Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

SIGNALING THROUGH ENZYME-COUPLED RECEPTORS
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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 TGFβ superfamily, act similarly: they directly
phosphorylate and activate Smads, which then oligomerize with another Smad,
translocate to the nucleus, and regulate gene transcription.
ALTERNATIVE SIGNALING ROUTES IN GENE
REGULATION
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
Signaling through the Notch receptor protein is used widely in animal development.
As discussed in Chapter 22, it has a general role in controlling cell fate
choices and regulating pattern formation during the development of most tissues,
as well as in the continual renewal of tissues such as the lining of the gut. It is best
known, however, for its role in the production of Drosophila neural cells, which
usually arise as isolated single cells within an epithelial sheet of precursor cells.
During this process, when a precursor cell commits to becoming a neural cell, it
signals to its immediate neighbors not to do the same; the inhibited cells develop
into epidermal cells instead. This process, called lateral inhibition, depends on a
contact-dependent signaling mechanism that is activated by a single-pass transmembrane
signal protein called Delta, displayed on the surface of the future
neural cell. By binding to the Notch receptor protein on a neighboring cell, Delta