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Molecular and Cellular Biology, June 2004, p. 4664-4676, Vol. 24, No. 11
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.11.4664-4676.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Rap2B-Dependent Stimulation of Phospholipase C-{varepsilon} by Epidermal Growth Factor Receptor Mediated by c-Src Phosphorylation of RasGRP3

Matthias B. Stope,{dagger} Frank vom Dorp,{dagger} Daniel Szatkowski, Anja Böhm, Melanie Keiper, Jan Nolte, Paschal A. Oude Weernink, Dieter Rosskopf, Sandrine Evellin,{ddagger} Karl H. Jakobs, and Martina Schmidt*

Institut für Pharmakologie, Universitätsklinikum Essen, 45122 Essen, Germany

Received 27 November 2003/ Returned for modification 16 January 2004/ Accepted 8 March 2004

Receptor tyrosine kinase regulation of phospholipase C-{varepsilon} (PLC-{varepsilon}), which is under the control of Ras-like and Rho GTPases, was studied with HEK-293 cells endogenously expressing PLC-coupled epidermal growth factor (EGF) receptors. PLC and Ca2+ signaling by the EGF receptor, which activated both PLC-{gamma}1 and PLC-{varepsilon}, was specifically suppressed by inactivation of Ras-related GTPases with clostridial toxins and expression of dominant-negative Rap2B. EGF induced rapid and sustained GTP loading of Rap2B, binding of Rap2B to PLC-{varepsilon}, and Rap2B-dependent translocation of PLC-{varepsilon} to the plasma membrane. GTP loading of Rap2B by EGF was inhibited by chelation of intracellular Ca2+ and expression of lipase-inactive PLC-{gamma}1 but not of PLC-{varepsilon}. Expression of RasGRP3, a Ca2+/diacylglycerol-regulated guanine nucleotide exchange factor for Ras-like GTPases, but not expression of various other exchange factors enhanced GTP loading of Rap2B and PLC/Ca2+ signaling by the EGF receptor. EGF induced tyrosine phosphorylation of RasGRP3, but not RasGRP1, apparently caused by c-Src; inhibition of c-Src interfered with EGF-induced Rap2B activation and PLC stimulation. Collectively, these data suggest that the EGF receptor triggers activation of Rap2B via PLC-{gamma}1 activation and tyrosine phosphorylation of RasGRP3 by c-Src, finally resulting in stimulation of PLC-{varepsilon}.

* Corresponding author. Mailing address: Institut für Pharmakologie, Universitätsklinikum Essen, Hufelandstrasse 55, D-45122 Essen, Germany. Phone: 49-201-723-3457. Fax: 49-201-723-5968. E-mail: martina.schmidt{at}uni-essen.de.

{dagger} M.B.S. and F.V.D. contributed equally to this work.

{ddagger} Present address: Dipartimento di Biologia Molecolare, 53100 Siena, Italy.

Molecular and Cellular Biology, June 2004, p. 4664-4676, Vol. 24, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.11.4664-4676.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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