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Increased EGF Receptor expression and activity is induced by deregulated N-Ras and may provide a therapeutic target in NF1 neurofibrosarcoma Joshua T. Dilworth, Janice M. Kraniak, Michael A. Tainsky, John J. Reiners, Jr., and Raymond R. Mattingly Department of Pharmacology and Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, U.S.A. Email: r.mattingly@wayne.edu Neurofibromatosis Type 1 (NF1) is the most common inherited cancer predisposition syndrome. NF1 is caused by functional loss of neurofibromin (Nf1), which compromises Ras inactivation and drives deregulated Ras-dependent signaling pathways. We have investigated a panel of neurofibrosarcoma-derived cell lines and have previously demonstrated that two Nf1-deficient lines have increased basal N-Ras and ERK MAPK activation, relative to a control line that is wild-type for Nf1. We now show that Nf1-deficient cells have an increased amount and activity of the epidermal growth factor receptor (EGFR) and demonstrate a hypersensitive and prolonged response to EGF stimulation. Our studies indicate that EGFR expression is modulated as a result downstream of Ras signaling. Maintenance of elevated EGFR expression depends on serum stimulation and the MAPK pathway. Furthermore, using tetracycline-repressible expression vectors, we show that expression of constitutively active N- or K-Ras but not H-Ras is sufficient to increase EGFR expression. Inhibition of the EGFR causes a selective reduction in the proliferation of Nf1-deficient cells. Our research proposes a mechanism to explain the clinical observation that malignant Schwann cells from NF1 patients overexpress the EGFR. In addition, we provide evidence that supports the EGFR as a potential pharmacological target in the treatment of this disease. DAMD170310182 Recent papers ; S. Beqaj, S. Jakkaraju, R.R. Mattingly, D. Pan & L. Schuger. High RhoA activity maintains the undifferentiated mesenchymal phenotype, whereas RhoA down-regulation by laminin-2 induces smooth muscle myogenesis. J. Cell Biol. 156: 893-903 (2002) V.G. Keshamouni, R.R. Mattingly & K.B. Reddy. Mechanism of 17-#-estradiol-induced ERK1/2 activation in breast cancer cells: A role for HER2 and PKC- . J. Biol. Chem. 277: 22558-22565 (2002) R.R. Mattingly, R.A. Gibbs, R.E. Menard & J.J. Reiners Jr.. Potent suppression of the proliferation of A10 vascular smooth muscle cells by combined treatment with lovastatin and 3-allylfarnesol, an inhibitor of protein farnesyltransferase. J. Pharmacol. Exp. Ther. 303: 74 - 81 (2002) H. Yang, D. Cooley, Q. Ge, R. Andrade & R.R. Mattingly. Phosphorylation of the Ras- GRF1 exchange factor at Serine-916/898 reveals activation of Ras signaling in the cerebral cortex. J. Biol. Chem. 278: 13278-13285 (2003) R.E. Menard & R.R. Mattingly. Cell surface receptors activate p21-activated protein kinase I (PAKI) via multiple Ras and PI3-kinase-dependent pathways. Cell. Signal. 15: 1099-1109 (2003) R.E. Menard & R.R. Mattingly. Gbetagamma subunits stimulate p21-activated kinase1 (PAK1) through activation of PI3-kinase and Akt but act independently of Rac1/Cdc42. FEBS Lett. 556: 187-192 (2004) - 70 -
D.P. Chopra, R.E. Menard, J. Januszewski & R.R. Mattingly. TNF-alpha mediated apoptosis in normal human prostate epithelial cells and tumor cell lines. Cancer Lett. 203: 145-154 (2004) D.R. Yingst, K.J. Massey, N.F. Rossi, M.J. Mohanty & R.R. Mattingly. Angiotensin II directly stimulates activity and alters phosphorylation of Na,K-ATPase in rat proximal tubule with a rapid time course. Am. J. Physiol. 287: F713-F721 (2004) J.H. Norum, T. Methi, R.R. Mattingly & F.O. Levy. Endogenous expression and PKAdependent phosphorylation of the guanine nucleotide exchange factor Ras-GRF1 in HEK293 cells. FEBS J. (formerly Eur. J. Biochem.) 272: 2304-2316 (2005) R.E. Menard & R.R. Mattingly. Active p21-activated protein kinase I (PAKI) rescues MCF10A breast epithelial cells from undergoing anoikis. Neoplasia 7: 638-645 (2005) R.R. Mattingly, J.A. Kraniak, J.T. Dilworth, P. Mathieu, B. Bealmear, J.E. Nowak, J.A. Benjamins, M.A. Tainsky & J.J. Reiners, Jr. The MEK inhibitor PD184352/CI-1040 selectively induces apoptosis in malignant schwannoma cell lines. J. Pharmacol. Exp. Ther. In press (2005) S.E. Ziemba, R.R. Mattingly, M.J. McCabe Jr & A.J. Rosenpire. Inorganic mercury inhibits the activation of LAT in T cell receptor-mediated signal transduction. Toxicol. Sci. In press (2005) H. Yang & R.R. Mattingly. The Ras-GRF1 exchange factor coordinates activation of H–Ras and Rac1 to control neuronal morphology. In revision for Mol. Biol. Cell (2005) - 71 -
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Table of content PREFACE ..........
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Preface In 1998, we organized the f
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Acknowledgments This meeting has be
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Group B (15h00 - 17h00) Session V.
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- 11 - Exhibition
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Visit our Expo (in alphabetical ord
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Thursday January 26th, 2006 (Early
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Thursday January 26th, 2006 (Evenin
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Session I : protein domains Poster
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Session I : protein domains Poster
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Session II. Receptor signaling and
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Session III. Protein kinase cascade
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IV. Protein kinase inhibitors: insi
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V. Phosphatases as key cell signali
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VI. Proteasome degradation pathways
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VI. Proteasome degradation pathways
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VIII. Inflammation specific signali
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Session XV : Reactive oxygen specie
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Session XVI : Chemopreventive agent
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Session XVII : Cell signaling in he
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Dr. Nassera Aouali L-1526 Luxembour
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Dr. Giordano Bianchi Clinic of inte
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Mrs. Isabel Burghardt Laboratory of
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Pr. Czeslaw Cierniewski 92-215 Lodz
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Mr. Igotz Delgado Biochemistry 4894
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Dr. Mark Ginsberg Mail code 0726 92
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Dr. Jochen Hefl Division of Signal
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Mr. Jan Jepsen 2100 Copenhagen DNK
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Pr. Young Min Kim Division of Biolo
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Mr. Christoph Lahtz AG Tumorgenetik
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Pr. Moncef ZOUALI Centre Viggo Pete
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