Competition by second messenger systems for receptor interaction and activation: implications for tissue-specific responses and disease therapy.
1. At any one instant, most receptors are now recognized to be able to stimulate multiple signal transduction pathways in a cell when activated by an appropriate hormone. These different signalling pathways appear to allow for distinct cellular responses, such as cell proliferation, differentiation, and shape change. 2. In addition, many different types of cell will possess the same type of receptor. Therefore, for a hormone to be able to transmit differential signals to the various cell types able to respond to it, cells must discriminate the stimulus at some point. Such discrimination would seem to be an absolute requirement to allow a tissue-specific response to an identical initial stimulus. In theory, this specificity could occur at many points in the receptor signal transduction cascade, including cytosolic receptor coupling systems and tissue/cell-specific responsive genes. 3. The present paper summarizes our work and that of others which has determined some of the coupling systems of G-protein-coupled receptors and tyrosine kinase receptors and how these systems may be interacting. 4. In addition to these theoretical considerations, a potential therapeutic strategy underlies the ability of receptors to couple to more than one signal transduction system. If a response to a hormone were, for example, either cell proliferation or cell morphological change or differentiation and separate receptor-coupled signalling systems were responsible for these effects, pharmacological intervention may allow the transfer from one signalling system to another. If such a change allowed a permanent change to the differentiated phenotype, this could potentially form the basis of a signal-based cancer therapy.
Crouch
M F
MF
Molecular Signalling Group, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia. michael.crouch@anu.edu.au
Frew
I J
IJ
Simson
L
L
Davy
D A
DA
D000818:Animals; D019204:GTP-Binding Proteins / Q000502:physiology; D008954:Models, Biological; D009369:Neoplasms / Q000628:therapy; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D017978:Receptors, Growth Factor / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D017978:Receptors, Growth Factor; D011505:Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins