HORMONAL-REGULATION OF MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVITY IN BOVINE ADRENOCORTICAL-CELLS - CROSS-TALK BETWEEN PHOSPHOINOSITIDES, ADENOSINE-3',5'-MONOPHOSPHATE, AND TYROSINE KINASE RECEPTOR PATHWAYS

Angiotensin-II (AII), which stimulates steroidogenesis in bovine adren ocortical (BAC) cells through the phosphoinositides pathway, activates p42-p44 mitogen-activated protein kinases (MAPKs) after 5 min of trea tment (EC(50) = 0.1 nM). This activation is 1) completely inhibited by the AII receptor AT(1) subtype antagonist Dup 753 (10 mu M)I but unaf fected by the AT(2) antagonist PD 123177; 2) not reproduced by the AT( 2) agonist CGP 42112A; 3) insensitive to pretreatment with pertussis t oxin; and 4) abolished by a 48-h preexposure of the cells to the phorb ol ester 12-O-tetradecanoylphorbol 13-acetate (TPA; 1 mu M), which dow n-regulates protein kinase-C activity. Fibroblast growth factor-2, a p otent mitogen far BAC cells, which acts through its tyrosine kinase re ceptor, also activates MAPK (EC(50) = 0.3 ng/ml) in a TPA-insensitive manner, while exhibiting no detectable effect on BAC cell steroidogene sis. In contrast, ACTH, which stimulates steroidogenesis via cAMP and inhibits BAC cell proliferation, does not stimulate MAPK. Indeed, ACTH completely blocks (IC50 = 0.01 nM) the stimulation of MAPK by AII, fi broblast growth factor-2, or TPA. Therefore, bovine adrenocortical cel ls provide an example of positive and negative hormonal regulation of MAPK activity through a cross-talk between the inositide-, cAMP-, and growth factor-activated tyrosine kinase pathways.