Disparate effects of thyroid hormone on actions of epidermal growth factor and transforming growth factor-alpha are mediated by 3',5'-cyclic adenosine 5'-monophosphate-dependent protein kinase II.
Epidermal growth factor (EGF) and TGFalpha share the same plasma membrane receptor. In the present studies in HeLa cells, both EGF and TGFalpha caused MAPK (ERK1/2) activation and expression of the immediate-early gene c-fos. Thyroid hormone (T(4)) nongenomically enhanced EGF- and TGFalpha-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. TGFalpha-induced MAPK activation was potentiated by 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP) but not 8-chloro-cyclic adenosine monophosphate. TGFalpha, 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 TGFalpha; T(4) enhanced the effect of TGFalpha 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 TGFalpha. Cells exposed to 8-Br-cAMP also inhibited TGFalpha-stimulated c-fos expression. Studies of cell proliferation indicated that T(4) potentiated EGF action but inhibited that effect in TGFalpha-treated cells. The disparate effects of T(4) on actions of EGF and TGFalpha, which share the same cell surface receptor, are mediated by hormone phosphorylation and activation of PKA-II.
Shih
Ai
A
Research Service, Stratton Veterans Affairs Medical Center, the Ordway Research Institute, Inc., New York State Department of Health, Albany 12208, USA.
Zhang
Shenli
S
Cao
H James
HJ
Tang
Heng-Yuan
HY
Davis
Faith B
FB
Davis
Paul J
PJ
Lin
Hung-Yun
HY
D016475:3T3 Cells; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D017781:Genes, Immediate-Early; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D013974:Thyroxine / Q000494:pharmacology / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000494:pharmacology / Q000502:physiology*
D016211:Transforming Growth Factor alpha; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004815:Epidermal Growth Factor; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D013974:Thyroxine