J Appl Biomed 2:1-14, 2004

ER-to-cell surface signalling: calreticulin and cell adhesion

Sylvia Papp, Marc P. Fadel, Michal Opas^*

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

Cell shape, adhesion, and motility are affected by Ca-regulated pathways, which depend on Ca-binding proteins. One such protein is calreticulin, a ubiquitous and major Ca-binding protein, resident in the ER of eukaryotic cells. In the lumen of the ER, calreticulin is a lectin-like chaperone, sharing this function with an ER-membrane protein, calnexin. Calreticulin also functions as an ER-lumenal Ca store and plays a central role in intracellular Ca homeostasis, including the regulation of store-operated Ca influx via plasma membrane and ER Ca channels. Calreticulin also affects processes outside of the ER; most notably, it modulates expression of several genes, some of them adhesion related, such as vinculin and fibronectin. Curiously, changes in the expression level of calreticulin strongly affect tyrosine phosphorylation of cellular proteins, which is known to affect many adhesion-related functions. Consequently, calreticulin affects cell adhesion via the regulation of expression of proteins important in adhesion, as well as via its effects on intracellular signalling pathways. One of the proteins differentially phosphorylated in a calreticulin-dependent manner is β-catenin, a structural component of cadherin-mediated adhesion complexes and a part of the Wnt signalling pathway. We suggest that the observed changes in cell adhesiveness may be due to calreticulin's influence on a signalling pathway from the ER, which includes the β-catenin/vinculin protein system. Differential expression of calreticulin may affect the phosphorylation status of β-catenin by either inhibition of specific phosphotyrosine kinase(s) or activation of phosphotyrosine phosphatase(s). This is likely to affect the balance between complexed and free β-catenin and impinge further down on the Wnt signalling. At present, the mechanism by which calreticulin affects gene expression can only be speculated upon, but our data indicate that calreticulin, via its effects on Ca release from the ER, may indirectly control the expression of several genes by interfering with calcineurin activity and the ability of the transcription factor, NFAT-3, to translocate to the nucleus. The activation of calcineurin depends on the sustained release of Ca from ER stores, which is dependent on calreticulin.
In summary, we propose that calreticulin may be a centrally located connector molecule in a signalling network in the lumen of the ER. Calreticulin is uniquely endowed for such regulation because it is a multifunctional protein that interacts with several other ER proteins in a Ca-dependent manner, suggesting that it may function as a signalling "toggle switch". We therefore hypothesize that calreticulin regulates gene expression by participating in an "ER-to-nucleus" signalling pathway, which parallels an "ER-to-cell surface" pathway based upon post-translational events.

Keywords: calreticulin; calcium; adhesion; extracellular matrix

Received: May 30, 2003; Published: March 31, 2004  Show citation