Three receptors form six distinct receptor combinations: IGF receptors type 1 and type 2 (IGF-1R and IGF-2R), insulin receptors A and B (IR-A and IR-B), and hybrid receptors (IGF-1R/IR-A and IGF-1R/IR-B) [10
]. The possible role of insulin and hybrid receptors in human cancers has been reviewed [11
]. IGF-2R preferentially binds IGF-II [5
]. However, IGF-2R lacks an intracellular kinase domain, precluding its ability to mediate cell signaling [4
]. This also helps explain the finding that loss of IGF-2R results in increased tumorigenicity, presumably by increasing the availability of IGF-II to bind to IGF-1R [12
]. The remainder of this review focuses on IGF-1R.
All of the IGF receptors have significant homology, thus resulting in structural similarity and the possibility of signaling crosstalk [10
]. IGF-1R is a tetrameric receptor consisting of two α-subunits and two transmembrane β-subunits that are linked by disulfide bonds [13
]. The α-subunits are extracellular and bind IGF. Each transmembrane β-subunit contains an intracellular tyrosine kinase domain.
Binding of IGF-I or IGF-II ligand to IGF-1R leads to phosphorylation of three key tyrosine residues in the kinase domain, leading to phosphorylation of downstream substrates [13
]. In addition, phosphorylation of additional tyrosine residues in other areas of the β-subunit provide “docking sites” that allow for the recruitment of adaptor proteins [14
]. Insulin receptor substrate family members are some of the many adaptor proteins that are known to have an important role in IGF-1R signaling [15
]. Phosphorylation of adaptor proteins leads to binding of additional proteins, allowing for signal transduction along several specific pathways (). Some of the key pathways and their endpoints include phosphorylation of mitogen-activated protein kinase (MAPK) and a subsequent increase in proliferation, activation of phosphatidylinositol 3′ kinase (PI3K), leading to decreased apoptosis, and modulation of mammalian target of rapamycin (mTOR), resulting in translational adaptation [13
Figure 1 Downstream targets of IGF-1R. The binding of IGF-I or IGF-II to IGF-1R results in autophosphorylation of tyrosine residues in the receptor. This leads to activation of the kinase domain and also provides the docking sites necessary for adaptor proteins (more ...)
In normal cells, tyrosine kinase receptor activity is tightly regulated, allowing for homeostatic growth. In tumor cells, these same molecules are activated, either by mutation, chromosomal translocation, abnormal stimulation (autocrine, endocrine, or paracrine), or loss of genomic imprinting. For the IGF pathway, dysregulation of the latter two appears to be most relevant. There is considerable evidence for a key role of IGF signaling in many pediatric malignancies. Specifics for each tumor type are discussed in subsequent sections.