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J. Biol. Chem., Vol. 275, Issue 39, 30644-30652, September 29, 2000

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[D-Arg¹,D-Trp^5,7,9,Leu¹¹]Substance P Inhibits Bombesin-induced Mitogenic Signal Transduction Mediated by Both G_q and G₁₂ in Swiss 3T3 Cells^*

James Sinnett-Smith, Chintda Santiskulvong, Javier Duque, and Enrique Rozengurt^§

From the Department of Medicine, School of Medicine and Molecular Biology Institute, UCLA, Los Angeles, California 90095-1786

Substance P (SP) analogues including [D-Arg¹,D-Trp^5,7,9,Leu¹¹]SP are broad spectrum neuropeptide antagonists and potential anticancer agents, but their mechanism of action is not fully understood. Here, we examined the mechanism of action of [D-Arg¹,D-Trp^5,7,9,Leu¹¹]SP as an inhibitor of G protein-coupled receptor (GPCR)-mediated signal transduction and cellular DNA synthesis in Swiss 3T3 cells. Addition of [D-Arg¹,D-Trp^5,7,9,Leu¹¹]SP, at 10 µM, caused a striking rightward shift in the dose-response curves of DNA synthesis induced by bombesin, bradykinin, or vasopressin and markedly inhibited the activation of p42^mapk (ERK-2) and p44^mapk (ERK-1) induced by these GPCR agonists. In addition, this SP analogue also prevented the protein kinase C-dependent activation of protein kinase D induced by these agonists. [D-Arg¹,D-Trp^5,7,9,Leu¹¹]SP, at a concentration (10 µM) that inhibited these G_q-mediated events, also prevented GPCR agonist-induced responses mediated through the G proteins of the G₁₂ subfamily. These include bombesin-induced assembly of focal adhesions, formation of parallel arrays of actin stress fibers, increase in the tyrosine phosphorylation of focal adhesion kinase (FAK), p130^Cas, and paxillin, and formation of a complex between FAK and Src. We conclude that [D-Arg¹,D-Trp^5,7,9,Leu¹¹]SP acts as a mitogenic antagonist of neuropeptide GPCRs blocking signal transduction via both G_q and G₁₂.

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