4 Signal Transduction and Intracellular Messengers

Abstract

I. OVERVIEW
Rapidly accumulating evidence indicates that many proto-oncogene proteins, especially those found in the cytoplasm and at the plasma membrane, act as detectors and generators of chemical signals in normal cells. These signals are called hormones or “second messengers,” depending on whether they are found in the extracellular fluid or inside cells. This chapter describes several well-studied signaling pathways. Of these, some serve only to illustrate the organization and principles that underlie cellular regulation by chemical signals, whereas other pathways may, in addition, be directly affected by oncogene-encoded proteins.

Organisms have evolved a number of molecular strategies for transducing extracellular signals across the bilayer (Fig. 1). The simplest (S1 in the figure) uses a hormonal signal that is itself sufficiently lipid soluble to be able to cross the membrane and act on an intracellular receptor (e.g., cortisol, thyroid hormones). Alternatively, a receptor oriented toward the exterior of the cell can transport the extracellular ligand itself into the cell by endocytosis of membrane vesicles (S2, e.g., cholesterol carried by the low-density lipoprotein receptor). Some signal transducers are transmembrane receptor proteins, in which binding of the ligand (S3) to a site on the extracellular portion of the receptor triggers an enzymatic activity located in an intracellular domain of the same polypeptide; examples in the family of receptors with protein tyrosine kinase activity include receptors for insulin, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF). At synapses and neuromuscular junctions, neurotransmitters (S4, including acetylcholine and γ-aminobutyric acid) act by binding to...