IGF1R (insulin-like growth factor 1 receptor)

2008-09-01   Itay Bentov , Haim Werner 

Department of Human Molecular Genetics, Biochemistry, Sackler School of Medecine, Tel Aviv University,Tel Aviv 69978, ISRAEL





The IGF1R gene contains 21 exons spanning approximately 100-kb of genomic DNA.


The IGF1R mRNA is a 11242-base, single-stranded linear molecule. Various hormones and growth factors were shown to regulate IGF1R gene transcription. Specifically, growth factors and oncogenic agents associated with positive stimulation of cell division were shown to upregulate IGF1R gene expression whereas negative modulators of cell growth (e.g., tumor suppressors) usually cause a reduction in IGF1R gene expression. Growth factors that stimulate IGF1R gene transcription include, among others, basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF). In addition, IGF1R gene expression is regulated by steroid hormones. Thus, estradiol was shown to increase, while progesterone decreased, IGF1R mRNA levels in breast cancer cells.



The IGF1R is a cell-surface tyrosine kinase receptor that is synthesized as a single polypeptide chain which is then processed to yield an around 180-kDa glycopeptide. The length of the IGF1R precursor is 1367 amino acids. Precursor chains include a 30-amino acid leader peptide rich in hydrophobic residues, which is involved in the transfer of the nascent protein into the endoplasmic reticulum. Partially processed proreceptors form disulfide-linked dimers that are subsequently glycosylated and proteolytically cleaved at a basic tetrapeptide sequence to yield mature α and ® subunits. The mature heterotetramers have a β-α-α-β conformation.
The α subunit is entirely extracellular and includes a cysteine-rich region and several potential N-linked glycosylation sites (Asn-X-Ser/Thr motifs). The cysteine-rich domain of the IGF1R is important for high-affinity IGF1 binding. The ® subunit features a unique hydrophobic sequence that constitutes the transmembrane domain. The cytoplasmic portion of the ® subunit contains a tyrosine kinase enzymatic domain. Inside this catalytic region there is a glycine-rich conserved element that participates in the transfer of the phosphate moiety of ATP to specific substrates.


The IGF1R is abundantly expressed in the embryo, with significant reduction in expression levels at adult stages.


The IGF1R is essentially expressed by most organs and tissues. Very high levels are detected in brain. Extremely low levels are seen in liver, due to downregulation by hepatic IGF1.


The IGF1R is involved in growth, development, and differentiation processes. The IGF1R displays a very strong antiapoptotic activity and protects IGF1R-expressing cells from programmed cell death.
IGF1R is vital for cell survival, as illustrated by the lethal phenotype of mice in which the IGF1R gene was disrupted by homologous recombination. During normal ontogenesis, the IGF1R is expressed at every developmental period, including the oocyte stage. Late embryonic and adult stages, in which the percentage of rapidly proliferating cells declines, are associated with an overall reduction in IGF1R mRNA levels.
IGF1R is involved in normal growth, development, and differentiation processes. IGF1R mediates the biological roles of both the IGF1 and IGF2 ligands. IGF1R binds IGF1 and IGF2 with high affinity, and insulin with significantly reduced affinity. IGF1R displays a very potent antiapoptotic activity, protecting IGF1R-expressing cells from programed cell death. Activation of the IGF1R by locally-produced or circulating IGF1 or IGF2 leads to autophosphorylation of the tyrosine kinase domain, with ensuing activation of the Ras-Raf-MAP kinase and PI3K-PKB/Akt signaling pathways. Activation of these cytoplasmic mediators is critical in order for the IGF1R to exert its mitogenic and antiapoptotic activities.
The biological actions of the IGF1R are modulated by a family of IGF-binding proteins (IGFBPs) that includes at least six members (IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6). IGFBPs control IGF1R action by regulating the bioavailability of the IGF1 and IGF2 ligands. The affinity of the IGFBPs for the ligands is 1-2 orders of magnitude higher than the affinity exhibited by the receptor. IGFBPs usually display inhibitory types of activities however, under certain circumstances, IGFBPs may also stimulate IGF1 action.



IGF1R mutations are very rare, suggesting that homozygous mutations are a lethal condition. Recently, IGF1R mutations were described in two cohorts of children. The first cohort consisted of children with unexplained intrauterine growth restriction and subsequent short stature, and the second group included children with short stature and high circulating IGF1 levels. A compound heterozygote for point mutations in IGF1R exon 2 was identified in a girl from the first group. Fibroblasts cultured from the patient had decreased IGF1R binding and IGF1-stimulated phosphorylation. In the second cohort a boy was identified with a nonsense mutation, leading to reduced IGF1R expression.
In a family harboring a ring chromosome 15, hemizygotes for the IGF1R locus showed severe growth failure, while a patient possessing two copies of the gene had borderline stature. On the other hand, a patient with three IGF1R gene copies due to a partial duplication of the long arm of chromosome 15, presented with height and weight above the 97th percentile and showed accelerated cellular growth.

Implicated in

Entity name
Various tumors
Clinical and experimental data collected over the past 25 years have suggested that the IGF1R gene exhibits a pattern of expression in malignant cells that reflects its pro-survival role. Using a variety of techniques, including IGF binding and radio-receptor assays, Northern and Western blottings, and immunohistochemical and in situ hybridization analyses, most studies consistently showed that the IGF1R is expressed at high levels in primary tumors and cancer-derived cells. These tumors include, among others, breast, prostate, ovarian, colon, hematopoietic, rhabdomyosarcoma, and renal cancers. These augmented IGF1R levels reflect a reversal to more primitive, less differentiated, ontogenetic stages that, in most species and body organs, are characterized by very high concentrations of IGF1R mRNA and IGF binding sites. Whereas the molecular mechanisms that lead to increased IGF1R gene expression in cancer remain largely unexplained, the dogma that emerged postulated that IGF1R expression is a fundamental prerequisite for cellular transformation. The appeal of this paradigm resides in the fact that enhanced IGF1R levels and IGF1 signaling are considered key factors, indispensable for the cell, in order to adopt proliferative/oncogenic pathways.
Anti-IGF1R strategies (e.g., humanized IGF1R antibodies, low molecular weight tyrosine kinase inhibitors, etc.) are currently being developed in order to target the IGF1R as a clinically relevant therapeutic target.


Pubmed IDLast YearTitleAuthors
146574282003IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation.Abuzzahab MJ et al
84029021993Role of insulin-like growth factors in embryonic and postnatal growth.Baker J et al
164370282004IGF, IGF receptor and overgrowth syndromes.Bentov I et al
90100341997Type I insulin-like growth factor receptor gene expression in normal human breast tissue treated with oestrogen and progesterone.Clarke RB et al
90305171997Differential regulation of insulin-like growth factor-I (IGF-I) receptor gene expression by IGF-I and basic fibroblastic growth factor.Hernández-Sánchez C et al
185151432008IGF signaling defects as causes of growth failure and IUGR.Klammt J et al
146712002003Cell proliferation activities on skin fibroblasts from a short child with absence of one copy of the type 1 insulin-like growth factor receptor (IGF1R) gene and a tall child with three copies of the IGF1R gene.Okubo Y et al
77891781995Hemizygosity at the insulin-like growth factor I receptor (IGF1R) locus and growth failure in the ring chromosome 15 syndrome.Peoples R et al
81437861994Platelet-derived growth factor increases the activity of the promoter of the insulin-like growth factor-1 (IGF-1) receptor gene.Rubini M et al
87120681996The role of the insulin-like growth factor system in human cancer.Werner H et al
168150292006The insulin-like growth factor-I receptor gene: a downstream target for oncogene and tumor suppressor action.Werner H et al

Other Information

Locus ID:

NCBI: 3480
MIM: 147370
HGNC: 5465
Ensembl: ENSG00000140443


dbSNP: 3480
ClinVar: 3480
TCGA: ENSG00000140443


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Autophagy - animalKEGGko04140
mTOR signaling pathwayKEGGko04150
Focal adhesionKEGGko04510
Adherens junctionKEGGko04520
Long-term depressionKEGGko04730
Progesterone-mediated oocyte maturationKEGGko04914
Prostate cancerKEGGko05215
Autophagy - animalKEGGhsa04140
mTOR signaling pathwayKEGGhsa04150
Focal adhesionKEGGhsa04510
Adherens junctionKEGGhsa04520
Long-term depressionKEGGhsa04730
Pathways in cancerKEGGhsa05200
Prostate cancerKEGGhsa05215
Progesterone-mediated oocyte maturationKEGGhsa04914
Oocyte meiosisKEGGko04114
Oocyte meiosisKEGGhsa04114
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
HIF-1 signaling pathwayKEGGhsa04066
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
Ovarian steroidogenesisKEGGhsa04913
Ovarian steroidogenesisKEGGko04913
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
FoxO signaling pathwayKEGGhsa04068
AMPK signaling pathwayKEGGhsa04152
AMPK signaling pathwayKEGGko04152
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
Signal TransductionREACTOMER-HSA-162582
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
SHC-related events triggered by IGF1RREACTOMER-HSA-2428933
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Longevity regulating pathwayKEGGhsa04211
Longevity regulating pathway - multiple speciesKEGGko04213
Longevity regulating pathway - multiple speciesKEGGhsa04213
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
Endocrine resistanceKEGGko01522
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
Endocrine resistanceKEGGhsa01522
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
124832262003IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice.608
183167252008Functionally significant insulin-like growth factor I receptor mutations in centenarians.282
183167252008Functionally significant insulin-like growth factor I receptor mutations in centenarians.282
177615192007Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling.132
117823782002Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling.129
121380942002Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved.125
230827602013Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells.122
116948882001Structure and autoregulation of the insulin-like growth factor 1 receptor kinase.109
145976182004The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase(p110alpha) pathway.109
128431792003Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control.103


Itay Bentov ; Haim Werner

IGF1R (insulin-like growth factor 1 receptor)

Atlas Genet Cytogenet Oncol Haematol. 2008-09-01

Online version: http://atlasgeneticsoncology.org/gene/40928/igf1r-(insulin-like-growth-factor-1-receptor)