Disease relevance of Mer

• The neurofibromatosis-2 homologue, Merlin, and the tumor suppressor expanded function together in Drosophila to regulate cell proliferation and differentiation [1].
• Loss of Merlin function in Drosophila results in hyperplasia of the affected tissue without significant disruptions in differentiation [1].

High impact information on Mer

• The tumor suppressors Merlin, expanded, hippo, salvador and mob as tumor suppressor also share multiple Fat pathway phenotypes but regulate Warts activity independently [2].
• Here, we show that Drosophila Merlin and Expanded are components of the Hippo signalling pathway, an emerging tumour-suppressor pathway [3].
• The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis [3].
• Merlin, and its function as a negative regulator of growth, is conserved in Drosophila, where it functions with Expanded, a related FERM domain protein [3].
• In addition, we provide evidence that the COOH-terminal region of Merlin has a negative regulatory role, as has been shown for ERM proteins [4].

Biological context of Mer

• Removal of a seven-amino acid conserved sequence within this domain results in a dominant-negative form of Merlin that is stably associated with the plasma membrane and causes overproliferation when expressed ectopically in the wing [4].
• Using in vitro mutagenesis, we define functional domains within Merlin required for proper subcellular localization and for genetic rescue of lethal Merlin alleles [4].
• Conversely, loss of mer substantially compromises normal developmental apoptosis in the pupal retina, while loss of ex has only mild effects [5].
• By individually analyzing ex and mer mutant phenotypes, we have found important qualitative and quantitative differences in the ways Mer and Ex function to regulate cell proliferation and cell survival [5].
• Though both mer and ex restrict cell and tissue growth, ex clones exhibit delayed cell cycle exit in the developing eye, while mer clones do not [5].

Anatomical context of Mer

• Investigation of Dmerlin cultured cells demonstrates that it is associated with endocytic compartments [6].
• Although many proteins in this family are thought to act by linking the actin-based cytoskeleton to transmembrane proteins, the cellular functions of merlin have not been defined [6].
• Merlin mutants show defects in nuclear migration and mRNA localisation in the oocyte [7].

Associations of Mer with chemical compounds

• Remarkably, the results of these experiments demonstrate that all essential genetic functions reside in the plasma membrane- associated NH2-terminal 350 amino acids of Merlin [4].
• Mutations that inactivate either merlin (mer) or expanded (ex) result in increased cell growth and proliferation in Drosophila [5].

Other interactions of Mer

• As a result of these studies, we propose that the merlin protein has unique functions in the cell which differ from those of other ERM family members [6].
• The Drosophila tumor suppressors Expanded and Merlin differentially regulate cell cycle exit, apoptosis, and Wingless signaling [5].
• Both Mer and Ex are members of the Band 4.1 protein superfamily, and, based on analyses of mer ex double mutants, they are proposed to function together in at least a partially redundant manner upstream of the Hippo (Hpo) and Warts (Wts) proteins to regulate cell growth and division [5].
• Finally, ex has a role in regulating Wingless protein levels in the eye that is not obviously shared by either mer or hpo [5].
• We propose that Merlin acts in response to the Gurken signal by apically targeting the signal that initiates axis specification in the oocyte [7].

References