Cadherin-mediated adhesion and the Notch signaling pathway are two critical processes developed at the start of the evolution of multicellular organisms. The first process arranges numerous cells into highly organized tissues. The second determines the differentiation program of individual cells. While some circumstantial evidence suggests that the two processes intersect, the levels and mechanisms of their interdependency are largely unknown. Our preliminary experiments identified two potentially crucial links between cadherin- mediated adhesion and Notch signaling. One of these links is a complex containing E-cadherin and gamma- secretase, the enzyme that generates a Notch-derived signal. The proteins are interconnected via p120- catenin, a critical regulator of cadherin-based adhesion. In a second complex, E-cadherin interacts with Notch ligands, either Dll1 or Jag2. This proposal addresses four questions: (i) What are the detailed structures of both complexes and how are they assembled? (ii) What is the role of cadherin in their cell surface dynamics, and in their endocytosis in particular? (iii) What are their roles in Notch signaling? (iv) What are their roles in keratinocyte differentiation? We propose that cadherin facilitates Notch signal transduction by co-clustering Notch signaling components within cell-cell junctions and/or within the endocytic structures. Furthermore, cadherin-driven endocytosis of these clusters may generate the shift in Notch conformation, thereby initiating a Notch signaling cascade. This proposal will shed light on mechanisms coordinating morphogenetic, proliferation and differentiation programs of keratinocytes during normal homeostasis and inflammatory skin diseases.

Public Health Relevance

We found that cadherin adhesion is required to co-cluster and co-endocytose different components of the Notch signaling machinery. In this proposal we will study the molecular links between cadherin-based adhesion and Notch signaling. Our experiments will shed light on basic mechanisms coordinating morphogenetic, proliferation and differentiation programs of keratinocytes during normal homeostasis, wound healing, and human skin inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR057992-03
Application #
8271257
Study Section
Intercellular Interactions (ICI)
Program Officer
Baker, Carl
Project Start
2010-07-15
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$329,400
Indirect Cost
$113,400
Name
Northwestern University at Chicago
Department
Dermatology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Indra, Indrajyoti; Hong, Soonjin; Troyanovsky, Regina et al. (2013) The adherens junction: a mosaic of cadherin and nectin clusters bundled by actin filaments. J Invest Dermatol 133:2546-54
Hong, Soonjin; Troyanovsky, Regina B; Troyanovsky, Sergey M (2013) Binding to F-actin guides cadherin cluster assembly, stability, and movement. J Cell Biol 201:131-43
Troyanovsky, Regina B; Klingelhofer, Jorg; Troyanovsky, Sergey M (2011) ýý-Catenin contributes to the strength of E-cadherin-p120 interactions. Mol Biol Cell 22:4247-55