How does the binding of an extracellular ligand activate the kinase domain on the other side of the plasma membrane? For a GPCR, ligand binding is thought to change the relative orientation of several of the transmembrane α helices, thereby shifting the position of the cytoplasmic loops relative to one another. It is unlikely, however, that a conformational change could propagate across the lipid bilayer
EGF receptor SS SS SS insulin receptor, NGF receptor FGF receptor CYTOSOL cysteine-immunoglobulin-like domain Eph receptor kinase insert region fbronectin-type-III-like domain
IGF1 PDGF VEGF receptor receptor, receptor MCSF receptor through a single transmembrane α helix. Instead, for most RTKs, ligand binding causes the receptors to dimerize, bringing the two cytoplasmic kinase domains together and thereby promoting their activation (Figure 15–44).
Dimerization stimulates kinase activity by a variety of mechanisms. In many cases, such as the insulin receptor, dimerization simply brings the kinase domains close to each other in an orientation that allows them to phosphorylate each other on specific tyrosines in the kinase active sites, thereby promoting conformational changes that fully activate both kinase domains. In other cases, such as the receptor for epidermal growth factor (EGF), the kinase is not activated by phosphorylation but by conformational changes brought about by interactions between the two kinase domains outside their active sites (Figure 15–45).
Figure 15–43 Some subfamilies of RTKs. Only one or two members of each subfamily are indicated. Note that in some cases, the tyrosine kinase domain is interrupted by a “kinase insert region” that is an extra segment emerging from the folded kinase domain. The functions of most of the cysteine-rich, immunoglobulinlike, and fibronectin-type-III-like domains are not known. Some of the ligands for the receptors shown are listed in Table 15–4, along with some representative responses that they mediate.
Figure 15–44 Activation of RTKs by dimerization. In the absence of extracellular signals, most RTKs exist as monomers in which the internal kinase domain is inactive. Binding of ligand brings two monomers together to form a dimer. In most cases, the close proximity in the dimer leads the two kinase domains to phosphorylate each other, which has two effects. First, phosphorylation at some tyrosines in the kinase domains promotes the complete activation of the domains. Second, phosphorylation at tyrosines in other parts of the receptors generates docking sites for intracellular signaling proteins, resulting in the formation of large signaling complexes that can then broadcast signals along multiple signaling pathways.
Mechanisms of dimerization vary widely among different RTK family members. In some cases, as shown here, the ligand itself is a dimer and brings two receptors together by binding them simultaneously. In other cases, a monomeric ligand can interact with two receptors simultaneously to bring them together, or two ligands can bind independently on two receptors to promote dimerization. In some RTKs—notably those in the insulin receptor family—the receptor is always a dimer (see Figure 15–43), and ligand binding causes a conformational change that brings the two internal kinase domains closer together. Although many RTKs are activated by transautophosphorylation as shown here, there are some important exceptions, including the EGF receptor illustrated in Figure 15–45.
Phosphorylated Tyrosines on RTKs Serve as Docking Sites for Intracellular Signaling Proteins