Cell Signaling: Architectural Beauty and Complexity
Author Name: Keith Howell
Category Name: Medical science
A clear theme that emerges is the enormous complexity that underlies most cellular responses and the vast variety of proteins and interaction/binding motifs used to transduce signals. The extent of complexity is particularly surprising when one considers that as recently as the late 80s and early 90s many believed that all cellular signaling pathways consisted of a relatively simple sequence of protein–protein interactions. The discovery that heterotrimeric GTP binding proteins (G proteins) act as molecular switches, linking the activation of seven-membrane spanning receptors (also known as hepathelical or serpentine receptors) to second messenger–generating enzymes and ion channels, provided a working paradigm for cellular signal transduction. In these pathways, signal propagation is initiated when an activated receptor binds to a G protein. This interaction accelerates GDP dissociation from the G protein and enables cellular GTP to replace the dissociated GDP, thus driving the G protein to its active signaling state. A relatively slow GTP hydrolytic activity (turnover numbers of only ∼1–4 per minute) switches off the signal but only after production of second messenger in amounts sufficient to trigger the desired biological response. These types of three component receptor/G protein/effector systems mediate a remarkable variety of biological responses ranging from cardiac and smooth muscle contraction to sensory responses including vision, taste, and smell. Perhaps the most important of several beautifully designed features is the potential for significant signal amplification. Upon activation, the G protein dissociates from its receptor, thus enabling a single receptor protein to switch on multiple G proteins. A classic example is the photoreceptor rhodopsin which can activate as many as 100 molecules of the retinal G protein transducin within 1 s. Each activated G protein can then stimulate an effector enzyme, generating 100–1000 molecules of second messenger per second, thus yielding as much as a 105 amplification of the initial signal. In the case of visual transduction, this allows individuals to see in very low light and explains how Mark McGwire is able to hit a fast ball approaching at 100 miles per hour.
Still, with each passing year it has become increasingly clear that most cellular responses are not produced via simple, linear signaling cascades. This may be best exemplified by growth factor–coupled signaling to the nucleus, which is essential for the regulation of cell cycle progression and for determining whether cells proliferate or undergo differentiation.
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Journal of Cell signaling