The long-term OBJECTIVE of our work is to gain a deep mechanistic understanding of the fundamental process of how a simple epithelium forms by defining how cell-cell adhesion initiates actin remodeling and polarized cell organization. Our RATIONALE is that a simple epithelium is the fundamental building block of metazoans and some non-metazoans. It comprises a closed monolayer of quiescent, functionally polarized cells held together by cell-cell adhesion complexes and surrounded by the extracellular matrix (ECM). Our results from the current period showed that the mechanistic link between cell-cell adhesion and epithelial polarity is ancient and fundamental to understanding how a simple epithelium forms. However, the current inventory of proteins and pathways involved in cadherin-mediated adhesion is likely incomplete, and is complicated by the overlapping roles of many of those proteins/pathways in other adhesion systems and cell migration. Our STRATEGY is to exploit the results of a novel genome-wide RNAi screen for Ca++- and E-cadherin-dependent cell-cell adhesion in Drosophila S2 cells that excluded Ca++-independent cell-cell adhesion, integrin-based ECM adhesion and spreading, and cell migration. Based on a stringent screen and validation protocol, we have provisionally assigned ~100 confirmed "hits" to 6 intersecting regulatory "hubs" that contain many proteins not previously associated directly with cadherin function. OUR GOALS in the next period are: 1). systematically define the functions of signaling pathways involved in cadherin-mediated cell-cell adhesion and the organization of epithelial polarity across a range of scales. We will use a prioritized list of proteins from the DE-cad/S2 screen, together with the spatial map and time line of protein reorganization during cell-cell adhesion defined in our previous work;and 2). Examine signaling pathways involved in the response of cell-cell adhesion complexes to perturbation of epithelial homeostasis upon mechanical strain, which results in the re-entry of quiescent cells into the cell cycle through different pathways that are dependent on E-cadherin, beta-catenin and alpha-catenin. We anticipate that our results will provide new a mechanistic understanding of pathways that regulate epithelial morphogenesis and homeostasis.
Understanding how cell-cell adhesion regulates the morphogenesis and homeostasis of simple epithelia is an important biomedical problem. Core components of the cadherin-catenin cell-cell adhesion complex are tumor suppressors and an oncogene. Defects in epithelial organization lead to a wide spectrum of genetic/metabolic diseases, with epithelial cancers being the most common type of cancer in humans.
|Toret, Christopher P; D'Ambrosio, Michael V; Vale, Ronald D et al. (2014) A genome-wide screen identifies conserved protein hubs required for cadherin-mediated cell-cell adhesion. J Cell Biol 204:265-79|
|Buckley, Craig D; Tan, Jiongyi; Anderson, Karen L et al. (2014) Cell adhesion. The minimal cadherin-catenin complex binds to actin filaments under force. Science 346:1254211|
|Mbom, Bertrade C; Siemers, Kathleen A; Ostrowski, Maggie A et al. (2014) Nek2 phosphorylates and stabilizes ?-catenin at mitotic centrosomes downstream of Plk1. Mol Biol Cell 25:977-91|
|Dash, Surjya Narayan; Lehtonen, Eero; Wasik, Anita A et al. (2014) Sept7b is essential for pronephric function and development of left-right asymmetry in zebrafish embryogenesis. J Cell Sci 127:1476-86|
|Lowndes, Molly; Rakshit, Sabyasachi; Shafraz, Omer et al. (2014) Different roles of cadherins in the assembly and structural integrity of the desmosome complex. J Cell Sci 127:2339-50|
|Miller, Phillip W; Clarke, Donald N; Weis, William I et al. (2013) The evolutionary origin of epithelial cell-cell adhesion mechanisms. Curr Top Membr 72:267-311|
|Arnspang, Eva C; Sundbye, Sabrina; Nelson, W James et al. (2013) Aquaporin-3 and aquaporin-4 are sorted differently and separately in the trans-Golgi network. PLoS One 8:e73977|
|Lowndes, Molly; Nelson, W James (2013) Fabricating surfaces with distinct geometries and different combinations of cell adhesion proteins. Methods Mol Biol 1046:219-30|
|Miller, Phillip W; Pokutta, Sabine; Ghosh, Agnidipta et al. (2013) Danio rerio *E-catenin is a monomeric F-actin binding protein with distinct properties from Mus musculus *E-catenin. J Biol Chem 288:22324-32|
|Mbom, Bertrade C; Nelson, W James; Barth, Angela (2013) *-catenin at the centrosome: discrete pools of *-catenin communicate during mitosis and may co-ordinate centrosome functions and cell cycle progression. Bioessays 35:804-9|
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