Disparate effects of thyroid hormone on actions of epidermal growth factor and transforming growth factor-α are mediated by 3′,5′-cyclic adenosine 5′-monophosphate-dependent protein kinase II

Epidermal growth factor (EGF) and TGFα share the same plasma membrane receptor. In the present studies in HeLa cells, both EGF and TGFα caused MAPK (ERK1/2) activation and expression of the immediate-early gene c-fos. Thyroid hormone (T ₄) nongenomically enhanced EGF- and TGFα-induced MAPK activation. This T ₄ action was duplicated by T ₄-agarose and blocked by tetraiodothyroacetic acid, which inhibits binding of T ₄ to plasma membranes. TGFα-induced MAPK activation was potentiated by 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP) but not 8-chloro-cyclic adenosine monophosphate. TGFα, T ₄, and 8-Br-cAMP each caused protein kinase A (PKA) II serine phosphorylation, whereas phosphorylation of PKA-II was not seen in cells treated with EGF or 8-chloro-cyclic adenosine monophosphate. In a PKA activity assay, the enzyme was stimulated by T ₄, EGF, and TGFα; T ₄ enhanced the effect of TGFα but not that of EGF. T ₄, although it potentiated c-fos gene expression in EGF-treated cells, suppressed this effect in cells treated with TGFα. Cells exposed to 8-Br-cAMP also inhibited TGFα-stimulated c-fos expression. Studies of cell proliferation indicated that T ₄ potentiated EGF action but inhibited that effect in TGFα-treated cells. The disparate effects of T ₄ on actions of EGF and TGFα, which share the same cell surface receptor, are mediated by hormone phosphorylation and activation of PKA-II.