The traditional linear view of signaling—that receptor activation triggers an orderly sequence of biochemical intermediates that ultimately leads to changes in gene expression and the desired biological response—is oversimplified. Instead, it is increasingly clear that any initial signal results in multiple primary and secondary effects, each of which contributes in varying degrees to the final outcome. This is particularly true of signaling pathways that rely on enzymatic activities, which typically modulate a web of polypeptides with complex interactions. For example, phosphorylation of any given protein can allow it to associate with a host of other molecules, resulting in multiple effects such as:
Nuclear (or cytoplasmic) localization of transcription factors (see later)
Activation of feedback inhibitory (or stimulatory) loops
Adaptor proteins play a key role in organizing intracellular signaling pathways. These proteins function as molecular connectors that physically link different enzymes and promote the assembly of complexes; adaptors can be integral membrane proteins or cytosolic proteins. A typical adaptor may contain a few specific domains (e.g., SH2 or SH3) that mediate protein–protein interactions. By influencing the proteins that are recruited to signaling complexes, adaptors can determine downstream signaling events.
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By analogy with computer networks, the protein– protein complexes can be considered nodes and the biochemical events feeding into or emanating from these nodes can be thought of as hubs. Signal transduction can therefore be visualized as a kind of networking phenomenon; understanding this higher-order complexity is the province of systems biology, involving a “marriage” of biology and computation.
Most signal transduction pathways ultimately influence cellular function by modulating gene transcription through the activation and nuclear localization of transcription factors. Conformational changes of transcription factors (e.g., following phosphorylation) can allow their translocation into the nucleus or can expose specific DNA or protein-binding motifs. Transcription factors may drive the expression of a relatively limited set of genes or may have much more widespread effects on gene expression. Among the transcription factors that regulate the expression of genes that are needed for growth are MYC and JUN, whereas a transcription factor that triggers the expression of genes that lead to growth arrest is p53. Transcription factors have a modular design, often containing domains that bind DNA and others that interact with other proteins, such as components of the RNA polymerase complex required for transcription.
• DNA-binding domains permit specific binding to short DNA sequences. Whereas some transcription factor binding sites are found in promoters, close to the site where transcription starts, it is now appreciated that most transcription factors bind widely throughout genomes, including to long-range regulatory elements such as enhancers. Enhancers function by looping back to gene promoters, and therefore are spatially located close to the genes that they regulate, even though it terms of genomic sequence they may appear to be far
Table 1.1 GrowthFactorsInvolvedinRegenerationandRepair away. These insights highlight the importance of chromatin organization in regulating gene expression, both normal and pathologic.
• For a transcription factor to induce transcription, it must also possess protein:protein interaction domains that directly or indirectly recruit histone-modifying enzymes, chromatin-remodeling complexes, and (most importantly) RNA polymerase—the large multiprotein enzymatic complex that is responsible for RNA synthesis.
A major role of growth factors is to stimulate the activity of proteins that are required for cell survival, growth and division. Growth factor activity is mediated through binding to specific receptors, ultimately influencing the expression of genes that can:
Promote entry of cells into the cell cycle
Enhance biosynthesis of cellular components (nucleic acids, proteins, lipids, carbohydrates) required for a mother cell to give rise to two daughter cells
Although some growth factors are proteins that “just” stimulate cell proliferation and/or survival, it is important to remember that they also can drive a host of other activities, including migration, differentiation, and synthetic capacity. Some of the important growth factors relevant to tissue regeneration and repair are listed in
Table 1.1 and described further in Chapter 3.