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Articles

The Neurofibromatosis 2 Protein, Merlin, Regulates Glial Cell Growth in an ErbB2- and Src-Dependent Manner

S. Sean Houshmandi, Ryan J. Emnett, Marco Giovannini, David H. Gutmann
S. Sean Houshmandi
1Department of Neurology, Washington University School of Medicine, St. Louis, Missouri
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Ryan J. Emnett
1Department of Neurology, Washington University School of Medicine, St. Louis, Missouri
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Marco Giovannini
2House Ear Institute, Los Angeles, California
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David H. Gutmann
1Department of Neurology, Washington University School of Medicine, St. Louis, Missouri
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  • For correspondence: gutmannd@neuro.wustl.edu
DOI: 10.1128/MCB.01392-08
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ABSTRACT

Individuals with the inherited cancer predisposition syndrome neurofibromatosis 2 (NF2) develop several central nervous system (CNS) malignancies, including glial cell neoplasms (ependymomas). Recent studies have suggested that the NF2 protein, merlin (or schwannomin), may regulate receptor tyrosine kinase signaling, intracellular mitogenic growth control pathways, or adherens junction organization in non-nervous-system cell types. For this report, we used glial fibrillary acidic protein conditional knockout mice and derivative glia to determine how merlin regulates CNS glial cell proliferation. We show that the loss of merlin in glial cells results in increased proliferation in vitro and in vivo. Merlin regulation of glial cell growth reflects deregulated Src activity, such that pharmacologic or genetic inhibition of Src activation reduces Nf2−/− glial cell growth to wild-type levels. We further show that Src regulates Nf2−/− glial cell growth by sequentially regulating FAK and paxillin phosphorylation/activity. Next, we demonstrate that Src activation results from merlin regulation of ErbB2 activation and that genetic or pharmacologic ErbB2 inhibition reduces Nf2−/− glial cell Src/Src effector activation and proliferation to wild-type levels. Lastly, we show that merlin competes with Src for direct binding to ErbB2 and present a novel molecular mechanism for merlin regulation of ErbB2-dependent Src signaling and growth control.

  • Copyright © 2009 American Society for Microbiology
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The Neurofibromatosis 2 Protein, Merlin, Regulates Glial Cell Growth in an ErbB2- and Src-Dependent Manner
S. Sean Houshmandi, Ryan J. Emnett, Marco Giovannini, David H. Gutmann
Molecular and Cellular Biology Feb 2009, 29 (6) 1472-1486; DOI: 10.1128/MCB.01392-08

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The Neurofibromatosis 2 Protein, Merlin, Regulates Glial Cell Growth in an ErbB2- and Src-Dependent Manner
S. Sean Houshmandi, Ryan J. Emnett, Marco Giovannini, David H. Gutmann
Molecular and Cellular Biology Feb 2009, 29 (6) 1472-1486; DOI: 10.1128/MCB.01392-08
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KEYWORDS

Neurofibromin 2
Neuroglia
Receptor, ErbB-2
src-Family Kinases

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