Cell signalling
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# 2.3.3 Receptors with intrinsic enzymatic activity

Receptors with intrinsic enzymatic activity are the second biggest group of receptors after the GPCRs. They include four types according to the form of enzymatic activity of the intracellular domain (Figure 23a).

- Receptor tyrosine kinases (RTKs) On activation, the kinase domain phosphorylates tyrosine amino acid residues. There are seven classes of RTK with different extracellular domains (Figure 23b).

- Receptor serine–threonine kinases On activation, the kinase domain phosphorylates serine and/or threonine amino acid residues.

- Receptor tyrosine phosphatases The intrinsic tyrosine phosphatase activity of the enzymatic domain is suppressed on activation.

- Receptor guanylyl cyclases The enzymatic domain generates the second messenger cGMP from GTP following activation.

Figure 23 (a) The four classes of receptors with intrinsic enzymatic activity. Note that the kinase domains can phosphorylate residues located on the other receptor chain (autophosphorylation) or on other signalling proteins (as shown here). Note that receptors with intrinsic enzymatic activity with the exception of tyrosine phosphatases, have been represented in their active state, that is, following the formation of dimers by the extracellular ligand. In contrast to other receptors, receptor tyrosine phosphatases suppress their enzymatic activity upon ligand binding. (b) The seven subfamilies of receptor tyrosine kinases (RTK). The functional role of most of the cysteine-rich, immunoglubulin-like, and fibronectin-like extracellular domains are not known. Only one member of each subfamily is indicated. Note that the PDGF, FGF and VEGF receptors have a split tyrosine kinase domain; the PDGF receptor is shown in more detail in Figure 25. (EGF = epidermal growth factor; NGF = nerve growth factor; PDGF = platelet-derived growth factor; FGF = fibroblast growth factor; VEGF = vascular endothelial growth factor; Eph = ephrin.)

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).

Although there can be a great deal of variation in the extracellular domains of RTKs (Figure 23b) and in the ways the extracellular signal binds to its receptor, the basic mechanism of receptor activation still applies (Figure 24). Association between receptors results in cross-phosphorylation of the kinase domain on each intracellular tail of the RTK, a process called autophosphorylation. This results in an increase in its intrinsic kinase activity, which causes phosphorylation of tyrosines in other parts of the cytoplasmic domain (and/or other proteins). Autophosphorylation generates docking sites on the receptor for downstream signalling proteins that contain SH2 domains.

Many proteins can bind to phosphotyrosine (pY) residues, but these interactions are influenced by nearby amino acid side-chains (see previous section). For example, the PDGF receptor has specific phosphotyrosine sites, which can bind the regulatory (p85) subunit of phosphatidylinositol 3-kinase (PI 3-kinase), a GTPase-activating protein (p120 RasGAP) and phospholipase C-g (PLC-γ), among others (Figure 25). The insulin receptor extends its docking potential by associating with a large protein, insulin receptor substrate 1 (IRS-1), which has many tyrosine residues that can be phosphorylated by the insulin receptor (Section 4). These proteins are called ‘docking proteins’ and may be activated by being directly phosphorylated by the RTK, or by interactions with other docking proteins or plasma membrane molecules. Some docking proteins are adaptor proteins that merely serve to bring other signalling molecules into place. The overall effect of this system is the recruitment of many different signalling pathways, allowing the modulation of many cellular processes.

Figure 25 Some of the binding (docking) sites on the activated PDGF receptor for SH2-containing proteins. (The domain structure of these proteins is shown in Figure 1.13.) Note that these are not the only autophosphorylation sites on the PDGF receptor. Additional phosphorylated tyrosines are docking sites for other SH2-containing proteins (not shown). For simplicity, only one PDGF receptor chain and one PDGF monomer are shown here.
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