COM4S_M.TTF

The Signal Transduction Laboratory has its own research programs, but also serves the investigative needs of the principal themes of the Ordway Research Institute in the research area of signal transduction.

Signal transduction is the conversion of a cell surface event—e.g., the binding by a specific receptor of a hormone, cytokine or growth factor—into a coherent cellular response. The latter may ultimately be mediated by the cell nucleus or may be locally expressed at the plasma membrane by altered activity of membrane ion transport proteins. Physical factors such as ultraviolet light, hypoxia or pH may also serve as signals. The transduction of signals usually depends upon pathways of kinase enzymes that act on substrates, one or more of which may:

• translocate to the cell nucleus to modulate transcription of specific genes important to the signal-specific responses of the cell or
• move to the plasma membrane to modulate activity of transport systems.

Improved understanding of sites of initiation of signals and of signal transducing cascades offers new targets for development of drugs that desirably modify cellular responses.

This laboratory has identified a cell surface receptor for thyroid hormone on plasma membrane integrin αVβ3. The binding of thyroid hormone by this receptor (‘signal’) on endothelial cells is transduced by cytoplasmic mitogen-activated protein kinase (MAPK), upon nuclear translocation, into a gene transcription sequence for new blood vessel growth (angiogenesis) (JJ Bergh et al., Endocrinology 146:2864-2871, 2005). We have shown that a thyroid hormone analogue, tetrac, that itself has no angiogenic activity, blocks the pro-angiogenic effect of traditional thyroid hormone molecules. Tetrac is proposed to be a novel inhibitor of pro-angiogenic activity of thyroid hormone that serves tumor growth.