Overexpression of pp60c-src is associated with altered regulation of adenylyl cyclase

The ability of activators of the beta-adrenergic receptor to elevate intracellular cAMP levels in murine fibroblasts is enhanced upon overexpression of avian c-src [Bushman et al. (1990) Proc. natn. Acad. Sci. U.S.A. 87, 7462-7466]. To investigate the molecular basis for this effect, we prepared par...

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Bibliographic Details
Published in:	Cellular signalling Vol. 4; no. 5; p. 531
Main Authors:	Luttrell, D K, Hausdorff, W P, Moyers, J E, Gilmer, T M, Parsons, S J, Caron, M G, Lefkowitz, R J
Format:	Journal Article
Language:	English
Published:	England 01-09-1992
Subjects:	Adenylyl Cyclases - metabolism Animals Cell Line Cyclic AMP - biosynthesis Enzyme Activation - drug effects GTP-Binding Proteins - metabolism Isoproterenol - pharmacology Mice Proto-Oncogene Proteins pp60(c-src) - metabolism Receptors, Adrenergic, beta - drug effects Receptors, Adrenergic, beta - metabolism Signal Transduction - physiology
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Summary:	The ability of activators of the beta-adrenergic receptor to elevate intracellular cAMP levels in murine fibroblasts is enhanced upon overexpression of avian c-src [Bushman et al. (1990) Proc. natn. Acad. Sci. U.S.A. 87, 7462-7466]. To investigate the molecular basis for this effect, we prepared particulate fractions from control and pp60c-src overexpressing C3H10T1/2 fibroblasts and assessed the relative abilities of several activators of the beta-adrenergic receptor-Gs-adenylyl cyclase (AC) signal transduction pathway to stimulate the enzymatic response. Two- to three-fold increases in both the sensitivity and maximum responsiveness of AC to the beta-adrenergic agonist isoproterenol were consistently observed in fractions prepared from the c-src overexpressing cells. Interestingly, the AC response to two agents believed to act directly at the level of the G protein were either enhanced (NaF) or unaffected (GTP gamma S) by c-src overexpression. Finally, overexpression of c-src was associated with a reduced ability of both Mn2+ and forskolin to activate AC directly. These results suggest that overexpression of wild type c-src may affect two distinct steps in the regulation of AC exerting a positive effect at the level of Gs activation and a negative effect on AC itself. As no differences in the relative number or affinity of beta-adrenergic receptors, or in the level of AC, Gs alpha or G beta, were detected between control cells and those overexpressing c-src, we propose that pp60c-src overexpression results in a modification of one or more components in this signal transduction pathway.
ISSN:	0898-6568
DOI:	10.1016/0898-6568(92)90022-Z