Cell-cell adhesion is a fundamental feature of multi-cellular systems. The goal of this proposal is to analyze how individual epithelial cells recognize neighboring cells to form mutual cell-cell adhesion while rejecting self-contact. Homophilic adhesive receptors on two opposing cells rapidly bind to form a cell-cell adhesion, yet the same receptors on two thin protrusions originating from the same cell surface do not. This self-awareness of individual cells suggests that cells can distinguish the chemically identical surface of neighboring cells from their own. We hypothesize that the self-recognition mechanism is mechanically regulated, and that the cadherin complex is a mechano-sensing complex that detects external forces, thereby providing a signaling cue for mutual cell adhesion. In the absence of external forces, the mechano-signal is off, and leads to the elimination of self-contacts. Using innovative micro-fabricated substrates to control self-contacting events, we will analyze the formation of self-contacts and the subsequent elimination of self-contacting sites. Furthermore, we have developed miniature force sensors to detect forces at the adhesive contacts and directly test our hypothesis. Our findings will also highlight how mutual cell-cell adhesion forms between neighboring cells. Once we understand the fundamental processes of self and other recognition by cells, our goal is to develop therapeutic agents that alter cell- cell adhesion and can be used to prevent cancer cell invasion or pathogen infection.
Regulation of cell-cell adhesion plays critical roles in development and homeostasis of multi-cellular organisms. The goal of this proposal is to analyze how individual epithelial cells recognize neighboring cells to form mutual cell-cell adhesions while rejecting self-contact. One potential outcome of the proposed research will be the development of advanced therapeutic agents that prevent cancer cell invasion or pathogen infection.
|Lee, Eliot; Ewald, Makena L; Sedarous, Mary et al. (2016) Deletion of the cytoplasmic domain of N-cadherin reduces, but does not eliminate, traction force-transmission. Biochem Biophys Res Commun 478:1640-6|
|Lee, Jennifer K; Hu, Jerry C Y; Yamada, Soichiro et al. (2016) Initiation of Chondrocyte Self-Assembly Requires an Intact Cytoskeletal Network. Tissue Eng Part A 22:318-25|
|Sumida, Grant M; Yamada, Soichiro (2015) Rho GTPases and the downstream effectors actin-related protein 2/3 (Arp2/3) complex and myosin II induce membrane fusion at self-contacts. J Biol Chem 290:3238-47|
|Sumida, Grant M; Yamada, Soichiro (2013) Self-contact elimination by membrane fusion. Proc Natl Acad Sci U S A 110:18958-63|
|Jorrisch, Melissa H; Shih, Wenting; Yamada, Soichiro (2013) Myosin IIA deficient cells migrate efficiently despite reduced traction forces at cell periphery. Biol Open 2:368-72|
|Cui, Yuanyuan; Yamada, Soichiro (2013) N-cadherin dependent collective cell invasion of prostate cancer cells is regulated by the N-terminus of Î±-catenin. PLoS One 8:e55069|
|Li, Li; Hartley, Robert; Reiss, Bjoern et al. (2012) E-cadherin plays an essential role in collective directional migration of large epithelial sheets. Cell Mol Life Sci 69:2779-89|
|Shih, Wenting; Yamada, Soichiro (2012) N-cadherin-mediated cell-cell adhesion promotes cell migration in a three-dimensional matrix. J Cell Sci 125:3661-70|
|Steele, Amanda N; Sumida, Grant M; Yamada, Soichiro (2012) Tandem zyxin LIM sequences do not enhance force sensitive accumulation. Biochem Biophys Res Commun 422:653-7|
|Shih, Wenting; Yamada, Soichiro (2012) N-cadherin as a key regulator of collective cell migration in a 3D environment. Cell Adh Migr 6:513-7|
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