The formation and stabilization of cell-cell adhesion complexes (adherens junctions) is essential for metazoan development, organogenesis and tissue homeostasis, and is also necessary for some pathophysiological conditions, for example wound healing. In contrast, loss of adherens junctions is a hallmark of cancer, leading to unrestricted cell proliferation and metastasis. Cell-cell adherens junctions require the proper assembly of multi-protein complexes at the plasma cell membrane. Here homotypic interactions between the calcium-binding ectodomains of single transmembrane pass cadherin receptors allows neighboring cells to bind to one another. The interactions of their cytoplasmic tail domains with ?-catenin, which in turn binds to ?-catenin, appears to direct the formation of adherens junctions, by inhibiting the production of lamellopodia. However, this ternary cadherin:??-catenin:??-catenin complex does not bind directly to the actin network, which is necessary for stabilizing these junctions and for tissue homeostasis. One thought is that local increases in the concentrations of ?-catenin at these complexes favors the formation of ?-catenin homodimers that then stabilize these complexes by directly binding to actin through a domain in their C-termini. By moving from crystal structures to biochemistry and then to biology, the proposed studies will define how adherens junctions are stabilized and control the organization of the actin cytoskeleton. Importantly, our studies will also lay the foundation for understanding how these controls are lost during tumor progression and may suggest new avenues for therapeutic intervention.

Public Health Relevance

Metazaon development and homeostasis requires that cells from stable contacts, coined adherens junctions, with their neighbors. Adherens junctions are multi- protein complexes that are directed by homotypic interactions of the extracellular domains of transmembrane cadherin receptors, which bind to ?-catenin via their intracellular tail domains;?-catenin then binds to ??-catenin and this ternary complex appears to direct the formation of adherens junctions. Our research program will define how these junctions are stabilized and control the actin network.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM094483-04
Application #
8731248
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Flicker, Paula F
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Florida
Department
Type
DUNS #
City
Jupiter
State
FL
Country
United States
Zip Code
33458
Rangarajan, Erumbi S; Izard, Tina (2013) Dimer asymmetry defines ?-catenin interactions. Nat Struct Mol Biol 20:188-93
Rangarajan, Erumbi S; Izard, Tina (2012) The cytoskeletal protein *-catenin unfurls upon binding to vinculin. J Biol Chem 287:18492-9