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Molecular Genetics and Cell Biology


Research Projects:

Tissue Growth Control

 
 

 

The precise coordination of signals that control proliferation is a key feature of growth regulation in developing tissues. While much has been learned about the basic components of signal transduction pathways, less is known about how receptor localization, compartmentalization, and trafficking affect signaling in developing tissues. We are examining this question by studying the functions of Merlin, the Drosophila homologue of the Neurofibromatosis 2 tumor suppressor gene, in controlling epithelial proliferation. We have shown previously that Merlin functions together with another tumor suppressor, Expanded, to regulate both proliferation and differentiation in developing imaginal epithelia. Both proteins localize to the apical junctional region of the plasma membrane. Our recent studies show that in the absence of Merlin and Expanded transmembrane receptors that control proliferation and cell fate specification, such as Notch, the EGF receptor, Patched and Smoothened all accumulate to abnormally high levels at the plasma membrane. As a result output of the corresponding signaling pathways also can be upregulated. Pulse labeling experiments of receptors at the cell surface indicate that trafficking of receptors off the plasma membrane is inhibited in mutant cells. We propose that Merlin and Expanded control proliferation by regulating the abundance, localization and turnover of cell surface receptors, and that misregulation of these processes may be a key component of tumorigenesis.

We are currently examining the cell biological basis of these effects by studying the localization and endocytosis of transmembrane receptors in mutant cells, as well as determining how simultaneous misregulation of multiple signaling pathways affects proliferation and differentiation in developing tissues. We are also examining the role of Merlin and Expanded in Hippo signaling pathway, which regulates proliferation via poorly understood mechanisms. A related study examines the coordinate regulation of Merlin function and the function of the closely related ERM proteins.

 


Mosaic Drosophila compound eyes carrying control (left) or Merlin mutant (right) ommatidia marked by the absence of red pigment.
Mutant cells were induced early in development by mitotic recombination and then allowed to proliferate throughout larval and pupal development. Merlin mutant cells overproliferate relative to wild-type cells marked simultaneously (dark red patches), and evidenced by the fact that the white patch is larger than the dark red patch.

 

 

Related publications:

McCartney BM, Fehon RG. Distinct cellular and subcellular patterns of expression imply distinct functions for the Drosophila homologues of moesin and the neurofibromatosis 2 tumor suppressor, merlin. J Cell Biol. 1996 May;133(4):843-52. (PubMed)

Fehon RG, Oren T, LaJeunesse DR, Melby TE, McCartney BM. Isolation of mutations in the Drosophila homologues of the human Neurofibromatosis 2 and yeast CDC42 genes using a simple and efficient reverse-genetic method. Genetics. 1997 May;146(1):245-52. (PubMed)

McCartney BM, Kulikauskas RM, LaJeunesse DR, Fehon RG. The neurofibromatosis-2 homologue, Merlin, and the tumor suppressor expanded function together in Drosophila to regulate cell proliferation and differentiation. Development. 2000 Mar;127(6):1315-24. (PubMed)

Bretscher A, Edwards K, Fehon RG. ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol. 2002 Aug;3(8):586-99. Review. (PubMed)

Formstecher E, Aresta S, Collura V, Hamburger A, Meil A, Trehin A, Reverdy C, Betin V, Maire S, Brun C, Jacq B, Arpin M, Bellaiche Y, Bellusci S, Benaroch P, Bornens M, Chanet R, Chavrier P, Delattre O, Doye V, Fehon R, Faye G, Galli T, Girault JA, Goud B, de Gunzburg J, Johannes L, Junier MP, Mirouse V, Mukherjee A, Papadopoulo D, Perez F, Plessis A, Rosse C, Saule S, Stoppa-Lyonnet D, Vincent A, White M, Legrain P, Wojcik J, Camonis J, Daviet L. Protein interaction mapping: a Drosophila case study. Genome Res. 2005 Mar;15(3):376-84. Epub 2005 Feb 14. (PubMed)

Maitra S, Kulikauskas RM, Gavilan H, Fehon RG. The tumor suppressors Merlin and expanded function cooperatively to modulate receptor endocytosis and signaling. Curr Biol. 2006 Apr 4;16(7):702-9. (PubMed)

Hughes SC, and Fehon RG. Phosphorylation and activity of the tumor-suppressor Merlin and the ERM protein Moesin are coordinately regulated by the Slik kinase. J. Cell Biol. 2006 Oct 23;175(2):305-13. (PubMed)

Cho E, Feng Y, Rauskolb C, Maitra S, Fehon R, Irvine KD. Delineation of a Fat tumor suppressor pathway. Nat Genet. 2006 Oct;38(10):1142-50 (PubMed)

Li Q, Nance MR, Kulikauskas R, Nyberg K, Fehon R, Karplus PA, Bretscher A, and Tesmer J. Self-masking in an intact ERM-merlin protein: an active role for the central alpha-helical domain. J Mol Biol. 2007 Feb 2;365(5):1446-59 (PubMed)

McClatchey, A.I. and Fehon, R.G. Merlin and the ERM proteins - regulators of receptor distribution and signaling at the cell cortex. Trends Cell Biol. 2009 19: 198-206. (PubMed)

Bensenor LB, Barlan K, Rice SE, Fehon RG, Gelfand VI. Microtubule-mediated transport of the tumor-suppressor protein Merlin and its mutants. Proc Natl Acad Sci U S A. 2010 107: 7311-6. (PubMed)

Boggiano, J.C, Vanderzalm, P.J. and Fehon, R.G. Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway. Dev. Cell. 2011 21:888-895. (PubMed)

Boggiano, J.C and Fehon, R.G. Growth control by committee: Intercellular junctions, cell polarity, and the cytoskeleton regulate Hippo signaling. Dev. Cell. 2012 22: 695-702. (PubMed)

Gavilan, H.S., Kulikauskas, R.M., Gutmann, D.H., and Fehon, R.G. In vivo Functional Analysis of the Human NF2 Tumor Suppressor Gene in Drosophila. PLoS ONE. 2014 9: e90853. (PubMed)

Zhang, Y., Wang, X., Matakatsu, H., Fehon, R. & Blair, S. S. The novel SH3 domain protein Dlish/CG10933 mediates fat signaling in Drosophila by binding and regulating Dachs. eLife. 2016 5: e16624. (PubMed)

Matakatsu, H., Blair, S. S., & Fehon, R.G. The palmitoyltransferase Approximated promotes growth via the Hippo pathway by palmitoylation of Fat. J.Cell Biol. 2017 216: 265-277. (PubMed)

Su T, Ludwig MZ, Xu J, Fehon R.G. Kibra and Merlin activate the Hippo pathway spatially distinct from and independent of Expanded. Dev. Cell. 2017 40: 478-490. (PubMed)

Matakatsu H, Blair SS, Fehon R.G. Size does matter! Cell Cycle. 2017 1-2. (PubMed)

 

Fehon Lab Research Projects:

Septate Junctions  
Epithelial Integrity  

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