Ligand binding to RTKs causes their dimerization, which leads to activation of their kinase domains. These activated kinase domains phosphorylate multiple tyrosines on the receptors, producing a set of phosphotyrosines that serve as docking sites for a set of intracellular signaling proteins, which bind via their SH2 (or PTB) domains. One such signaling protein serves as an adaptor to couple some activated receptors to a Ras-GEF (Sos), which activates the monomeric GTPase Ras; Ras, in turn, activates a three-component MAP kinase signaling module, which relays the signal to the nucleus by phosphorylating transcription regulatory proteins. Another important signaling protein that can dock on activated RTKs is PI 3-kinase, which phosphorylates specific phosphoinositides to produce lipid docking sites in the plasma membrane for signaling proteins with phosphoinositide-binding PH domains, including the serine/threonine protein kinase Akt (PKB), which plays a key part in the control of cell survival and cell growth. Many receptor classes, including some RTKs, activate Rho family monomeric GTPases, which functionally couple the receptors to the cytoskeleton.
Tyrosine-kinase-associated receptors depend on various cytoplasmic tyrosine kinases for their action. These kinases include members of the Src family, which associate with many kinds of receptors, and the focal adhesion kinase (FAK), which associates with integrins at focal adhesions. The cytoplasmic tyrosine kinases then phosphorylate a variety of signaling proteins to relay the signal onward. The largest family of receptors in this class is the cytokine receptor family. When stimulated by ligand binding, these receptors activate JAK cytoplasmic tyrosine kinases, which phosphorylate STATs. The STATs then dimerize, translocate to the nucleus, and activate the transcription of specific genes. Receptor serine/threonine kinases, which are activated by signal proteins of the TGFβsuperfamily, act similarly: they directly phosphorylate and activate Smads, which then oligomerize with another Smad, translocate to the nucleus, and regulate gene transcription.
Major changes in the behavior of a cell tend to depend on changes in the expression of numerous genes. Thus, many extracellular signaling molecules carry out their effects, in whole or in part, by initiating signaling pathways that change the activities of transcription regulators. There are numerous examples of gene regulation in both GPCR and enzyme-coupled receptor pathways (see Figures 15–27 and 15–49). In this section, we describe some of the less common signaling mechanisms by which gene expression can be controlled. We begin with several pathways that depend on regulated proteolysis to control the activity and location of latent transcription regulators. We then turn to a class of extracellular signal molecules that do not employ cell-surface receptors but enter the cell and interact directly with transcription regulators to perform their functions. Finally, we briefly discuss some of the mechanisms by which gene expression is controlled by the circadian rhythm: the daily cycle of light and dark.
The Receptor Notch Is a Latent Transcription Regulatory Protein