Abstract
Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-II (IGF-II) play a crucial factor in the growth, differentiation and survival of cells in health and disease. IGF-I and IGF-II primarily activate the IGF-I receptor (IGF-IR), which is present on the cell surface. Activation of the IGF-IR stimulates multiple pathways which finally results in multiple biological effects in a variety of tissues and cells. In addition, activation of the IGF-IR has been found to be essential for the growth of cancers. The conventional view in the past was that the IGF-IR was exclusively a tyrosine kinase receptor and that phosphorylation of tyrosine residues, after binding of IGF-I to the IGF-IR, started a cascade of post-receptor events. Recent research has shown that this view was too simplistic. It has been found that the IGF-IR also has kinase-independent functions and may even emit signals in the unoccupied state through some yet-to-be-defined non-canonical pathways. The IGF-IR may further form hybrids with the insulin receptors but also with receptor tyrosine kinases (RTKs) outside the insulin-IGF system. In addition, the IGF-IR has extensive cross-talk with many other receptor tyrosine kinases and their downstream effectors. Moreover, there is now emerging evidence that the IGF-IR utilizes parts of the G-protein coupled receptor (GPCR) pathways: the IGF-IR can be considered as a functional RTK/GPCR hybrid, which integrates the kinase signaling with some IGF-IR mediated canonical GPCR characteristics. Like the classical GPCRs the IGF-IR can also show homologous and heterologous desensitization. Recently, it has been found that after activation by a ligand, the IGF-IR may be translocated into the nucleus and function as a transcriptional cofactor. Thus, in recent years, it has become clear that the IGF-IR signaling pathways are much more complex than first thought. Therefore a big challenge for the (near) future will be how all the new knowledge about IGF-IR signaling can be translated into the clinical practice and improve diagnosis and treatment of diseases.
Highlights
The insulin-IGF system is formed by insulin, two insulin-like growth factors (IGF-I and insulin-like growth factor-II (IGF-II)), four cell-membrane receptors (insulin receptor-A (IR-A), insulin receptor-B (IR-B), insulin-like growth factor-I receptor (IGF-IR) and insulin-like growth factor receptor-II (IGF-II-R)) and six IGF-binding proteins (IGFBP-1-6), several Insulin-like Growth Factor Binding Proteins (IGFBPs)- related proteins and IGFBP proteases [1,2,3,4]
Utilizes parts of the G-protein coupled receptor (GPCR) pathways: the IGF-I receptor (IGF-IR) can be considered as a functional receptor tyrosine kinases (RTKs)/GPCR hybrid, which integrates the kinase signaling with some IGF-IR mediated canonical GPCR characteristics
The IGF-IR is considered to be a functional RTK/GPCR hybrid, which integrates the kinase signaling with some IGF-IR mediated canonical GPCR characteristics [62]
Summary
The insulin-IGF system is formed by insulin, two insulin-like growth factors (IGF-I and IGF-II), four cell-membrane receptors (insulin receptor-A (IR-A), insulin receptor-B (IR-B), insulin-like growth factor-I receptor (IGF-IR) and insulin-like growth factor receptor-II (IGF-II-R)) and six IGF-binding proteins (IGFBP-1-6), several IGFBP- related proteins and IGFBP proteases [1,2,3,4]. The IGF-I gene comprises a highly conserved sequence and contains six exons, which give rise to heterogeneous mRNA transcripts by a combination of multiple transcription initiation sites and alternative splicing [7]. These multiple transcripts code in humans for different precursor IGF-I polypeptides, namely the IGF-IEa, IGF-IEb and IGF-IEc isoforms, which undergo posttranslational. The IR-B is predominantly expressed in the liver, muscles and fat cells, the major target tissues for the metabolic effects of insulin [14]. Binding of insulin to the IR-A will predominantly induce growth-promoting effects in fetal tissues and tumors. In contrast to IR-B, the IR-A may bind IGF-II with high affinity and thereby stimulate growth-promoting effects [14].
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