The ability of individual cells to adhere and coalesce into distinct tissues is a major feature of multicellular organisms. Cell-cell adhesion is largely mediated by a protein complex that projects from the cell surface to form a structural """"""""Velcro"""""""" that holds cells to one another. This complex is comprised of a transmembrane """"""""cadherin"""""""" component that mediates Ca++-dependent homophilic recognition, and associated """"""""catenins"""""""" that link cadherins to the underlying cytoskeleton. Epithelial (E)-cadherin is the prototypic """"""""classical cadherin"""""""" present on epithelia. Reduction or loss of E-cadherin has been observed in numerous human epithelial cancers and is considered a key rate-limiting step in tumor metastasis. The cytoplasmic domain of classical cadherins binds the dual function adhesion/transcriptional co-activator protein, ?-catenin, which in turn binds the F-actin binding protein, ?-catenin, effectively coupling adhesion to the actin cytoskeleton. It has been known for over a decade that cytoplasmic tail of E-cadherin is robustly phosphorylated in the ?-catenin binding region and that this phosphorylation increases the affinity for ?-catenin in vitro. However, the function and regulation of E-cadherin phosphorylation in vivo remain poorly defined. We find that E-cadherin phosphorylation is required for effective binding to ?-catenin binding in vivo, suggesting the hypothesis that modulation of E-cadherin phosphorylation directs changes in cell-cell adhesion. We seek to determine the kinase (or kinases) that phosphorylates the cytoplasmic tail of E-cadherin and the specific amino acids that are phosphorylated using a dsRNA Drosophila cell screen and mass spectrometry (Aim 1).
In Aim 2 we seek to determine the contribution of E-cadherin phosphorylation and ?-catenin binding on its trafficking to and endocytosis from the plasma membrane. Altogether, these aims will lead to an understanding of how E-cadherin phosphorylation is regulated and will define its role in cell-cell adhesion, two questions that are broadly relevant to both normal epithelial integrity and tumor metastasis.

Public Health Relevance

The loss of cell-cell adhesion is an important step in tumor metastasis. Our goal is to understand how phosphorylation of the adhesion molecule E-cadherin regulates how cells stick together. This knowledge will aid in the development of both molecular diagnostic tools and chemotherapeutic drugs.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Damico, Mark W
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Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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McEwen, Abbye E; Maher, Meghan T; Mo, Rigen et al. (2014) E-cadherin phosphorylation occurs during its biosynthesis to promote its cell surface stability and adhesion. Mol Biol Cell 25:2365-74
McEwen, Abbye E; Escobar, David E; Gottardi, Cara J (2012) Signaling from the adherens junction. Subcell Biochem 60:171-96