Analysis of p21-Activated Kinase Function in Neurofibromatosis Type 2

摘要

In this project, we sought to determine if p21-activated kinases (Paks) are required for Schwann cell growth and invasiveness in cells lacking the tumor suppressor Merlin (the protein product of the neurofibromatosis-2 gene). We found that Paks are highly expressed in Schwann cells and that inhibitor of Pak - either by a peptide or by a small molecule developed by us during the course of this project - blocked proliferation and invasiveness of two different Merlin-deficient cell lines. Importantly, inhibition of Pak also blocked tumor formation in mice xenografted with Merlin-deficient cells. We also found that the beneficial effects of Pak blockade in Merlin-deficient cells were not mediated by the ERK signaling pathway. These results are important because they 1) establish Paks as potential therapeutic targets in NF2, and 2) they show that these events occur through an unexpected molecular mechanism, a problem we will continue to examine in future work.