Receptor tyrosine kinases, or RTKs, are single mem brane spanning receptors and are defined by the presence of tyrosine kinase activity as the main cytoplasmic constituent and initiator of signal transduction. There are 58 receptor tyrosine kinases encoded in the human genome, several of which are important in hormone signaling. Figure 1 illustrates some of the differences in structure seen in this type of receptor. In their monomeric forms RTKs are single membrane-spanning receptors. However, these receptors dimerize upon the binding of one ligand molecule, two ligand molecules, or one ligand dimer. In some cases, closely related receptors (e.g., EGFR and HER2) in the same cell may heterodimerize. The insulin and IGF-1 receptors, members of the same family, are an exception to this pat tern. They exist as dimers of two hemireceptors, each consisting of two subunits, the extracellular α-subunit and the intracellular β-subunit, joined by disulfide bonds. A further set of disulfide bonds joins the two hemireceptors to form the dimerized receptor that then binds one molecule of ligand.
Fig1. General structure of receptor tyrosine kinases. The structural features of the receptor tyrosine kinases (RTK) are illustrated in three examples: the epidermal growth factor receptor (EGFR); the Ins/IGF-1 receptor; and the fibroblast growth factor receptor (FGFR). The RTKs are single membrane spanning proteins with a variable extracellular N-terminal region and a cytoplasmic carboxyl portion that contains the catalytic activity to phosphorylate tyrosines (tyrosine kinase; blue) in itself (autophosphorylation) or in nearby proteins. In some receptors (e.g., insulin, FGF), the catalytic domain is split by a non-tyrosine kinase sequence. Examples of N-terminal region motifs include cysteine rich sequences (gold), fibronectin type III-like regions (green), a series of IgG (immunogammaglobulin; blue) regions, and the acid box (red) as seen between the first and second IgG sequence in the FGF receptor. Most RTKs are monomers that dimerize upon ligand binding. The members of the insulin/ IGF-1 family, however, exist as a dimer of disulfide-linked monomers, each consisting of two subunits.
The N-terminal extracellular ligand binding domains of RTKs consist of one or a few of about 20 structural motifs. In the examples of RTKs in Figure 1, cysteine rich regions appear in the EGF and insulin/IGF-1 families, whereas the FGFR (fibroblast growth factor receptor) family, along with several others not shown here, consists of a group of IgG (immunogammaglobulin) like domains. The carboxy terminals differ primarily in whether the tyrosine kinase catalytic domain is present as a contiguous sequence of amino acids or whether it is interrupted by a stretch of up to 100 non-TK amino acids, as in the insulin/IGF-1 receptors and FGFR. This is referred to as a split tyrosine kinase domain. The insertion has autophosphorylation sites, which suggests that it may be important in interacting with signal-transducing molecules.
