Insulin-like growth factor 1 receptor

UniProt P08069 Organism Homo sapiens Gene IGF1R EC 2.7.10.1

Also known as: IGF1R

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.

Classification

Family (Pfam): PF00757 Furin-like, PF07714 PK_Tyr_Ser-Thr, PF01030 Recep_L_domain
InterPro: FN3_dom, FN3_sf, Furin-like_Cys-rich_dom, Furin_repeat, Growth_fac_rcpt_cys_sf, Ig-like_fold, Kinase-like_dom_sf, Prot_kinase_dom, Protein_kinase_ATP_BS, Rcpt_L-dom, Rcpt_L-dom_sf, RTK, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_AS, Tyr_kinase_cat_dom, Tyr_kinase_insulin-like_rcpt, Tyr_kinase_rcpt_2_CS
Functional cluster: Immunoglobulin-Domain Cell Adhesion Proteins

Experimental structures · PDB · 45

1IGR X-ray 2.60A
1JQH X-ray 2.10A
1K3A X-ray 2.10A
1M7N X-ray 2.70A
1P4O X-ray 1.50A
2OJ9 X-ray 2.00A
2ZM3 X-ray 2.50A
3D94 X-ray 2.30A
3F5P X-ray 2.90A
3I81 X-ray 2.08A
3LVP X-ray 3.00A
3LW0 X-ray 1.79A
… and 33 more

A predicted model is available from AlphaFold.

Gene Ontology · 40

Disease associations

growth delay due to insulin-like growth factor I resistance MONDO:0010038

Drugs targeting this protein · 8

LINSITINIB inhibitor
AXL-1717 inhibitor
MASOPROCOL inhibitor
XL-228 inhibitor
CONTELTINIB inhibitor
KW-2450 inhibitor
AEW-541 inhibitor
BMS-754807 inhibitor

Neighborhood · nearest proteins

Nearest neighbours of Insulin-like growth factor 1 receptor: 3 by sequence/function similarity (left); 3 co-cited in the literature (right).

Related proteins · sequence + function similarity

Insulin-like growth factor 1 receptor 1.00
Insulin-like growth factor 1 receptor 1.00
Insulin-like growth factor 1 receptor 0.96
Insulin receptor 0.94
Insulin receptor 0.93
Insulin receptor 0.92
Insulin receptor 0.92
Insulin-like receptor 0.90
Insulin-like peptide receptor 0.90
Putative molluscan insulin-related peptide(s) receptor 0.86
Epidermal growth factor receptor 0.81
Protein CG10702 0.79

Co-cited proteins · studied together in the literature

Insulin receptor 7 shared papers
Suppressor of cytokine signaling 3 1 shared papers
Fusion glycoprotein F0 1 shared papers
Insulin receptor substrate 1 2 shared papers
Insulin-like growth factor 1 2 shared papers
Mitogen-activated protein kinase kinase kinase 5 1 shared papers
E3 ubiquitin-protein ligase Mdm2 2 shared papers
Small ribosomal subunit protein RACK1 1 shared papers
Suppressor of cytokine signaling 1 1 shared papers
Beta-arrestin-1 2 shared papers
Suppressor of cytokine signaling 2 1 shared papers
Beta-arrestin-2 2 shared papers

Literature · 60 cited papers

IGF1R is an entry receptor for respiratory syncytial virus. Nature · 2020
Loss of the proteostasis factor AIRAPL causes myeloid transformation by deregulating IGF-1 signaling. Nat. Med. · 2016
mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR. Cell Res. · 2016
Three novel IGF1R mutations in microcephalic patients with prenatal and postnatal growth impairment. Clin. Endocrinol. (Oxf.) · 2015
Cross-talk between integrin alpha6beta4 and insulin-like growth factor-1 receptor (IGF1R) through direct alpha6beta4 binding to IGF1 and subsequent alpha6beta4-IGF1-IGF1R ternary complex formation in anchorage-independent conditions. J. Biol. Chem. · 2012
Polyubiquitination of insulin-like growth factor I receptor (IGF-IR) activation loop promotes antibody-induced receptor internalization and down-regulation. J. Biol. Chem. · 2011
Discovery of the first non-ATP competitive IGF-1R kinase inhibitors: advantages in comparison with competitive inhibitors. Bioorg. Med. Chem. Lett. · 2011
Discovery of 2,4-bis-arylamino-1,3-pyrimidines as insulin-like growth factor-1 receptor (IGF-1R) inhibitors. Bioorg. Med. Chem. Lett. · 2011
Proline isosteres in a series of 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitors of IGF-1R kinase and IR kinase. Bioorg. Med. Chem. Lett. · 2010
Development and validation of a method for profiling post-translational modification activities using protein microarrays. PLoS ONE · 2010
Design of potent IGF1-R inhibitors related to bis-azaindoles. Chem. Biol. Drug Des. · 2010
Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci. Signal. · 2010
… and 48 more in the literature graph

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