L-thyroxine acts as a hormone as well as a prohormone at the cell membrane

P. J. Davis, F. B. Davis, H. Y. Lin

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


The higher affinity of the nuclear thyroid hormone receptor TR for 3,5,3'-triodo-L-thyronine (T3) relative to L-thyroxine (T4), the well-characterized genomic actions of T3 and the existence of cellular deiodinases that convert T4 to T3 support the concept that T4 is a prohormone for T3. In the past decade, however, a number of actions of thyroid hormones, initiated at the plasma membrane and involving the cytoskeleton or specific events in the cell nucleus, have been described that are primary responses to T4. Two prototypes of such nongenomic actions are 1) actin polymerization and its consequences in terms of neuritogenesis and interactions of astrocytes with extracellular matrix proteins and 2) stimulation of the mitogen-activated protein kinase signal transduction pathway with subsequent serine phosphorylation of transactivator nucleoproteins, including TR, p53 and STAT1α. These actions of T4 appear to be independent of entry of thyroid hormone into the cell. From the cell surface, T4-dictated serine phosphorylation of transactivators such as TRβ1 modulate the transcriptional activity of these proteins. This is a postulated cooperative interface between nongenomic and genomic effects of thyroid hormone, prompted by action of T4 at the plasma membrane. Biological endpoints of such actions of T4 in model systems are angiogenesis and increased growth of certain tumor cells. The membrane receptor for activation by T4 of mitogen-activated protein kinase is on an integrin, αVβ3. From its cell surface receptor, T4 can also influence intracellular protein trafficking and modulate activities of plasm membrane ion pumps or channels. Thus, T4 has plasma membrane-initiated actions as a hormone, as well as its function as a source of the more metabolically important iodothyronine analogue, T3.

Original languageEnglish
Pages (from-to)235-240
Number of pages6
JournalImmunology, Endocrine and Metabolic Agents in Medicinal Chemistry
Issue number3
Publication statusPublished - Jun 2006
Externally publishedYes


  • Actin-related effects
  • Arg-Gly-Asp recognition
  • MAPK activation
  • Nuclear thyroid hormone receptor
  • Signal transduction pathway

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Immunology and Allergy
  • Pharmacology


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