Investigating the putative function of Merlin in the nucleus. Cameron Berry, Amanda Neisch, Richard Fehon. Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL.
Within epithelial cells, the need to control cell proliferation and cell death is paramount, particularly in development where the number of proliferating cells is highly regulated to maintain correct organ size. One protein that has been implicated in cellular proliferation and regulation of tissue size is the FERM-domain containing protein Merlin. Merlin has been shown to regulate downstream signaling pathways, i.e. the Hippo tumor suppressor pathway. However, the precise molecular mechanism by which Merlin participates in this pathway is unclear. Endogenous Merlin in Drosophila is primarily vesicular and membrane-associated, suggesting that it functions in these subcellular domains. Merlins functions appear well conserved evolutionarily, but surprisingly, a recent study has proposed that its tumor suppressor functions in mammalian cells are carried out in the nucleus via suppression of a nuclearly-localized ubiquitin ligase, called CRL4DCAF1, (Li et al, 2010, Cell 140,477-490). This work further proposes that CRL4DCAF1 inhibits expression of genes involved in cell proliferation, possibly including members of the Hippo pathway. We are testing these contrasting models for Merlin function using modified forms of Merlin that are either membrane anchored or carry nuclear localization signals. Using expression in S2 cells or whole animals, we are testing their functionality in Hippo pathway signaling and in genetic rescue assays. These experiments should give insight into the subcellular domains in which Merlin functions and specifically whether it may function in the nucleus in Drosophila.