Type 1 Insulin-like Growth Factor Receptor
The IGF signalling system can be briefly summarised as follows. Signalling by IGF I is mediated by IGF-1R, which binds IGF I with high affinity. Signalling by IGF II is also mediated by IGF-1R (which binds IGF II with ~20% affinity for IGF I) and by the exon 11 minus isoform (IR A) of IR. An expanding repertoire of intra cellular proteins act as substrates/effectors of ligand activated IGF-1R signalling. The bioavailability of IGF I and IGF II is regulated by six soluble IGF binding proteins IGFBP 1, 2, 3, 4, 5 and 6 whilst the bioavailability of IGF II is further regulated by the Type 2 IGF receptor (IGF 2R).
IGF-1R is involved in normal growth and development. However, there is a compelling body of evidence for the involvement of the IGF signalling system in cancer progression. The critical role of IGF-1R in tumorigenesis is highlighted by the fact that fibroblasts from IGF-1R null mice are resistant to oncogenic transformation. Over expression of IGF-1R in mice has been shown to accelerate the invasion and growth of tumors and mice expressing constitutively active IGF-1R have been shown to develop invasive adenocarcinomas. It has been shown that humans with levels of circulating IGF I at the high end of the population distribution have an increased risk of cancer. Over-expression of IGF I, IGF II and/or IGF-1R has been detected in a number of different tumor types. Taken together, these results strongly suggest that antagonists of IGF-1R and the hybrid receptors may be anti cancer therapeutics.
We now are seeking to use structural biology techniques to determine the three dimensional structure of the IGF-1R ectodomain both in its native and ligand bound conformations.