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Vol. 58, Issue 3, 608-613, September 2000

Pertussis Toxin Inhibits Cholecystokinin- and Epidermal Growth Factor-Induced Mitogen-Activated Protein Kinase Activation by Disinhibition of the cAMP Signaling Pathway and Inhibition of c-Raf-1

Albrecht Piiper, Ralph Gebhardt, Bernd Kronenberger, Claudio D. Giannini, Robert Elez, and Stefan Zeuzem

Department of Internal Medicine, Johann Wolfgang Goethe-University, Frankfurt, Germany

Pertussis toxin (PTx), which inactivates Gi/o type G proteins, is widely used to investigate the involvement of Gi/o proteins in signal transduction. Activation of extracellular-regulated kinases 1 and 2 (ERK1/2) by G protein-coupled receptors has been described to occur either through a PTx-insensitive pathway involving activation of phospholipase C and protein kinase C (PKC), or through a PTx-sensitive pathway involving Gibeta gamma -mediated activation of Src. Cholecystokinin (CCK) activates ERK1/2 by a PKC-dependent, and thus presumably PTx-insensitive, pathway. However, CCK has recently been shown to induce activation of Gi proteins in addition to Gq/11. In the present study, PTx partially inhibited CCK-induced ERK1/2 activation in pancreatic AR42J cells, although activation of phospholipase C was not reduced. PTx also inhibited ERK1/2 activation in response to the PKC activator 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF) as well as activation of c-Raf-1 by EGF and CCK. In contrast, PTx, CCK, and EGF had only minor effects on A-Raf and B-Raf activity. Forskolin, a direct activator of adenylyl cyclase, inhibited CCK- and EGF-induced activation of c-Raf-1 and ERK1/2 in a manner similar to that of PTx. In PTx-treated cells, the cAMP content was increased and forskolin did not further inhibit CCK- and EGF-induced activation of c-Raf-1 or ERK1/2. In conclusion, the present study shows that PTx-sensitivity of receptor-induced ERK1/2 activation could be a consequence of disinhibition of the adenylyl cyclase signaling pathway, which in turn causes inhibition of c-Raf-1 activation rather than indicating involvement of a PTx-sensitive G protein in this signaling pathway.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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