_HUMAN » Insulin-like growth factor 1 receptor
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Topology in Plasma membrane
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cytoplasmic side
IGF1R_HUMAN » Insulin-like growth factor 1 receptor » Insulin-like growth factor I receptor;IGF-I receptor;
Hydrophobic Thickness 39.6 ± 1.0 Å
Tilt Angle 0 ± 0°
ΔGtransfer -51.8 kcal/mol
ΔGfold -25.6 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 933-958 (930-962)
Pathways

Adherens junction (KEGG)

Endocytosis (KEGG)

Focal adhesion (KEGG)

Glioma (KEGG)

HIF-1 signaling pathway (KEGG)

Long-term depression (KEGG)

Melanoma (KEGG)

Oocyte meiosis (KEGG)

Ovarian steroidogenesis (KEGG)

Pathways in cancer (KEGG)

PI3K-Akt signaling pathway (KEGG)

Progesterone-mediated oocyte maturation (KEGG)

Prostate cancer (KEGG)

Proteoglycans in cancer (KEGG)

Signal Transduction (Reactome)

Transcriptional misregulation in cancer (KEGG)

PDB 1igr (31-492), 3lvp (951-1286), 1m7n (974-1294), 1jqh (979-1286), 3o23 (982-1286), 3nw7 (982-1286), 3nw6 (982-1286), 3nw5 (982-1286), 3i81 (982-1286), 2oj9 (982-1286), 3lw0 (983-1286), 3qqu (988-1286), 3f5p (A/B...=981-1286), 2zm3 (A/B/C/D=981-1286), 1p4o (A/B=974-1294), 3d94 (A=986-1286), 1k3a (A=988-1286)
OPM 1p4o
Complexes none
Interactions

A4, Complex: A4:IGF1R, PubMed

CADH3, Complex: CADH3:IGF1R, PubMed

CP17A, Complex: CP17A:IGF1R, PubMed

EGFR, Complex: IGF1R:EGFR, PubMed

ERBB2, Complex: IGF1R:ERBB2, PubMed

ESR1, Complex: SHC1:ESR1:IGF1R, PubMed

GHR, Complex: IGF1R:GHR:JAK2, PubMed

I13R2, Complex: I13R2:IGF1R, PubMed

INSR, Complex: INSR:IGF1R, PubMed

ITB1, Complex: IGF1R:ITB1, PubMed

KLOT, Complex: KLOT:IGF1R, PubMed

LEPR, Complex: IGF1R:LEPR, PubMed

Domains

AA: 51-161, PDBID: 1IGR, Subunit A, Seq Identity:100%, Receptor L domain

AA: 175-333, PDBID: 1IGR, Subunit A, Seq Identity:100%, Furin-like cysteine rich region

AA: 352-466, PDBID: 1IGR, Subunit A, Seq Identity:100%, Receptor L domain

AA: 999-1266, PDBID: 1JQH, Subunit B, Seq Identity:100%, Protein tyrosine kinase

UniProt annotation for IGF1R_HUMAN » Insulin-like growth factor 1 receptor
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 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 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 [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

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.

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 GNB2L1/RACK1. Interacts with SOCS1, SOCS2 and SOCS3. Interacts with 14-3-3 proteins. Interacts with NMD2. Interacts with MAP3K5. Interacts with STAT3.

TISSUE SPECIFICITY: 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.

DISEASE: Insulin-like growth factor 1 resistance (IGF1RES) OMIM: A disorder characterized by intrauterine growth retardation, poor postnatal growth and increased plasma IGF1 levels. mutations affecting the gene represented in this entry.

UniProt features for IGF1R_HUMAN » Insulin-like growth factor 1 receptor
SIGNAL 1 30
CHAIN 31 736 Insulin-like growth factor 1 receptor alpha chain.
CHAIN 741 1367 Insulin-like growth factor 1 receptor beta chain.
DOMAIN 488 606 Fibronectin type-III 1.
DOMAIN 611 689 Fibronectin type-III 2.
DOMAIN 831 926 Fibronectin type-III 3.
DOMAIN 999 1274 Protein kinase.
MOTIF 977 980 IRS1- and SHC1-binding.
ACT_SITE 1135 1135 Proton acceptor (By similarity).
DISULFID 33 52
DISULFID 150 178
DISULFID 182 205
DISULFID 192 211
DISULFID 215 224
DISULFID 219 230
DISULFID 231 239
DISULFID 235 248
DISULFID 251 260
DISULFID 264 276
DISULFID 282 303
DISULFID 307 321
DISULFID 324 328
DISULFID 332 353
DISULFID 455 488
CROSSLNK 1168 1168 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin).
CROSSLNK 1171 1171 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin).
Amino Acid Sequence for IGF1R_HUMAN » Insulin-like growth factor 1 receptor
MKSGSGGGSP TSLWGLLFLS AALSLWPTSG EICGPGIDIR NDYQQLKRLE NCTVIEGYLH ILLISKAEDY RSYRFPKLTV ITEYLLLFRV AGLESLGDLF PNLTVIRGWK LFYNYALVIF EMTNLKDIGL YNLRNITRGA IRIEKNADLC YLSTVDWSLI LDAVSNNYIV GNKPPKECGD LCPGTMEEKP MCEKTTINNE YNYRCWTTNR CQKMCPSTCG KRACTENNEC CHPECLGSCS APDNDTACVA CRHYYYAGVC VPACPPNTYR FEGWRCVDRD FCANILSAES SDSEGFVIHD GECMQECPSG FIRNGSQSMY CIPCEGPCPK VCEEEKKTKT IDSVTSAQML QGCTIFKGNL LINIRRGNNI ASELENFMGL IEVVTGYVKI RHSHALVSLS FLKNLRLILG EEQLEGNYSF YVLDNQNLQQ LWDWDHRNLT IKAGKMYFAF NPKLCVSEIY RMEEVTGTKG RQSKGDINTR NNGERASCES DVLHFTSTTT SKNRIIITWH RYRPPDYRDL ISFTVYYKEA PFKNVTEYDG QDACGSNSWN MVDVDLPPNK DVEPGILLHG LKPWTQYAVY VKAVTLTMVE NDHIRGAKSE ILYIRTNASV PSIPLDVLSA SNSSSQLIVK WNPPSLPNGN LSYYIVRWQR QPQDGYLYRH NYCSKDKIPI RKYADGTIDI EEVTENPKTE VCGGEKGPCC ACPKTEAEKQ AEKEEAEYRK VFENFLHNSI FVPRPERKRR DVMQVANTTM SSRSRNTTAA DTYNITDPEE LETEYPFFES RVDNKERTVI SNLRPFTLYR IDIHSCNHEA EKLGCSASNF VFARTMPAEG ADDIPGPVTW EPRPENSIFL KWPEPENPNG LILMYEIKYG SQVEDQRECV SRQEYRKYGG AKLNRLNPGN YTARIQATSL SGNGSWTDPV FFYVQAKTGY ENFIHLIIAL PVAVLLIVGG LVIMLYVFHR KRNNSRLGNG VLYASVNPEY FSAADVYVPD EWEVAREKIT MSRELGQGSF GMVYEGVAKG VVKDEPETRV AIKTVNEAAS MRERIEFLNE ASVMKEFNCH HVVRLLGVVS QGQPTLVIME LMTRGDLKSY LRSLRPEMEN NPVLAPPSLS KMIQMAGEIA DGMAYLNANK FVHRDLAARN CMVAEDFTVK IGDFGMTRDI YETDYYRKGG KGLLPVRWMS PESLKDGVFT TYSDVWSFGV VLWEIATLAE QPYQGLSNEQ VLRFVMEGGL LDKPDNCPDM LFELMRMCWQ YNPKMRPSFL EIISSIKEEM EPGFREVSFY YSEENKLPEP EELDLEPENM ESVPLDPSAS SSSLPLPDRH SGHKAENGPG PGVLVLRASF DERQPYAHMN GGRKNERALP LPQSSTC