Analysis of p21-Activated Kinase Function in Neurofibromatosis Type 2
Annual rept. 1 Jan 2008-31 Dec 2008
INSTITUTE FOR CANCER RESEARCH PHILADELPHIA PA
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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 andor 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.
- Anatomy and Physiology
- Medicine and Medical Research