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. An ER resident protein, calreticulin emerged as universally important calcium-storage protein implicated to play a role in a variety of diverse areas of cell biology and as such has attracted substantial research interest in our laboratory.

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 substratum. In brief,  our research might be referred to as the cytomechanics of differentiation.

 

We have been studying ES cell differentiation toward adipogenic and osteogenic lineages where the effect of calreticulin seems to be that of a switch either promoting (bone) or suppressing (fat) differentiation. 

Relevant papers from our lab:
Feng, T., E. Szabo, E. Dziak and M. Opas. 2010: Cytoskeletal disassembly and cell rounding promotes adipogenesis from ES cells. Stem Cell Rev. Rep. 6, 74-85.

Szabo, E., T. Feng and M. Opas. 2009: Cell adhesion and spreading affect adipogenesis from ES cells: the role of calreticulin. Stem Cells. 27, 2092-2102.
Szabo, E., J. Soboloff, E. Dziak and M. Opas. 2009: Tamoxifen-inducible Cre-mediated calreticulin excision to study mouse embryonic stem cell differentiation. Stem Cells Devel. 18, 187-193.
Szabo, E., Y. Qiu, S. Baksh, M. Michalak and M. Opas. 2008: Calreticulin modulates commitment to adipocyte differentiation. J. Cell Biol. 182, 103-116. With commentary by Dr. Jacopo Meldolesi.

In another line of research, we have been studying cardiac differentiation from ES cells in which the calreticulin gene has been genetically manipulated.  As heart-targeted overexpression of calreticulin also causes lethality due to cardiac defects, the protein seems to play a role not only in cardiomyogenesis but also in proper functioning of the differentiated cardiomyocyte. 

Relevant papers from our lab:
Papp, S., E. Dziak, G. Kabir, P. Backx, S. Clement and M. Opas. 2010: Evidence for cardiac hypertrophy attenuation by calreticulin induction using pressure overload and soluble agonists. Am. J. Pathol. 176, 1113-1121.

Papp, S., E. Dziak and M. Opas. 2009: Embryonic stem cell derived cardiomyogenesis: a novel role for calreticulin as a regulator. Stem Cells 27, 1507-1515.
Szabo, E., J. Soboloff, E. Dziak and M. Opas. 2009: Tamoxifen-inducible Cre-mediated calreticulin excision to study mouse embryonic stem cell differentiation. Stem Cells Devel. 18, 187-193.
Papp, S., Zhang, X., E.. Szabo and M. Opas. 2008: Expression of endoplasmic reticulum chaperones in cardiac development. The Open Cardiovasc. Med. J. 2, 31-35.
Lozyk, M.D., S. Papp, X. Zhang, K. Nakamura, M. Michalak and M. Opas. 2006: Ultrastructural analysis of development of myocardium in calreticulin-deficient mice. BMC Developmental Biology 6:54 doi:10.1186/1471-213X-6-54.

Reviews:
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.