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The receptor tyrosine kinases (RTKs) are the second major type of cell-surface receptors. The ligands for RTKs are soluble or membrane-bound peptide/protein hormones including nerve growth factor (NGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and insulin. Binding of a ligand to this type of receptor stimulates the receptor’s intrinsic protein-tyrosine kinase activity, which subsequently stimulates a signal-transduction cascade leading to changes in cellular physiology and/or patterns of gene expression. RTK signaling pathways have a wide spectrum of functions including regulation of cell proliferation and differentiation, promotion of cell survival, and modulation of cellular metabolism.
Some RTKs have been identified in studies on human cancers associated with mutant forms of growth-factor receptors, which send a proliferative signal to cells even in the absence of growth factor. One such mutant receptor, encoded at the neu locus, contributes to the uncontrolled proliferation of certain human breast cancers. Other RTKs have been uncovered during analysis of developmental mutations that lead to blocks in differentiation of certain cell types in C. elegans, Drosophila, and the mouse.
All RTKs comprise an extracellular domain containing a ligand-binding site, a single hydrophobic transmembrane α helix, and a cytosolic domain that includes a region with protein-tyrosine kinase activity. Binding of ligand causes most RTKs to dimerize; the protein kinase of each receptor monomer then phosphorylates a distinct set of tyrosine residues in the cytosolic domain of its dimer partner, a process termed autophosphorylation (Figure 20-21). Autophosphorylation occurs in two stages. First, tyrosine residues in the phosphorylation lip near the catalytic site are phosphorylated. This leads to a conformational change that facilitates binding of ATP in some receptors (e.g., the insulin receptor) and binding of protein substrates in other receptors (e.g., FGF receptor). The receptor kinase activity then phosphorylates other sites in the cytosolic domain; the resulting phosphotyrosines serve as docking sites for other proteins involved in RTK-mediated signal transduction.