Expression of full-length polyglutamine-expanded Huntingtin disrupts growth factor receptor signaling in rat pheochromocytoma (PC12) cells.
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.
Song
Cheng
C
Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Perides
George
G
Liu
Ya Fang
YF
D000310:Adrenal Gland Neoplasms; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000502:physiology; D005973:Glutamine; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation; D020932:Nerve Growth Factor / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D016716:PC12 Cells; D010455:Peptides / Q000235:genetics*; D010673:Pheochromocytoma; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017978:Receptors, Growth Factor / Q000502:physiology*; D017475:Receptors, Nerve Growth Factor / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
C086055:HTT protein, human; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; D005973:Glutamine; C097188:polyglutamine; D004815:Epidermal Growth Factor; D020932:Nerve Growth Factor; D066246:ErbB Receptors; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases