New Insights from IGF-IR Stimulating Activity Analyses: Pathological Considerations

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.

Novel peptide derived from IGF‐2 displays anti‐angiogenic activity in vitro and inhibits retinal angiogenesis in a model of oxygen‐induced retinopathy

“…(a) Blockage of the canonical signalling pathway: CW‐703 competes with IGFs binding to IGF‐1R and suppresses phosphorylation of IGF‐1R and downstream signalling molecules PI3K/AKT, leading to the reduction of VEGF expression. (b) Blockage of IGF‐1R internalization: IGFs‐induced IGF‐1R autophosphorylation triggers IGF/IGF‐1R complex to internalize via clathrin‐coated pits, subsequently leading to dissociation of IGFs in the intracellular endosome system and recycling of IGF‐1R 32,33 . Since CW‐703 competes with IGFs binding to IGF‐1R and suppresses the autophosphorylation of IGF‐1R, the internalization and recycling of IGF‐1R could be blocked, which disables the sustained IGFs angiogenic activity.…”

“…(b) Blockage of IGF-1R internalization: IGFs-induced IGF-1R autophosphorylation triggers IGF/IGF-1R complex to internalize via clathrin-coated pits, subsequently leading to dissociation of IGFs in the intracellular endosome system and recycling of IGF-1R. 32,33 Since CW-703 competes with IGFs binding to IGF-1R and suppresses the autophosphorylation of IGF-1R, the internalization and recycling of IGF-1R could be blocked, which disables the sustained IGFs angiogenic activity.…”

Lessons Learned from Targeting IGF-I Receptor in Thyroid-Associated Ophthalmopathy

“…In addition to the aforementioned signaling pathway use, IGF-IR can also activate components of GPCR pathways and thus might be considered to be functional tyrosine kinase/GPCR hybrids, integrating kinase signaling with IGF-IR-mediated GPCR features [15,23,24]. IGF-IR may exhibit homologous and heterologous desensitization and biased agonist-like behavior such as that historically considered typical for classical GPCRs [15]. Down-regulation and degradation of the IGF-IR after stimulation by a biased agonist may not only inhibit the "classical" RTK pathways, but paradoxically might stimulate β-arrestin-1-dependent MAPK-pathway activation [25] (Figure 2A Binding of IGF-I to the IGF-IR induces stimulates both the β-arrestin-1 pathway that leads to MAPK activation and proteasome degradation of the IGF-IR through an ubiquitin-mediated mechanism resulting in a loss of the number of IGF-IRs at cellular membrane.…”

Tyrosine phosphorylation-dependent localization of TmaR, a novel E. coli polar protein that controls activity of the major sugar regulator by polar sequestration

“…1G) reveals a slight reduction in the intensity of the band compared to WT. Phosphorylation on multiple residues, depending on the conditions has often been observed in eukaryotes (e.g., (40) (41) (42)). An alternative explanation is that TmaR is phosphorylated on different tyrosine residues depending on the growth phase and the environmental conditions.…”