14.4 Many Elements Recur with Variation in Different Signal-Transduction Pathways

1. Protein kinases are central to many signal-transduction pathways. Protein kinases are central to all three signal-transduction pathways described in this chapter. In the epinephrine-initiated pathway, cAMP-dependent protein kinase (PKA) lies at the end of the pathway, transducing information represented by an increase in cAMP concentration into covalent modifications that alter the activity of key metabolic enzymes. In the insulin- and EGF-initiated pathways, the receptors themselves are protein kinases and several additional protein kinases participate downstream in the pathways. Signal amplification due to protein kinase cascades is a feature common to all three pathways. Although not presented in this chapter, protein kinases often phosphorylate multiple substrates and are thus able to generate a diversity of responses.

2. Second messengers participate in many signal-transduction pathways. We have encountered several second messengers, including cAMP, Ca²⁺, IP₃, and the lipid DAG. Because second messengers are generated by enzymes or by the opening of ion channels, their concentrations can be tremendously amplified compared with the signals that lead to their generation. Specialized proteins sense the concentrations of these second messengers and continue the flow of information along signal- transduction pathways.

   The second messengers that we have seen recur in many additional signal-transduction pathways. For example, in a consideration of the sensory systems in Chapter 33, we will see how Ca²⁺-based signaling and cyclic nucleotide-based signaling play key roles in vision and olfaction.

3. Specialized domains that mediate specific interactions are present in many signaling proteins. The “wiring” of many signal-transduction pathways is based on particular protein domains that mediate the interactions between protein components of a particular signaling cascade. We have encountered several of them, including pleckstrin homology domains, which facilitate protein interactions with the lipid PIP₃; SH2 domains, which mediate interactions with polypeptides containing phosphorylated tyrosine residues; and SH3 domains, which interact with peptide sequences that contain multiple proline residues. Many other such domain families exist. In many cases, individual members of each domain family have unique features that allow them to bind to their targets only within a particular sequence context, making them specific for a given signaling pathway and avoiding unwanted cross-talk. Signal-transduction pathways have evolved in large part by the incorporation of DNA fragments encoding these domains into genes encoding pathway components.

   The presence of these domains is tremendously helpful to scientists trying to unravel signal-transduction pathways. When a protein in a signal-transduction pathway is identified, its amino acid sequence can be analyzed for the presence of these specialized domains by the methods described in Chapter 6. If one or more domains of known function is found, it is often possible to develop clear hypotheses about potential binding partners and signal-transduction mechanisms.