ErbB2 Trafficking and Signaling in Human Vestibular Schwannomas
Abstract
We find that the ErbB2 receptor tyrosine kinase is active in vestibular schwannoma (VS) cells and drives proliferation. Our overall hypothesis is that defects in merlin lead to constitutive ErbB2 activation at the cell membrane and that inhibition of ErbB2 will reduce the survival of VS cells and potentiate the effects of radiation on VSs. In this report we show that VS cells, which lack functional merlin, constitutively express activated ErbB2 in lipid rafts contributing to their proliferative potential; this is related to the merlin status of the cells. Furthermore, protein kinase A inactivates merlin by phosphorylation in Schwann cells in vitro and in vivo following denervation, correlated with movement of ErbB2 into lipids rafts and re-entry into the cell cycle. VS cells are relatively radioresistance, due at least in part, to persistent JNK activity which promotes cell survival and limits oxidative stress. Finally, inhibition of ErbB2 reduces VS cell radiosensitivity whereas activation of ErbB2 enhances radiosensitivity, likely by regulating cell proliferation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2010
- Accession Number
- ADA554583
Entities
People
- Marlan R. Hansen
Organizations
- University of Iowa