Calreticulin and cellular adhesion/migration-specific signalling pathways

Abstract

Calreticulin is a Ca2+-binding protein of the ER/SR, from where it acts as a chaperone, and affects calcium homeostasis, gene expression and cell adhesion. Cell adhesion to the extracellular matrix can generate transmembrane signals important for cell survival and migration. In a variety of cell types, integrin stimulation by ECM proteins, such as fibronectin, leads to changes in intracellular protein tyrosine phosphorylation. Tyrosine phosphorylation leads to the co-localization of focal adhesion kinase, vinculin and paxillin at focal contacts. Interaction between focal adhesion kinase and paxillin is critical for the activation of signaling cascades involved in cell survival and motility. Fibroblasts either over- or underexpressing calreticulin show differences in their adhesive properties, which are related to the calmodulin/CaMKII pathway. Inhibition of these pathways causes the weekly adhesive calreticulin underexpressing cells to behave like the calreticulin overexpressers, through increased spreading and increased levels of focal adhesion kinase, paxillin and fibronectin. We propose that calreticulin, via its Ca2+-homeostatic effects, may affect fibronectin synthesis and matrix assembly by modulating fibronectin gene expression, and by influencing formation of cellular adhesions, both of which are instrumental in matrix assembly and remodelling. Interestingly, it appears that besides the calmodulin/CaMKII pathway, differential calreticulin expression also modulates the c-src pathway.