The nongenomic actions of thyroid hormone require a plasma membrane receptor or 
nuclear receptors located in cytoplasm. The plasma membrane receptor is located 
on integrin alphaVbeta3 at the Arg-Gly-Asp recognition site important to the 
binding by the integrin of extracellular matrix proteins. l-Thyroxine (T(4)) is 
bound with greater affinity at this site than 3,5,3'-triiodo-l-thyronine (T(3)). 
Mitogen-activated protein kinase (MAPK; ERK1/2) transduces the hormone signal 
into complex cellular/nuclear events including angiogenesis and tumor cell 
proliferation. Acting at the integrin receptor and without cell entry, thyroid 
hormone can foster ERK1/2-dependent serine phosphorylation of nuclear thyroid 
hormone receptor-beta1 (TRbeta1) and de-repress the latter. The integrin 
receptor also mediates actions of the hormone on intracellular protein 
trafficking and on plasma membrane ion pumps, including the sodium/protein 
antiporter. Tetraiodothyroacetic (tetrac) is a T(4) analog that inhibits binding 
of iodothyronines to the integrin receptor and is a probe for the participation 
of this receptor in cellular actions of the hormone. Tetrac blocks thyroid 
hormone effects on angiogenesis and cancer cell proliferation. Acting on a 
truncated form of nuclear TRalpha1 (TRDeltaalpha1) located in cytoplasm, T(4) 
and 3,3',5'-triiodothyronine (reverse T(3)), but not T(3), cause conversion of 
soluble actin to fibrous (F) actin that is important to cell motility, e.g., in 
cells such as glia and neurons. Normal development of the central nervous system 
requires such motility. TRbeta1 in cytoplasm mediates action of T(3) on 
expression of certain genes via phosphatidylinositol 3-kinase (PI 3-K) and the 
protein kinase B/Akt pathway. PI 3-K and, possibly, cytoplasmic TRbeta1 are 
involved in stimulation by T(3) of insertion of Na,K-ATPase in the plasma 
membrane and of increase in activity of this pump. Because ambient thyroid 
hormone levels are constant in the euthyroid intact organism, these nongenomic 
hormone actions are likely to be contributors to basal rate-setting of 
transcription of certain genes and of complex cellular events such as 
angiogenesis and cancer cell proliferation.