Each cell-cell contact integrates many individual junctions of several functionally and structurally different types. These junctions must be coordinately remodeled during morphogenetic changes. The long-term goal of our project is to define the mechanisms of this coordination. In the current funding cycle of our grant, we study the interplay between adhesive extracellular module and actin-binding intracellular module of adherens junctions (AJs). These junctions consist of the transmembrane adhesive receptor, cadherin, that interacts with the actin cytoskeleton through proteins called catenins. We discovered a remarkable binding process - the cooperative binding of a-catenin to actin filaments. This process is likely to regulate the strength of the cadherin adhesive interface. We also found that the same process bundles the actin filaments attached to the junction and that the resulting bundle promotes the assembly of another junction, called nectin junction (NJ). Our preliminary data suggests that this assembly is based on the specific recognition of this bundle by the NJ protein, afadin. This and other data, outlined in our proposal, suggest a new hypothesis that the actin-binding proteins of NJs, tight junctions, and desmosomes recognize the local actin filament organization produced by AJs and that this recognition coordinates the assembly and dynamics of all junctions in the cell-cell contact. This study will not only explore this conceptually new type of cell signaling, but also will lay the foundation for understanding th role of this signaling in complex morphogenetic processes.
Our preliminary studies show that the actin-binding proteins of different cell-cell junctions, including adherens junctions and tight junctions, play a much more interesting role than simply interconnecting the junctions with the actin cytoskeleton. These proteins remodel the cytoskeleton in the junction sites in a way that it becomes a binding substrate for the actin-binding protein of another junction. We propose that this remodeling of the junction-associated actin cytoskeleton and the sensing the remodeled cytoskeleton by other junctions is a new type of signaling process that coordinates different junctions in a cell-cell contact. This study is a critical step toward the development of synthetic adhesion modulators and their applications in medicine.
| Indra, Indrajyoti; Choi, Jongho; Chen, Chi-Shuo et al. (2018) Spatial and temporal organization of cadherin in punctate adherens junctions. Proc Natl Acad Sci U S A 115:E4406-E4415 |
| Chen, Chi-Shuo; Hong, Soonjin; Indra, Indrajyoti et al. (2015) ?-Catenin-mediated cadherin clustering couples cadherin and actin dynamics. J Cell Biol 210:647-61 |
| Biswas, Kabir H; Hartman, Kevin L; Yu, Cheng-han et al. (2015) E-cadherin junction formation involves an active kinetic nucleation process. Proc Natl Acad Sci U S A 112:10932-7 |
| Strale, Pierre-Olivier; Duchesne, Laurence; Peyret, Grégoire et al. (2015) The formation of ordered nanoclusters controls cadherin anchoring to actin and cell-cell contact fluidity. J Cell Biol 210:333-46 |
| Troyanovsky, Regina B; Indra, Indrajyoti; Chen, Chi-Shuo et al. (2015) Cadherin controls nectin recruitment into adherens junctions by remodeling the actin cytoskeleton. J Cell Sci 128:140-9 |
| Indra, Indrajyoti; Troyanovsky, Regina; Troyanovsky, Sergey M (2014) Afadin controls cadherin cluster stability using clathrin-independent mechanism. Tissue Barriers 2:e28687 |
| 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 133:2546-2554 |
| 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 |
| Harrison, Oliver J; Vendome, Jeremie; Brasch, Julia et al. (2012) Nectin ectodomain structures reveal a canonical adhesive interface. Nat Struct Mol Biol 19:906-15 |
| Hong, Soonjin; Troyanovsky, Regina B; Troyanovsky, Sergey M (2011) Cadherin exits the junction by switching its adhesive bond. J Cell Biol 192:1073-83 |
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