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Originally published In Press as doi:10.1074/jbc.M110338200 on December 3, 2001

J. Biol. Chem., Vol. 277, Issue 8, 6703-6707, February 22, 2002
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Expression of Full-length Polyglutamine-expanded Huntingtin Disrupts Growth Factor Receptor Signaling in Rat Pheochromocytoma (PC12) Cells*

Cheng SongDagger , George Perides§, and Ya Fang LiuDagger

From the Dagger  Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118 and the § Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

We reported previously that normal Huntingtin is associated with epidermal growth factor receptor (EGF) signaling complex (Liu, Y. F., Deth, C. R., and Devys, D. (1997) J. Biol. Chem. 272, 8121-8124). To investigate the potential role of normal and polyglutamine-expanded Huntingtin in the regulation of growth factor receptor-mediated cellular signaling and biological function, we stably transfected full-length Huntingtin containing 16, 48, or 89 polyglutamine repeats into PC12 cells where cellular signaling mechanisms, mediated by nerve growth factor (NGF) or EGF receptors, are well characterized. Expression of polyglutamine-expanded Huntingtin, but not normal Huntingtin, leads to a dramatic morphological change. In clones carrying the mutated Huntingtin, both NGF and EGF receptor-mediated activation of mitogen-activated protein kinase, c-Jun N-terminal kinase, and Akt are significantly attenuated, and NGF receptor-mediated neurite outgrowth is blocked. Co-immunoprecipitation studies show that the associations of NGF or EGF receptors with growth factor receptor-binding protein 2 (Grb2) and phosphoinositide 3-kinase are significantly inhibited. NGF-induced tyrosine phosphorylation of NGF receptors (TrkA) is also consistently suppressed. Our data demonstrate that polyglutamine-expanded Huntingtin disrupts cellular signaling mediated by both EGF and NGF receptors in PC12 cells. It is known that Huntington's disease patients exhibit an extremely low incidence of a variety of cancers and are deficient in glucose metabolism. Thus, our results may reflect an important molecular mechanism for the pathogenesis of the disease.

* This work was supported by United States Army Medical Research and Materiel Command under a Cooperative Agreement DAMD17-00-2-0012 (to Y. F. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pharmacology, Boston University Medical School, 715 Albany St., Boston, MA 02118. Tel.: 617-638-4593; Fax: 617-638-4329; E-mail: yafliu@bu.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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