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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM076561-06
Application #
7984859
Study Section
Intercellular Interactions (ICI)
Program Officer
Flicker, Paula F
Project Start
2006-01-01
Project End
2015-04-30
Budget Start
2011-06-01
Budget End
2012-04-30
Support Year
6
Fiscal Year
2011
Total Cost
$294,541
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Folmsbee, Stephen Sai; Gottardi, Cara J (2017) Cardiomyocytes of the Heart and Pulmonary Veins: Novel Contributors to Asthma? Am J Respir Cell Mol Biol 57:512-518
Wood, Megan N; Ishiyama, Noboru; Singaram, Indira et al. (2017) ?-Catenin homodimers are recruited to phosphoinositide-activated membranes to promote adhesion. J Cell Biol 216:3767-3783
Sennello, Joseph A; Misharin, Alexander V; Flozak, Annette S et al. (2017) Lrp5/?-Catenin Signaling Controls Lung Macrophage Differentiation and Inhibits Resolution of Fibrosis. Am J Respir Cell Mol Biol 56:191-201
Loffredo, L F; Abdala-Valencia, H; Anekalla, K R et al. (2017) Beyond epithelial-to-mesenchymal transition: Common suppression of differentiation programs underlies epithelial barrier dysfunction in mild, moderate, and severe asthma. Allergy 72:1988-2004
Serebryannyy, Leonid A; Yemelyanov, Alex; Gottardi, Cara J et al. (2017) Nuclear ?-catenin mediates the DNA damage response via ?-catenin and nuclear actin. J Cell Sci 130:1717-1729
Folmsbee, Stephen Sai; Wilcox, Douglas R; Tyberghein, Koen et al. (2016) ?T-catenin in restricted brain cell types and its potential connection to autism. J Mol Psychiatry 4:2
Flozak, Annette S; Lam, Anna P; Gottardi, Cara J (2016) A Simple Method to Assess Abundance of the ?-Catenin Signaling Pool in Cells. Methods Mol Biol 1481:49-60
Folmsbee, Stephen Sai; Budinger, G R Scott; Bryce, Paul J et al. (2016) The cardiomyocyte protein ?T-catenin contributes to asthma through regulating pulmonary vein inflammation. J Allergy Clin Immunol 138:123-129.e2
Reinke, Lauren; Lam, Anna P; Flozak, Annette S et al. (2016) Adiponectin inhibits Wnt co-receptor, Lrp6, phosphorylation and ?-catenin signaling. Biochem Biophys Res Commun 470:606-612
Serebryannyy, Leonid A; Parilla, Megan; Annibale, Paolo et al. (2016) Persistent nuclear actin filaments inhibit transcription by RNA polymerase II. J Cell Sci 129:3412-25

Showing the most recent 10 out of 42 publications