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Weizmann Institute scientists propose a model regulating cell adhesion -- central to embryonic development, cellular movement, and communication
'Hard times,' or more specifically, exposure to rigid environments, enhances the tendency of cells to form tight adhesions and communicate, according to a recent Weizmann Institute study published in the March issue of Nature Cell Biology. The findings reveal a new parameter regulating cell attachment, namely, the physical properties of the immediate surroundings.
Cell adhesion, whereby cells bind to adjacent cells and to the extracellular matrix between them, is critical to the formation of tissues and organs, as well as to cellular movement and the exchange of information between cells, known as signaling. Impaired adhesion can lead to the onset of disease, such as cancer. If detached from a surrounding matrix, cells usually die within a short time, a process called anoikis, Greek for homelessness.
Migrating while sensing the environment until finding their specific location, cells become anchored, proliferate, and develop. Yet, what are the dynamics of this mechanism? Which cues exist within a living organism influencing adhesion properties, and instructing a cell to change its location, connect, or disconnect? This is what the Weizmann team, headed by Prof. Benjamin Geiger of the Department of Molecular Cell Biology, set out to understand.
The research group included doctoral student Eli Zamir and Professors Zvi Kam and Alexander Bershadsky of the Department of Molecular Cell Biology, together with Kenneth Yamada of the National Institutes of Health (NIH), and Ben-Zion Katz of the Tel Aviv Medical Center.
Previous studies by this group had revealed that cell adhesion sites show extraordinary structural and molecular diversity. They discovered the existence of two major types of adhesion: 'focal contacts,' located mainly at the cell periphery, which form tight adhesions and play an important role in cellular signaling, and 'fibrillar adhesions,' forming scattered connections, and found primarily around the cell center.
Mobile adhesions? Sounds paradoxical, yet cell adhesions are indeed mobile according to the Weizmann study, and this trait is jointly regulated by the rigidity of the surrounding environment and cellular contractility. Using digital microscopic analysis combined with fluorescent proteins expressed in live cells, the team captured time-lapse 'movies' revealing the mobility and fate of cell adhesions in different environments.
Fibrillar adhesions and focal contacts were found to originate together near the cell periphery, and then segregate. While focal contacts generally stay put, fibrillar adhesions are continuously transported towards the cell center by a conveyor belt - the cell's contractile microfilament system.
Surprisingly, the researchers found that in addition to the chemical nature of the environment, its physical properties also have a say in adhesion 'demography.' The rigidity of the surrounding matrix was shown to serve as a 'mechanical switch,' affecting cell adhesion dynamics. Focal contacts develop upon interaction with a rigid matrix and remain largely immobile, while interaction with a flexible matrix results in the formation of fibrillar adhesions, which are then carted away together with their accompanying proteins towards the cell center. 'Cells demonstrate a tactile-like sense that informs them of changes in their environment,' says Geiger. 'While cellular adhesion was previously believed to be primarily influenced by the types of molecules a cell encounters, it turns out that physical cues also influence adhesion and a cell's decision to strike roots in a certain 'neighborhood,' or, alternatively, disconnect and move on.'
Changing physical environments switch on cell communication lines as well, the study suggests. Previous research performed by Bershadsky and others had shown that high-tension environments lead to enhanced signaling, triggering a cascading message transferred from the cell periphery to its command center -- the nucleus. This understanding fits nicely with the recent discovery that rigid, high-tension environments drive the formation of focal contacts, which are characterized by enhanced phosphorylation -- an essential element of cell communication and signal transduction.
Matrix rigidity and cellular contractility serve as 'biomechanical switches' regulating cell adhesion. Fibrillar adhesions are formed upon interaction with soft fibronectin matrixes and carted away together with tensin and other proteins towards the cell center. In contrast, rigid substrates make cells switch to focal contact adhesions, stick tightly together, and communicate
This study was funded by the Israel Science Foundation, Yad Abraham Center for Cancer Diagnosis and Therapy, and the Minerva Foundation.
Prof. Geiger holds the Erwin Neter Chair of Cell and Tumor Biology. Prof. Kam holds the Israel Pollak Chair of Biophysics.
The Weizmann Institute of Science is a major center of scientific research and graduate study located in Rehovot, Israel.