The role of E-cadherin in regulating signalling pathways

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Novelty, research program and short-term goal - E-cadherin exhibits broad biological functions and is crucial during embryonic development, reprogramming of adult cells to embryonic stem-like cells and adult tissue maintenance/homeostasis. While the majority of studies thus far focus on how growth factors, extracellular signals, transcriptional factors, and intracellular signaling pathways regulate E-cadherin expression, a fundamental question that has been largely overlooked and yet to be answered is whether and to what extent the dynamic E-cadherin expression and its intracellular partners, in turn, affect their regulators to co-control embryonic development and adult cell homeostasis and functions. This will be the long-term goal of our research program. The short-term goal of this proposed project (and hypothesis) will determine whether intracellular partners of E-cadherin and Rap1-regulated E-cadherin recycling differentially affect NF-kB, Wnt and AKT signaling activities and adult cell functions (Fig 1). Our recent progress and preliminary work related to this proposed research project - The trainees in my lab have demonstrated that E-cadherin is capable of actively regulating Wnt signaling in embryonic stem cells (Stem Cells 2010 and 2015, Mol Cell Proteomics 2011, etc.). We recently observed that E-cadherinhigh adult cells markedly inhibits NF-kB whereas upregulating Wnt and Akt activity; Wnt inhibition differentially affects other signaling pathways and the expression of stem cell-associated proteins (preliminary data). Short term objectives - Adult cells, gain- and loss-of-function and multidisciplinary approaches will be used in three aims. In Aim 1, group 1 trainees will determine which intracellular partners of E-cadherin (a-catenin, ß-catenin, and p120) affect NF-kB, Wnt, and AKT activities, stem cell-associated genes/proteins and cell functions (proliferation, apoptosis, migration and cell cycle). In Aim 2, group 2 trainees will determine the extent by which Rap1-regulated E-cadherin recycling affects three signaling activity. In Aim 3, trainees will determine whether inhibition or activation of one signaling (using gene overexpression, siRNA/shRNA knockdown, and small-molecule activators/inhibitors) differentially affects other two pathways and cell functions in an E-cadherin-intracellular partners-dependent manner. Significance - As part of our research program, knowledge gained from this proposed project will provide new insights into the currently unknown roles of intracellular partners of E-cadherin and Rap1-regulated E-cadherin cycling in the regulation of NF-kB, Wnt, and Akt signaling pathways that are crucial for adult cell functions. This will have broad impacts in cell biology, and will also offer an excellent platform for trainees to prepare their careers for academia or biotechnology companies.