Signaling Pathways That Control Gene Activity

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Fluorescence resonance energy transfer (FRET) detects time and location of activation of Ras protein in live cells triggered by epidermal growth factor. [Michiyuki Matsuda, Research Institute for Microbial Diseases, Osaka University.]

The development of all organisms requires execution of a complex program whereby specific genes are activated and repressed in specific sets of cells and in a precise time sequence. Many developmental changes in gene expression are generated by extracellular signaling molecules that act on cell-surface receptors. Most of these signals are soluble, secreted factors that act in a paracrine fashion on receiving (target) cells near the releasing cell. However, some signaling proteins are themselves attached to the cell surface, where they interact with cell-surface receptors on adjacent cells to alter the receiving cell's pattern of gene expression.

Even mature cells that are part of a differentiated tissue constantly change their patterns of gene expression. In large measure this occurs because of many different cell-surface receptors that continually receive information from extracellular signals and transduce this information into activation of specific transcription factors that stimulate or repress expression of specific target genes. Many such signaling pathways lead to alterations in the cell's metabolic activities. Liver, for example, responds to fluctuations in the levels of many hormones (e.g., insulin, glucagon, and epinephrine) by altering expression of many genes encoding enzymes of glucose and fat metabolism. Other signaling pathways influence the levels of proteins that affect the ability of cells to progress through the cell cycle and divide.

A typical mammalian cell often expresses cell-surface receptors for more than 100 different types of extracellular signaling molecules that function primarily to regulate the activity of transcription factors (see Figure 13-1). The signal-induced activation of transcription factors occurs by several mechanisms. In the last chapter, for instance, we saw that stimulation of some G protein-coupled receptors leads to a rise in cAMP and the cAMP-dependent activation of protein kinase A. After translocating to the nucleus, protein kinase A phosphorylates and thereby activates the CREB transcription factor.

In this chapter, we focus on five other classes of cell-surface receptors that illustrate additional signal-induced mechanisms of activating transcription factors. Stimulation of transforming growth factor ft (TGFft) receptors and cytokine receptors leads directly to activation of cytosolic transcription factors as the result of phosphorylation by a kinase that is part of the receptor or associated with it. The activated transcription factors then translocate into the nucleus and act on specific target genes. In the case of receptor

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