Interacting Pathways, Defective Signaling, And Treatments For Disease
The GPCR and RTK pathways do not necessarily remain separate, either from each other or from other signaling pathways. One of the most important pathways is directly downstream of RTKs and also many GPCRs, and is called the mitogen activated protein (MAP) kinase cascade. MAP kinase is an abundant ser/thr kinase that, when activated, phosphorylates and powerfully affects the activity of a large number of cytoskeletal, signaling, and nuclear proteins, including an important family of transcription factors, thus directly influencing gene expression.
Both pathways also help regulate a particularly important process called apoptosis. Many cells need specific growth factors to stay alive; the growth factors trigger pathways involving various ser/thr protein kinases that ultimately inactivate molecules that would otherwise promote apoptosis.
The entire signal transduction system normally works astonishingly well, but serious problems can occur. Cancer is unregulated cell growth and occurs when the machinery tightly regulating cell growth breaks down. It is often easy to see how this has occurred. Mutations in growth factor receptors, G proteins, MAP kinases, and other molecules frequently contribute to cancer, and generally result in these molecules losing their normal switching function, staying in the activated form and therefore inappropriately stimulating these important enzyme cascades.
The complexity of the signaling system makes for challenging research, but once understood it holds the promise for better treatments for cancer and other diseases. This is because each step in each pathway provides one or more targets for drugs. Designing a drug that could quiet the excess signaling caused by defective MAP kinase, for example, might provide a promising cancer treatment.
The examples given thus far provide only an outline of how signal transduction cascades work and an overview of a few of the most important enzymes. The actual process is much more complex, and there is much about the process that remains mysterious. Perhaps the biggest mystery is how the cell makes sense of all of the input from different growth factors, hormones, extracellular substrates, and so on to produce an appropriate response. The solution to this problem will result from a complete understanding and computer modeling of the biochemical and kinetic properties of the components of all these signaling cascades.
SEE ALSO APOPTOSIS; CELL, EUKARYOTIC; CELL CYCLE; GENE; GENE EXPRESSION: OVERVIEW OF CONTROL; PHARMACOGENETICS AND PHARMACOGENOMICS.
Alberts, Bruce., et al. Molecular Biology of the Cell, 4th ed. New York: Garland Science, 2002.
Scott, John D., and Tony Pawson. "Cell Communication: The Inside Story." Scientific American (June 2000).
Special Issue on Mapping Cellular Signaling. Science 296, no. 5573 (May 31, 2002).
Medicine EncyclopediaGenetics in Medicine - Part 4Signal Transduction - Signals, Receptors, And Cascades, The Importance Of Phosphorylation And Dephosphorylation, Signal Transduction: The Rtk Pathway