IGF1R (insulin like growth factor 1 receptor; HGNC:5465, NCBI Gene ID 3480) is a human locus mapped to chromosome band 15q26.3 that encodes disulfide-linked alpha2-beta2 heterotetrameric receptor tyrosine kinase IGF1R (1,367 aa precursor; EC 2.7.10.1). IGF1R acts in IGF1/IGF2-IRS1/2-PI3K-AKT1-mTORC1 somatic growth & FOXO3 longevity regulation, together with IGF1 (Insulin-Like Growth Factor 1 Gene), IGF2 (Insulin-Like Growth Factor 2 Gene), and Insulin Receptor (INSR). Encodes the heterotetrameric receptor tyrosine kinase mediating IGF-1 and IGF-2 anabolic signaling; hypomorphic variants are enriched in centenarians.
Heterozygous LoF causes IGF-1 resistance & microcephaly; hypomorphic variants enriched in human centenarians; target of teprotumumab (Tepezza)
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 21-exon gene spanning ~315 kb at chromosome 15q26.3, encoding a single 1,367-amino-acid proreceptor polypeptide that is cleaved by furin at an Arg-Lys-Arg-Arg tetrabasic site into an entirely extracellular 706-residue ligand-binding alpha chain and a 627-residue transmembrane tyrosine-kinase beta chain, assembling via disulfide bonds into a mature alpha2-beta2 heterotetramer.
Cellular & Tissue Expression Profile: Widely expressed on chondrocytes of epiphyseal growth plates, osteoblasts, skeletal muscle fibers and satellite cells, cardiac myocytes, orbital fibroblasts, central nervous system neurons, and epithelial malignancies (with minimal expression on mature hepatocytes and adipocytes, which instead express INSR).
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Binding of IGF-1 (or IGF-2) to the L1-Cys-rich-L2 ectodomain pocket releases autoinhibition of the transmembrane helices and juxtaposes the two cytoplasmic beta-subunit kinase domains for trans-autophosphorylation of the Tyr1131/Tyr1135/Tyr1136 activation loop; phosphorylated Tyr950 in the juxtamembrane NPXY motif then recruits IRS-1/2 and Shc to activate PI3K-AKT1-mTORC1 (inhibiting FOXO1/3) and RAS-MAPK proliferation.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Compound heterozygous or heterozygous loss-of-function mutations cause intrauterine and postnatal growth retardation with elevated plasma IGF-1; notably, Ashkenazi Jewish centenarian cohorts are significantly enriched for functional heterozygous missense variants in IGF1R (such as p.Ala37Thr and p.Arg407His) that partially attenuate IGF1R phosphorylation and up-regulate stress-resistant FOXO3 target genes.
Therapeutic & Clinical Pharmacology: Clinically targeted by the FDA-approved human anti-IGF1R monoclonal antibody teprotumumab (Tepezza), which disrupts the orbital fibroblast IGF1R-TSHR signaling complex to reverse proptosis in thyroid eye disease (Graves ophthalmopathy).