The basic model of activation for receptors with intrinsic enzymatic activity is that ligand binding induces dimerization (in some cases oligomerization) of the receptor, which brings together the cytoplasmic enzymatic domains and leads to a change in enzymatic activity. Dimerization may occur between different receptors that bind the same ligand (heterodimerization), or between the same type of receptor chains (homodimerization), or either. RTKs, RTPs and guanylyl cyclase receptors generally form homodimers (an exception being the epidermal growth factor (EGF) receptor tyrosine kinase), whereas receptor serine–threonine kinases generally form heterodimers. In some cases, oligomerization of several receptors is required for activation.
We shall now describe the general mechanism of activation of RTKs in more detail. There are several strategies by which an extracellular signal may achieve RTK dimerization leading to activation of the receptor:
- Ligands such as EGF, which is a monomer, have two binding sites for each receptor unit.
- Platelet-derived growth factor (PDGF) is a covalently linked dimer, in which one subunit binds to one PDGF receptor chain, and the other subunit binds to another PDGF receptor chain (Figure 24).
- Fibroblast growth factor (FGF) binds to proteoglycans (located on the cell surface or on the extracellular matrix) and induces clustering of FGF receptors.
- Ephrins are bound to the plasma membrane of the signalling cell in clusters, and thereby induce association of their receptors (called Eph receptors) on the target cells following cell–cell contact.
- The insulin receptor is a tetramer prior to binding insulin: on insulin binding, activation occurs by rearrangement of the different receptor chains that brings the kinase domains in close proximity.
Figure 24 RTKs are activated by autophosphorylation of their intracellular kinase domains following dimerization in response to binding the extracellular signal (in this example, a dimer such as PDGF).
