Our laboratory is interested in the mechanical, biophysical and cellular aspects of cell interactions with its surroundings. Cells are not only exquisitely sensitive to biomechanical properties of their environment, but also actively participate in its remodelling by both biomechanical and biochemical means. Conversely, biomechanical properties of cell environment affect cell differentiation and function. All of these processes depend on calcium as a signalling molecule and, consequently, on calcium-binding proteins. One such protein is calreticulin, the cell biology of which has been the subject of research in my laboratory for some time. Calreticulin is a ubiquitous calcium-storage protein and a chaperone of the ER/SR. Calreticulin affects calcium homeostasis and gene expression, particularly that of steroid-sensitive and adhesion-related genes. Any of these effects may affect cell differentiation and downstream developmental processes.
Our interest is in the role of calreticulin in determining the output of ES cell differentiation. Calreticulin, either by its role in intracellular calcium homeostasis or as a chaperone, modulates actions of tissue-specific transcription factors and signalling pathways that control cell lineage specification and expression of the differentiated phenotype. It has long been accepted that the biomechanical properties of the growth substratum, by modulating cell adhesiveness, shape, and cytoarchitecture, influence the phenotype of many cells, including ES cells. Cell adhesion and shape are modulated by calreticulin. Thus, both cell shape and signalling pathways are affected by calreticulin expression level. Consequently, we postulate that the cell fate choice may be controlled by the combinatorial action of calreticulin level of expression and biomechanics of the cell's environment (niche). Thus our research might be referred to as cytomechanics of differentiation.
To elucidate role of calreticulin in development we have been studying its role in embryonic stem (ES) cell choice of fate. We discovered that calreticulin acts as a molecular switch either promoting (bone) or suppressing (fat) stem cell differentiation, while it seems to deregulate cardiogenesis.
Reviews related to our work:
Michalak, M. and M. Opas. 2009: Endoplasmic and sarcoplasmic reticulum in the heart. Trends Cell Biol. 19, 253-259.
Villagomez, M., E. Szabo, A. Podcheko, T. Feng, S. Papp and M. Opas. 2009: Calreticulin and focal contact-dependent adhesion. Biochem. Cell Biol. 87, 545-556.
Michalak, M., J. Groenendyk, E. Szabo, L. Gold and M. Opas. 2009: Calreticulin, a multi-process calcium buffering chaperone of the endoplasmic reticulum. Biochem. J. 417, 651-666.
Szabo, E., S. Papp and M. Opas. 2006: Calreticulin and cell-substratum adhesion. Ca Binding Proteins 1, 86-91.
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