Ligand-Regulated Transmembrane Enzymes Including Receptor Tyrosine Kinases

Ligand-Regulated Transmembrane Enzymes Including Receptor Tyrosine Kinases

This class of receptor molecules mediates the first steps in signaling by insulin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), atrial natriuretic peptide (ANP), trans-forming growth factor-β (TGF-β), and many other trophic hor-mones. These receptors are polypeptides consisting of an extracellular hormone-binding domain and a cytoplasmic enzyme domain, which may be a protein tyrosine kinase, a serine kinase, or a guanylyl cyclase (Figure 2–7). In all these receptors, the two domains are connected by a hydrophobic segment of the polypep-tide that crosses the lipid bilayer of the plasma membrane.

The receptor tyrosine kinase signaling pathway begins with binding of ligand, typically a polypeptide hormone or growth fac-tor, to the receptor’s extracellular domain. The resulting change in receptor conformation causes two receptor molecules to bind to one another (dimerize), which in turn brings together the tyrosine kinase domains, which become enzymatically active, and phos-phorylate one another as well as additional downstream signaling proteins. Activated receptors catalyze phosphorylation of tyrosine residues on different target signaling proteins, thereby allowing a single type of activated receptor to modulate a number of bio-chemical processes. (Some receptor tyrosine kinases form oligo-meric complexes larger than dimers upon activation by ligand, but the pharmacologic significance of such higher-order complexes is presently unclear.)

Insulin, for example, uses a single class of receptors to trigger increased uptake of glucose and amino acids and to regulate metabolism of glycogen and triglycerides in the cell. Similarly, each of the growth factors initiates in its specific target cells a complex program of cellular events ranging from altered mem-brane transport of ions and metabolites to changes in the expres-sion of many genes.

Inhibitors of receptor tyrosine kinases are finding increased use in neoplastic disorders in which excessive growth factor signaling is often involved. Some of these inhibitors are monoclonal anti-bodies (eg, trastuzumab, cetuximab), which bind to the extracel-lular domain of a particular receptor and interfere with binding of growth factor. Other inhibitors are membrane-permeant “small molecule” chemicals (eg, gefitinib, erlotinib), which inhibit the receptor’s kinase activity in the cytoplasm.

The intensity and duration of action of EGF, PDGF, and other agents that act via receptor tyrosine kinases are limited by a processcalled receptor down-regulation. Ligand binding often induces accelerated endocytosis of receptors from the cell surface, followed by the degradation of those receptors (and their bound ligands). When this process occurs at a rate faster than de novo synthesis of receptors, the total number of cell-surface receptors is reduced (down-regulated), and the cell’s responsiveness to ligand is corre-spondingly diminished. A well-understood example is the EGF receptor tyrosine kinase, which undergoes rapid endocytosis fol-lowed by proteolysis in lysosomes after EGF binding; genetic mutations that interfere with this process cause excessive growth factor-induced cell proliferation and are associated with an increased susceptibility to certain types of cancer. Endocytosis of other receptor tyrosine kinases, most notably receptors for nerve growth factor, serves a very different function. Internalized nerve growth factor receptors are not rapidly degraded and are translo-cated in endocytic vesicles from the distal axon, where receptors are activated by nerve growth factor released from the innervated tissue, to the cell body. In the cell body, the growth factor signal is transduced to transcription factors regulating the expression of genes controlling cell survival. This process effectively transports a critical survival signal from its site of release to its site of signaling effect, and does so over a remarkably long distance—up to 1 meter in certain sensory neurons.

A number of regulators of growth and differentiation, including TGF-β, act on another class of transmembrane receptor enzymes that phosphorylate serine and threonine residues. ANP, an impor-tant regulator of blood volume and vascular tone, acts on a trans-membrane receptor whose intracellular domain, a guanylyl cyclase, generates cGMP . Receptors in both groups, like the receptor tyrosine kinases, are active in their dimeric forms.