The ability of individual cells to adhere and differentiate into distinct tissues is a major feature of multicellular organisms. The cadherin/catenin adhesion signaling system plays a central role in coordinating cell-cell adhesion and differentiation, as catenin proteins not only comprise the structural "Velcro" that holds cells together, but also direct gene expression in the nucleus. The multifunctional protein, b-catenin, is widely viewed as a model for such adhesion signaling. b-catenin transduces extracellular Wnt signals by interacting with T-cell factor (TCF)-type DN -binding factors to form a binary transcription complex that activates genes. At cell-cell contacts, b-catenin also links the cytoplasmic domain of cadherin-type adhesion receptors to the actin-binding protein, 1-catenin, which allows cells to interact through robust intercellular adhering junctions. Since b-catenin exhibits either tumor suppressive or oncogenic activities depending on its subcellular distribution and binding partners, understanding how b-catenin is targeted to adhesive or nuclear signaling complexes is relevant to strategies that seek to inhibit the oncogenic, but spare the tumor suppressive activities of b-catenin. While the contribution of b-catenin to signaling and cell adhesion is largely determined through its respective binding to TCF and cadherin proteins, the phosphorylations and upstream signals that modulate these interactions remain poorly defined. This proposal seeks to determine how phosphorylation of cadherins (Aim 1) and 2-catenin (Aim 2) impact b-catenin adhesive and nuclear signaling functions. The actin binding protein, 1-catenin, links the 2-catenin/cadherin complex to the underlying actin cytoskeleton, but mechanisms that control 1-catenin binding to actin remain poorly defined.
Aim 3 seeks to determine how phosphorylation of 1-catenin impacts cell-cell adhesion. Altogether, this proposal will lead to an understanding of how catenin-based adhesive and nuclear signaling functions are regulated by phosphorylation, which are fundamental questions broadly relevant to normal tissue integrity and tumor biology.

Public Health Relevance

Activation of nuclear b-catenin signaling is found in numerous epithelial cancers and is the major cause of hereditary and sporadic forms of colon cancer-the 4th most common cancer in the United States. b-catenin is also a critical component of cadherin-based adhesion complexes, which can serve as a tumor suppressive unit. Since b-catenin exhibits both tumor suppressive and promoter functions depending on its localization, understanding the phosphorylation events that promote cadherin/catenin adhesive function and restrict 2-catenin nuclear signaling function will further strategies to inhibit the oncogenic activity of b-catenin, while preserving the tumor suppressive activities of catenins.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Intercellular Interactions (ICI)
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Nie, Zhongzhen
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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
Lam, Anna P; Herazo-Maya, Jose D; Sennello, Joseph A et al. (2014) Wnt coreceptor Lrp5 is a driver of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 190:185-95
Daugherty, Rebecca L; Serebryannyy, Leonid; Yemelyanov, Alex et al. (2014) ?-Catenin is an inhibitor of transcription. Proc Natl Acad Sci U S A 111:5260-5
Barry, Adrienne K; Tabdili, Hamid; Muhamed, Ismaeel et al. (2014) ?-catenin cytomechanics--role in cadherin-dependent adhesion and mechanotransduction. J Cell Sci 127:1779-91
Hamanaka, Robert B; Glasauer, Andrea; Hoover, Paul et al. (2013) Mitochondrial reactive oxygen species promote epidermal differentiation and hair follicle development. Sci Signal 6:ra8
Campos, M Luisa; Sanchez-Arevalo Lobo, Victor J; Rodolosse, Annie et al. (2013) ICAT is a novel Ptf1a interactor that regulates pancreatic acinar differentiation and displays altered expression in tumours. Biochem J 451:395-405
Mirkovic, Ivana; Gault, William J; Rahnama, Maryam et al. (2011) Nemo kinase phosphorylates ?-catenin to promote ommatidial rotation and connects core PCP factors to E-cadherin-?-catenin. Nat Struct Mol Biol 18:665-72
Burkhalter, Rebecca J; Symowicz, Jaime; Hudson, Laurie G et al. (2011) Integrin regulation of beta-catenin signaling in ovarian carcinoma. J Biol Chem 286:23467-75
Lam, Anna P; Gottardi, Cara J (2011) ?-catenin signaling: a novel mediator of fibrosis and potential therapeutic target. Curr Opin Rheumatol 23:562-7
Lam, Anna P; Flozak, Annette S; Russell, Susan et al. (2011) Nuclear ?-catenin is increased in systemic sclerosis pulmonary fibrosis and promotes lung fibroblast migration and proliferation. Am J Respir Cell Mol Biol 45:915-22

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