Structure and function of the type 1 insulin-like growth factor receptor

Abstract

The type 1 insulin-like growth factor receptor (IGF-1R), a transmembrane tyrosine kinase, is widely expressed across many cell types in foetal and postnatal tissues. Activation of the receptor following binding of the secreted growth factor ligands IGF-1 and IGF-2 elicits a repertoire of cellular responses including proliferation, and the protection of cells from programmed cell death or apoptosis. As a result, signalling through the IGF-1R is the principal pathway responsible for somatic growth in foetal mammals, whereas somatic growth in postnatal animals is achieved through the synergistic interaction of growth hormone and the IGFs. Forced overexpression of the IGF-1R results in the malignant transformation of cultured cells: conversely, downregulation of IGF-1R levels can reverse the transformed phenotype of tumour cells, and may render them sensitive to apoptosis in vivo. Elevated levels of IGF-IR are observed in a variety of human tumour types, whereas epidemiological studies implicate the IGF-1 axis as a predisposing factor in the pathogenesis of human breast and prostate cancer. The IGF-1R has thus emerged as a therapeutic target for the development of antitumour agents. Recent progress towards the elucidation of the three-dimensional structure of the extracellular domain of the IGF-1R represents an opportunity for the rational assembly of small molecule antagonists of receptor function for clinical use.

Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1

“…The insulin-like growth factor 1 receptor (IGF-1R), a tetrameric receptor tyrosine kinase (RTK), is important for transformation, proliferation of malignant cells (Baserga, 1995;Baserga et al, 1997;Adams et al, 2000;LeRoith and Roberts, 2003;Larsson et al, 2005), crucial for preventing apoptosis, maintaining malignant phenotype and for resistance to chemotherapy (Baserga, 1995(Baserga, , 2000Yu and Rohan, 2000;Samani et al, 2007).…”

“…Numerous studies have demonstrated that the IGF-1R is overexpressed in multiple cancer types (Xie et al, 1999;Adams et al, 2000;All-Ericsson et al, 2002;Loughran et al, 2005). The elevated expression of IGF-1R in neoplastic cells combined with its crucial roles in malignant growth makes IGF-1R an attractive target in cancer therapy.…”

The insulin-like growth factor-1 receptor inhibitor PPP produces only very limited resistance in tumor cells exposed to long-term selection

“…The importance of IGF-1R in human cancer has raised therapeutic possibilities (Rohlik et al, 1987;Adams et al, 2000;Brodt et al, 2000;Girnita et al, 2000b;Kanter-Lewensohn et al, 2000;Navab et al, 2001; All-Ericsson et al, 2002; Larsson et al, 2005). We recently demonstrated that the cyclolignan PPP specifically inhibits the IGF-1R activity , where it did not inhibit the highly homologous insulin receptor .…”

Role of insulin-like growth factor 1 receptor signalling in cancer

“…The IGF-2R/6-mannose receptor is a monomeric receptor without TK activities. Both IGF-1R and IR are preformed dimeric TK receptors made up by two extracellular a-subunits and two b-subunits involving a small extracellular domain, an intramembraneous one as well as an intracellular domain (Adams et al, 2000). The latter includes the juxtamembraneous domain, the TK domain and the C-terminal domain.…”