Mechanisms of adrenocorticotropin-induced activation of extracellularly regulated kinase 1/2 mitogen-activated protein kinase in the human H295R adrenal cell line.
The role of ACTH in stimulating or inhibiting growth of adrenal cells has been a subject of some controversy. Reports that ACTH may stimulate ERK/MAPK in Y1 cells have suggested a role for cAMP in this process. In attempting to extend this work, the ACTH responses in the human H295R cell line have been studied. This cell line makes only a very modest cAMP response to ACTH, yet the ERK1/2 response is highly reproducible and immediate but not prolonged. It is minimally reduced by the protein kinase A inhibitor, H89, but unaffected by protein kinase C and calcium inhibitors. Inhibition of epidermal growth factor receptor or other tyrosine kinase receptor transactivation was without effect, as was inhibition of c-Src activity or c-Src phosphorylation. The most effective inhibitor of this pathway was dansylcadaverine, an inhibitor of receptor internalization. These findings imply that ACTH-induced ERK1/2 activation in H295R cells is dependent on a mechanism distinct from that by which most G protein-coupled receptors activate ERK1/2 but that nevertheless seems to depend on receptor internalization.
Janes
Mandy E
ME
Centre for Endocrinology, Barts and the London School of Medicine, London, United Kingdom.
Chu
K M Emily
KM
Clark
Adrian J L
AJ
King
Peter J
PJ
D000302:Adrenal Cortex / Q000201:enzymology*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D044103:Receptor, Melanocortin, Type 2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000502:physiology
D044103:Receptor, Melanocortin, Type 2; D043562:Receptors, G-Protein-Coupled; D000324:Adrenocorticotropic Hormone; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3