Sensitivity of a Cell to External Signals Is Determined by the Number of Cell-Surface Receptors and Their Affinity for Ligand

683

Because the cellular response to a particular signaling molecule depends on the number of receptor-ligand complexes, the fewer receptors for a ligand present on the surface of a cell, the less sensitive the cell is to that ligand. As a consequence, a higher ligand concentration is necessary to induce the physiological response than would be the case if more receptors were present. In contrast, if the level of a receptor for a particular ligand is increased, the cell will become more sensitive to the ligand.

Epidermal growth factor (EGF), as its name implies, stimulates the proliferation of many types of epithelial cells (see Chapters 16 and 20), including those that line the ducts of the mammary gland. In about 25 percent of breast cancers, the tumor cells have elevated levels of one particular EGF receptor called HER2. The overproduction of HER2 makes the cells hypersensitive to ambient levels of EGF and related hormones, which are normally too low to stimulate cell proliferation; as a consequence, growth of these tumor cells is inappropriately stimulated by EGF. We will see in Chapter 24 that an understanding of the role of HER2 in certain breast cancers led to the development of monoclonal antibodies that bind HER2 and thereby block signaling by EGF; these antibodies have proved useful in treatment of breast cancer patients whose tumors overexpress HER2.

The HER2–breast cancer connection vividly demonstrates that regulation of the number of receptors for a given signaling molecule expressed by a cell plays a key role in directing physiological and developmental events. Such regulation can occur at the levels of transcription, translation, and post-translational processing or by control of the rate of receptor degradation. Alternatively, endocytosis of receptors on the cell surface can sufficiently reduce the number present that the cellular response is effectively eliminated. As we discuss in later sections, other mechanisms can reduce a receptor’s affinity for ligand and so reduce the cell’s response to a given concentration of ligand. Thus reduction of a cell’s sensitivity to a particular ligand, called desensitization, which is critical to the ability of cells to respond appropriately to external signals, can result from various mechanisms.