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The hidden power of growth factors: How do RTKs trigger a chain reaction of cell signaling?
Receptor Tyrosine Kinases (RTKs) are high-affinity receptors on the cell surface, responsible for receiving a variety of peptide growth factors, cytokines and hormones. According to research on the human genome, 90 unique tyrosine kinase genes have been identified, 58 of which encode receptor tyrosine kinases. RTKs are not only key regulators of normal cellular processes, but also play an important role in the development and progression of various cancers.
Mutation of receptor tyrosine kinases can lead to the activation of signaling chain reactions and have multiple effects on protein expression.
Structure and function of RTKs
Most RTKs are single-subunit receptors, but some receptors exist in multimeric complexes, such as in the insulin receptor, which forms a disulfide-linked dimer in the presence of insulin. Each monomer possesses a hydrophobic transmembrane region consisting of 25 to 38 amino acids, as well as an extracellular N-terminal region and an intracellular C-terminal region. The extracellular N-terminal region contains a variety of conserved elements, such as immunoglobulin (Ig)-like regions or epidermal growth factor (EGF)-like regions, and these features are unique to each RTK subfamily.
The intracellular C-terminal region shows the highest conservation and contains the catalytic region responsible for kinase activity, which enables the receptor to catalyze its own autophosphorylation and tyrosine phosphorylation of downstream RTK substrates.
Signal transduction mechanism
When growth factors bind to the extracellular domain of RTKs, they trigger the dimerization of adjacent RTKs and rapidly activate the cytoplasmic kinase domain of the protein. At this point, the receptor itself will become the first substrate of the kinase network and undergo autophosphorylation. This phosphorylation changes the structure of the receptor, providing binding sites for other proteins containing Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains, thereby initiating various signal transduction pathways.
Activation of RTKs can initiate multiple signal transduction pathways simultaneously, which makes them crucial in regulating cell proliferation, differentiation and other processes.
RTK family differences
RTKs can be divided into multiple families, including epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR). For example, insufficient signaling of the EGFR family leads to the development of neurodegenerative diseases, while excessive EGFR signaling leads to the formation of a variety of solid tumors.
Vascular endothelial growth factor (VEGF) is a major factor that promotes endothelial cell proliferation and vascular permeability, and its receptor VEGFR mediates almost all known cellular responses that interact with VEGF.
Regulatory mechanism of RTK
Receptor tyrosine kinase signaling pathways are strictly regulated by multiple positive feedback mechanisms. Because RTKs coordinate numerous cellular functions, excessive or insufficient signaling may lead to serious cellular dysfunction such as cancer and fibrosis. Protein tyrosine phosphatases (PTPs) can terminate signal transmission by dephosphorylating activated RTKs, and some PTPs can positively regulate signal transduction and promote cell proliferation.
Herstatin is an auto-inhibitor that can interfere with the receptor function of the ErbB family, thereby reducing cell proliferation and signaling activity.
RTK in drug therapy
Due to their important role in a variety of cellular abnormalities, including cancer, degenerative diseases, and cardiovascular diseases, RTKs have become ideal targets for drug therapy. The U.S. Food and Drug Administration (FDA) has approved several anticancer drugs targeting RTKs, such as Herceptin, which binds to the extracellular region of RTKs and is used to treat HER2-overexpressing breast cancer.
How can we use the properties of these receptors to develop more targeted and effective treatment options to improve existing cancer treatments?
