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Amazing RTK structure reveals: Why are their external domains so important for cellular life?
Signal transmission is crucial between cells in organisms. Receptor tyrosine kinases (RTKs), as high-affinity receptors on the cell surface, are responsible for transmitting signals such as various polypeptide growth factors, cytokines, and hormones into cells. According to statistics, 58 of the 90 unique tyrosine kinase genes in the human genome encode receptor tyrosine kinase proteins. These receptors are not only key regulators of normal cellular processes, but also play an important role in the development and progression of various cancers. What impact do the external domains of these RTKs have on the life activities of cells?
The structure and function of RTK
The basic structure of RTK can be summarized as a unit consisting of a transmembrane domain and an intracellular domain. These receptors generally exist as monomers, however some RTKs, such as the insulin receptor, usually exist as dimers and can form disulfide-linked dimers in the presence of hormones such as insulin.
Receptor activation is usually achieved through dimerization and substrate presentation.
The most important part related to the external structure of RTK is its extracellular N-terminal region. This region contains several conserved elements, including immunoglobulin-like structures or epidermal growth factor-like structures, whose presence confers the receptor's ability to bind its ligands.
The process of signal transduction
When growth factors bind to the external domain of RTKs, receptor dimerization is triggered, followed by rapid activation of the receptor's cytoplasmic kinase domain. These kinases first autophosphorylate themselves. This activated receptor will autophosphorylate on multiple specific intracellular tyrosine residues. This process can activate downstream signaling pathways.
Phosphorylation of tyrosine residues in the receptor creates protein interaction sites, thereby opening a series of signal transduction pathways.
Important RTK family
The RTK family is very diverse. There are about 20 known RTK categories, including the epidermal growth factor receptor family (EGFR), the fibroblast growth factor receptor family (FGFR), and the vascular endothelial growth factor receptor family. (VEGFR). Each type of receptor has a unique biological function, and the loss of signal transduction of certain receptors may lead to a variety of diseases in the embryo and nervous system.
Epidermal growth factor receptor family
The epidermal growth factor receptor (EGFR) family consists of four structurally related RTK members. Insufficient signaling in this family is associated with multiple neurodegenerative diseases, while excess signaling is associated with the development of multiple types of tumors.
Fibroblast growth factor receptor family
The fibroblast growth factor family consists of 23 members, which form more than 48 different isoforms through natural alternative splicing.
Vascular endothelial growth factor receptor family
As a major endothelial cell proliferation factor, VEGF mainly promotes blood vessel formation and permeability through binding to VEGFR-1 and VEGFR-2.
Regulatory mechanism of RTK
The RTK signaling pathway is tightly regulated by numerous positive feedback loops, which is critical for preventing serious cell dysfunction such as cancer and fibrosis. Therefore, the regulation of RTKs is a critical part of organismal balance and a potential target for cancer therapy.
Phosphatase is a type of enzyme that can remove phosphate groups on target molecules, thereby regulating RTK activity.
Possibility of disease treatment
Research on RTKs not only deepens our understanding of cell signal transduction, but also provides new directions for the treatment of various diseases. Monoclonal antibodies against RTKs such as Herceptin have been used to treat certain cancers that overexpress the receptor. The success of these treatments has also made receptor tyrosine kinases a hot topic in the development of many new drugs.
Through these studies, we may not only improve treatments for cancer and other related diseases, but may also uncover more secrets of cellular activity. In the future biomedical field, how will the role of RTK further affect the development of cell medicine?
