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SIGNAL TRANSDUCTION |
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PRINCIPAL INVESTIGATORS Paul J. Davis, M.D.
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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 novel cell surface receptor for thyroid hormone on plasma membrane integrin αvβ3. This integrin is primarily expressed on endothelial cells, on vascular smooth muscle cells and on cancer cells. It is therefore not surprising that action of thyroid hormone (L-thyroxine, T4; 3, 5, 3’-triiodo-L-thyronine, T3) at this receptor is transduced into angiogenesis and into tumor cell proliferation. Transduction of the thyroid hormone signal at the integrin into blood vessel and tumor biology is effected by the mitogen-activated protein kinase (MAPK; extracellular-regulated kinase [ERK]1/2) pathway. The hormone signal at the αvβ3 receptor may also be transduced by phosphatidylinositol 3-kinase (PI 3-K) into intracellular protein trafficking regulation or specific gene expression, such as that of hypoxia-inducible factor-1α (HIF-1α). A thyroid hormone-based drug development platform is based on the integrin receptor. Among the drugs emerging from this platform is nanoparticulate tetraiodothyroacetic acid (tetrac), an inhibitor of thyroid hormone actions at the integrin and a drug that has anti-angiogenic and anti-proliferative activity. Growth of human solid tumor xenografts in mice is arrested by nanoparticulate and unmodified tetrac and the compounds also reduce tumor-related angiogenesis that is mediated by vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and other endogenous factors that are pro-angiogenic. Tetrac also increases intracellular residence time of standard chemothera-peutic agents.
Collaborating institutions in these studies are the Pharmacologic Research Institute of Albany College Representative Publications
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Signal transduction is the conversion of a cell surface event – e.g., the binding by a specific plasma membrane receptor of a hormone, cytokine or growth factor – into a coherent cellular response. The latter may be a complex cell nucleus-mediated event or may be locally expressed at the cell membrane as altered activity of ion transport proteins. Transduction of the initiating signal usually depends upon pathways of kinase enzymes that, when activated, follow a scaffold to a biologic endpoint. Alternatively, a constituent of the kinase pathway may translocate from one intracellular compartment to another (cytoplasm to nucleus) to change specific gene expression or move to the plasma membrane to act on a substrate substituent of an ion transport system.
The laboratory has also described cell surface receptors for the polyphenol, resveratrol, and for androgen (dihydrotestosterone, DHT). The functions of these receptors have been defined.