Calreticulin is essential for integrin-mediated calcium signalling and cell adhesion

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Abstract
Integrins are important mediators of cell adhesion to extracellular ligands and can transduce biochemical signals both into and out of cells1,2. The cytoplasmic domains of integrins interact with several structural and signalling proteins and consequently participate in the regulation of cell shape, motility, growth and differentiation3. It has been shown that calreticulin associates with the cytoplasmic domains of integrin α-subunits and that this interaction can influence integrin-mediated cell adhesion to extracellular matrix4,5. We have now developed calreticulin-deficient embryonic stem (ES) cells and isolated embryonic fibro-blasts from calreticulin mutant mice. We find that in both cell types integrin-mediated adhesion is severely impaired, although integrin expression is unaltered. Expression of recombinant calreticulin in double knockout ES cells by complementary DNA transfection rescued integrin-mediated adhesion. In wild-type cells, engagement of surface integrins induced a transient elevation in cytosolic calcium concentration owing to influx of extracellular calcium. This calcium transient was absent in calreticulin-deficient cells. In contrast, the amount of calcium in endomembrane stores, which is sensitive to both inositol 1,4,5-trisphosphate and thapsigargin, was indistinguishable in the two cell types. Our results indicate that calreticulin is an essential modulator both of integrin adhesive functions and integrin-initiated signalling, but that it may not play a significant role in the storage of luminal calcium.