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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM094798-04
Application #
8536844
Study Section
Special Emphasis Panel (ZGM1-GDB-7 (EU))
Program Officer
Nie, Zhongzhen
Project Start
2010-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$280,061
Indirect Cost
$88,991
Name
University of California Davis
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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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 α-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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