Analysis of p21-Activated Kinase Function in Neurofibromatosis Type 2
Abstract
The NF2 product, Merlin, has recently been shown to inhibit p21-activated kinases (Paks), enzymes known to activate cell cycle progression and to induce changes in the actin cytoskeleton. These findings suggest that loss of Pak function might inhibit the abnormal growth and/or movement of cells lacking Merlin. We had proposed two aims: to test if loss of all Pak function affects signaling in NF2-/- cells and to test if Paks are required for tumorigenesis in an NF2 mouse model system. In the third year of this project, we published a manuscript describing the first selective small molecule inhibitor of group A Paks; completed crossing NF2 and Pak1-/- mice into a C3H genetic background; used a retroviral vector to express an enhanced Pak inhibitor (the Pak2 inhibitor domain) in normal and NF2 BBA (dominant negative) mutant mouse fibroblasts, and showed that loss of Pak function impedes NF2-driven cell proliferation and abnormal morphology; and used the same approach in xenograft experiments to show that loss of Pak function reduces NF2-induced tumor formation. With these advances, we have matched and in some cases exceeded our timetable for year three.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2008
- Accession Number
- ADA587741
Entities
People
- Jonathan Chernoff