Visit our Expo - Redox and Inflammation signaling 2012

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)
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