| Description | 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. |
| Expression | The IGF1R is abundantly expressed in the embryo, with significant reduction in expression levels at adult stages. |
| Localisation | 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. |
| Function | 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. |
| Entity | Various tumors |
| Note | 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. |
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