Figure 1. IGF-1 Signaling Pathway.
IGF-1(Insulin-like growth factor 1), also called somatomedin C, is a protein that in humans is encoded by the IGF1 gene. IGF-1 is an important growth factor secreted by skeletal cells and one of the bone-derived growth factors (BDGF). It can regulate osteoblast function and participate in bone remodeling in various forms. The insulin-like growth factors (IGFs) and their receptors are implicated in the regulation of protein turnover and exert potent mitogenic and differentiating effects on most cell types. IGF-I and IGF-II belong to an integrated growth factor system that includes three hormones (insulin, IGF-I, IGF-II), three receptors, and six binding proteins.
IGF-1 acts as a secretory protein in the body. IGF-1 is unstable in blood and easy to degrade. In order to achieve functional stability, IGF-1 needs to bind to specific IGF binding proteins (IGFBPs) to prolong its half-life so that it can be transported in the blood for a long time and ultimately play a role. Studies have shown that IGFBP can also help IGF-1 recognize target cells, and the activity of IGF-1 is regulated by IGFBP.
The insulin-like growth factor 1 receptor (IGF1R) is a protein found on the surface of human cells. It is a transmembrane receptor that is activated by a hormone called insulin-like growth factor 1 (IGF-1) and by a related hormone called IGF-2. It belongs to the large class of tyrosine kinase receptors. This receptor mediates the effects of IGF-1.
IGF-1 signaling pathway
IGF-1 signaling cascade
The signal transduction of IGFs on the growth axis is mainly through the activation of two signal transduction chains: the phosphoinositide-3 kinase (PI3-K) activation pathway and MAPK kinase activation pathway, which transmit mitotic and metabolic signals to the nucleus of the cells, thereby initiating the secretion of IGFs, promoting cell proliferation, differentiation and inhibiting cell apoptosis. In the IRS-1-mediated PI3-K/Akt pathway, IGF1 ligands bind to receptors, then activate downstream signaling pathways through IRS, CRK, SHC and other proteins, and finally induce metabolic activity through the downstream PI3K (phosphatidylinositol 3-kinase) / PKB (protein kinase B) pathway. After binding to its receptor, insulin substrate 1 (IRS-1) will be phosphorylated first. After IRS-1 is phosphorylated, PI3-K and growth factor binding protein 2 (Grb2) can bind to insulin substrate 1, thereby initiating two signal transduction chains. One pathway is the activation of PI3-K and the formation of phosphoinositol phosphate (PIP3). PIP3 is a signal of cell growth, and PIP3 pathway is the most classical way to inhibit cell apoptosis. Another pathway is to activate extracellular signal-regulated kinase (ERK), which transmits signals into the nucleus and initiates mitosis. It can be concluded that on the one hand, IGF-1 promotes the growth of the body by increasing cell mitosis, on the other hand, inhibiting cell apoptosis.
The binding system of IGFs with IGFBP and its receptors initiates intracellular signaling, which is called the downstream signaling pathway of the growth axis. Its mechanism is that IGF-1 binds to cell surface receptors through IGFBP transport, enhances some intracellular protein expressions related to energy and protein metabolism, promotes cell energy and protein synthesis, and enhances glucose transport and phosphorylation through a signal transduction mechanism. MAPK pathway is also mediated by IRS, which mainly regulates the proliferation and differentiation of tissue cells. In addition, IGF1 also acts through the JAK/STAT pathway. JAK, or Janus Kinase, is a non-receptor tyrosine protein kinase. STAT is a signal transduction and transcription activator that binds to a specific peptide containing phosphotyrosine. When STAT is phosphorylated, it enters the nucleus in the form of activated transcription activator and promotes the transcription of target genes.
IGF-I-induced phosphorylation of IRS-1 results also in the recruitment of the phosphotyrosine phosphatase Syp through its two SH2 domains, leading to increased phosphatase activity and downregulation of hormone-triggered tyrosine phosphorylation events. PTP-1B and PP-2A represent additional phosphatases involved in the fine regulation of IGF-I/insulin-induced signaling.
Relationship with diseases
IGF-1 signaling pathway plays an important role in the occurrence and development of breast cancer through its mechanism of promoting mitosis and inhibiting apoptosis. Studies have shown that 39% to 93% of primary breast cancer patients have an overexpression of IGF-1R, while in normal breast tissues and benign breast lesions, the expression of IGF-1R is low. Overexpression of IGF-1R and elevated circulating levels of IGF-1 are essential for malignant transformation of normal and benign breast cells, which has been widely accepted. IGF-1R signaling pathway can promote cell proliferation by up-regulation of cyclin D1 and CDK4, phosphorylation of Rb protein, release of E2F transcription factor and expression of downstream target gene cyclin E through Ras and AKT signaling pathways. At the same time, it can also inhibit the expression of BAD and FKHR through AKT signaling pathway, and activate anti-apoptotic factors MDM2 and NF-κB to play an anti-apoptotic role. In addition, the activation of IGF-1R signaling pathway can down-regulate the expression of tumor suppressor genes p27, p57 and PTEN, thus promoting the occurrence of breast cancer.
Regarding the IGF-1 signaling pathway as a new target for breast cancer treatment, current research focuses on blocking the activation of IGF-1R by small molecule inhibitors and monoclonal antibodies. Small molecule inhibitors block the signal transduction of IGF-1R by competing to bind ATP sites in the region of IGF-1R tyrosine kinase, which is characterized by high biological efficiency but poor specificity. Insulin receptors (IR), which are highly homologous to IGF-1R, are also inhibited. Monoclonal antibodies block ligand binding by binding to the extracellular domain of IGF-1R, resulting in internalization and degradation of the receptor, characterized by high specificity.
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