The search for the membrane thyroid hormone receptor.

THE 2009 SOLOMON BERSON AWARD LECTURE was delivered by Paul Davis, Director of the Ordway Research Institute in Albany, New York. In his invited review (5), which appears in this issue of the Journal, Dr. Davis presents a compelling argument for the identity of the membrane thyroid hormone receptor, its signaling cascades, and the physiological importance of that hormone-receptor interaction. Stimulated by the demonstration of rapid actions of thyroid hormone on glucose transport in thymocytes by Segal and Ingbar in 1979 (9), Dr. Davis and his long-standing collaborator and wife, Dr. Faith Davis, first in Buffalo and then after relocation to Albany, began the difficult search for the identity of a plasma membrane thyroid hormone receptor. In 1980, Sterling, Brenner, and Sakurada (10) reported further evidence for rapid cellular actions of thyroid hormones, in this case stimulation of mitochondrial function in the absence of de novo protein production, and the following year the Davis group published their first paper (3), titled “In vitro stimulation of human red blood cell Ca -ATPase by thyroid hormone,” clearly establishing a nongenomic action. Over the ensuing 20-plus years, Dr. Davis continued his quest for the identity of the plasma membrane thyroid hormone receptor, and the literature continued to grow with suggestive evidence for its existence. By the time of his review of the field in 1996 (4), extranuclear actions of thyroid hormones had been demonstrated at the levels of the plasma membrane, mitochondria, endoplasmic reticulum, cytoskeleton, and cytoplasm; however, a unique, nongenomic receptor had not been identified. Eight years later, the first clues to the identity of the receptor became apparent. With Shaker Mousa, the Davis team reported (2) that thyroid hormones were proangiogenic in chick chorioallantoic membranes (CAM). A role for the integrins in the angiogenic action of several factors in the CAM model had been previously recognized, and, putting two and two together, the group focused their attention on the integrins. As detailed in the accompanying review, in 2005 they reported (1) that “Integrin v 3 contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis.” The door was now opened to a flood of studies by the Davis group and others detailing the interaction of thyroid hormones with a site on the integrin and the cellular consequences of that interaction. Identifying a novel plasma membrane receptor is a major endeavor, particularly when it breaks the mold of the traditional thinking of hormones that have been recognized for years to exert genomic actions, so the 2005 announcement was a significant advance. However, that finding is dwarfed now by the wealth of information that has come forth since, in particular the potential clinical significance of the actions of agents that act at this receptor site. The development of the deaminated analog of T4 (thyroxine), tetraiodothyroacetic acid (tetrac), which displaces thyroid hormone from the receptor without activating the signaling cascade, provided a potential therapeutic approach for the treatment of hormone-responsive cancers. Actions of tetrac unrelated to thyroid hormones have been demonstrated as well, in particular its ability to antagonize the angiogenic actions of vascular endothelial growth factor (VEGF) and bovine fibroblast growth factor (bFGF). By itself, without interacting with endogenous growth factors, tetrac activates proapoptotic genes, and its potential use in the treatment of several cancers can now be envisioned (6). Exciting new findings include the observation (7) that tetrac sensitized cultured cancer cells to subsequent radiation exposure (i.e., radiosensitization) and that in human breast cancer cells tetrac treatment prolonged the residence time of doxorubicin (8), suggesting a potential mechanism by which the efficacy of chemotherapeutic agents can be enhanced. This is an outstanding story of discovery and dedication. It demonstrates the importance of clinical observations that can be examined experimentally in animal models and the important boost that research received as we progressed into the molecular era. Just as significant is the demonstration in this story of the translational aspect of endocrine research and how quickly discoveries at the bench can progress to potential treatments for devastating diseases. The work of Pepper and Faith Davis serves as an inspiration and a lesson to all researchers and particularly to young scientists. Keep your eyes open and be flexible; an unexpected answer is often right in front of you.