R-Ras GTPases in the regulation of the Wnt Planar Cell Polarity pathway
Final Report Abstract
The NF2 tumour suppressor gene is mutated in the familial cancer syndrome Neurofibromatosis type 2. Merlin, the protein product of NF2, displays significant homology to members of the ERM (Ezrin/Radixin/Moesin) family of cytoskeletal linkers. None of the ERM proteins however, behaves as a tumour suppressor and the molecular function of Merlin remains elusive. The research presented here shows that Merlin interacts with the RNA Polymerase Il-associated factor 1 complex (PafC), a multifunctional complex that coordinates transcriptional and post-transcriptional events. The Cdc73/parafibromin subunit of the PafC is the product of the CDC73/HRPT2 tumour suppressor gene, which is mutated in hyperparathyroidism-jaw tumour syndrome and in sporadic tumours. The PafC is required for growth inhibition by Merlin and tumour derived loss-of-function mutations in Merlin invariably disrupt the interaction with the PafC. Inactivating Cdc73 mutations also disrupt the interaction with Merlin highlighting the importance of this interaction in cancer. Finally, Merlin modulates PafC association with chromatin, indicafing a novel role for Merlin in regulating gene expression. Taken together, Merlin suppresses tumourigenesis by regulating gene expression through its interaction with the PafC.
