The ability to form specialized membrane domains composed of unique sets of transmembrane proteins, associated cytoplasmic proteins, and phospholipids, is a fundamental property of polarized epithelial cells. Membrane domains, such as the apical surface or junctional complex, allow spatial segregation of functions at the plasma membrane that are essential for polarized epithelia. Central to this process is the formation of protein complexes on the cytoplasmic side of the membrane that localize transmembrane proteins, regulate their signaling output and control their abundance via regulated endocytosis. The Ezrin, Radixin, Moesin (ERM) proteins organize a key role in this process. In this proposal we describe experiments designed to take advantage of the combined expertise of two investigators, Andrea McClatchey (Harvard/MGH) and Richard Fehon (University of Chicago), to extend our understanding of ERM function. The investigators and their laboratories bring together expertise in two powerful experimental systems, the mouse and Drosophila. The proposed research utilizes a multifaceted approach, including genetics, biochemistry, cell biology and proteomics to better understand the functions of these highly conserved proteins. Specifically, we plan to: 1) Determine the molecular mechanisms that link the ERM proteins to the activation state of Rho in developing epithelial cells. 2) Examine the molecular mechanisms that regulate ERM activity, particularly in the context of how ERM activity is dynamically regulated. 3) Delineate the function of the ERM proteins in cell:cell junction remodeling. 4) To build an integrated model of ERM-mediated complex formation. These experiments are expected to provide novel insight into the functions of ERM proteins in biological processes such as apical-basal polarity cytoskeletal regulation, intestinal lumen formation and homeostasis, and metastasis. They should also yield a better understanding of the cellular processes that establish specialized membrane domains in polarized cells, and inform our understanding of cytoskeletal and junctional dynamics during morphogenesis and in disease.
We will carry out complementary and synergistic studies in two powerful model systems - Drosophila and the mouse - to examine the function of ERM proteins in epithelial morphogenesis. Specifically, we will test the hypothesis that ERM proteins provide local regulation of RhoGTPase activity in response to upstream signals/receptors using molecular tools and genetic models that we have developed in each system. We will also delineate the function of ERM proteins in cell junction remodeling/stability as suggested by the phenotypes of ERM loss in both flies and mammals.
|Sherrard, Kristin M; Fehon, Richard G (2015) The transmembrane protein Crumbs displays complex dynamics during follicular morphogenesis and is regulated competitively by Moesin and aPKC. Development 142:1869-78|
|Boggiano, Julian C; Fehon, Richard G (2012) Growth control by committee: intercellular junctions, cell polarity, and the cytoskeleton regulate Hippo signaling. Dev Cell 22:695-702|
|McClatchey, Andrea I; Yap, Alpha S (2012) Contact inhibition (of proliferation) redux. Curr Opin Cell Biol 24:685-94|
|Hebert, Alan M; DuBoff, Brian; Casaletto, Jessica B et al. (2012) Merlin/ERM proteins establish cortical asymmetry and centrosome position. Genes Dev 26:2709-23|
|Casaletto, Jessica B; Saotome, Ichiko; Curto, Marcello et al. (2011) Ezrin-mediated apical integrity is required for intestinal homeostasis. Proc Natl Acad Sci U S A 108:11924-9|
|Neisch, Amanda L; Fehon, Richard G (2011) Ezrin, Radixin and Moesin: key regulators of membrane-cortex interactions and signaling. Curr Opin Cell Biol 23:377-82|
|Neisch, Amanda L; Speck, Olga; Stronach, Beth et al. (2010) Rho1 regulates apoptosis via activation of the JNK signaling pathway at the plasma membrane. J Cell Biol 189:311-23|
|Fehon, Richard G; McClatchey, Andrea I; Bretscher, Anthony (2010) Organizing the cell cortex: the role of ERM proteins. Nat Rev Mol Cell Biol 11:276-87|
|Benhamouche, Samira; Curto, Marcello; Saotome, Ichiko et al. (2010) Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes Dev 24:1718-30|
|Hughes, Sarah C; Formstecher, Etienne; Fehon, Richard G (2010) Sip1, the Drosophila orthologue of EBP50/NHERF1, functions with the sterile 20 family kinase Slik to regulate Moesin activity. J Cell Sci 123:1099-107|
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