[The signal transduction of receptor tyrosine kinase].
Polypeptides such as growth factors, differentiation factors, and hormones are crucial components of the regulatory system that coordinates development of multicellular organisms. Many of these factors mediate their pleiotropic actions by binding to and activating cell surface receptors with an intrinsic protein tyrosine kinase activity. The receptor activation due to ligands binding are translated across the membrane barrier into activation of intracellular domain functions. All receptor tyrosine kinase are composed of three major domains; an extracellular domain connected via a single membrane-spanning domain to a cytoplasmic domain. The extracellular domain is responsible for ligand binding and transmission of the biological signal to the cytoplasmic domain, whose role is to transmit the biological signal to intracellular target proteins. The cytoplasmic domain contains, in addition to the catalytic protein tyrosine kinase, distinct regulatory sequences with tyrosine, serine, and threonine phosphorylation sites. It appears that ligand-induced activation of the kinase domain and its signaling potential are mediated by receptor oligomerization. Ligand binding and the subsequent conformational alteration of the extracellular domain induce receptor oligomerization, which stabilizes interaction between adjacent cytoplasmic domains and leads to activation of kinase function and autophosphorylation of themselves. These receptor and substrate phosphorylation create binding sites for SH2 containing signaling molecule, such as Grb2, Shc, PI3 kinase and SHP-2. Binding of SH2 domains to tyrosine-phosphorylated regions of receptors or adaptor proteins, and a number of protein, such as SH3 containing protein, cytosol protein tyrosine kinase, protein tyrosine phosphatase and serine/threonine kinase, mediate intracellular signaling cascade and play critical roles in activated receptor protein tyrosine kinase to downstream signaling pathways.
Second Department of Internal Medicine, Kobe University School of Medicine.
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Takada
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Matozaki
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Kasuga
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D018909:src Homology Domains / Q000502:physiology
D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases