Calreticulin Affects Fibronectin-based Cell-Substratum Adhesion via the Regulation of c-Src Activity

Calreticulin is an endoplasmic reticulum Ca2+-storage protein, which influences gene expression and cell adhesion. In this study, we show that calreticulin induces fibronectin gene expression and matrix deposition, leading to differences in cell spreading and focal adhesion formation in cells differentially expressing calreticulin. We further show that these effects of calreticulin occur via a c-Src-regulated pathway and that c-Src activity is inversely related to calreticulin abundance. Since c-Src is an important regulator of focal contact turnover, we investigated the effect of c-Src inhibition on cells differentially expressing calreticulin. Inhibition of c-Src rescued the poorly adhesive phenotype of the calreticulin-underexpressing cells in that they became well spread, commenced formation of numerous focal contacts, and deposited a rich fibronectin matrix. Importantly, we show that c-Src activity is dependent on releasable Ca2+ from the endoplasmic reticulum, thus implicating Ca2+-sensitive pathways that are affected by calreticulin in cell-substratum adhesion. We propose that calreticulin affects fibronectin synthesis and matrix assembly via the regulation of fibronectin gene expression. In parallel, calcium-dependent effects of calreticulin on c-Src activity influence the formation and/or stability of focal contacts, which are instrumental in matrix assembly and remodeling. Calreticulin is an endoplasmic reticulum Ca2+-storage protein, which influences gene expression and cell adhesion. In this study, we show that calreticulin induces fibronectin gene expression and matrix deposition, leading to differences in cell spreading and focal adhesion formation in cells differentially expressing calreticulin. We further show that these effects of calreticulin occur via a c-Src-regulated pathway and that c-Src activity is inversely related to calreticulin abundance. Since c-Src is an important regulator of focal contact turnover, we investigated the effect of c-Src inhibition on cells differentially expressing calreticulin. Inhibition of c-Src rescued the poorly adhesive phenotype of the calreticulin-underexpressing cells in that they became well spread, commenced formation of numerous focal contacts, and deposited a rich fibronectin matrix. Importantly, we show that c-Src activity is dependent on releasable Ca2+ from the endoplasmic reticulum, thus implicating Ca2+-sensitive pathways that are affected by calreticulin in cell-substratum adhesion. We propose that calreticulin affects fibronectin synthesis and matrix assembly via the regulation of fibronectin gene expression. In parallel, calcium-dependent effects of calreticulin on c-Src activity influence the formation and/or stability of focal contacts, which are instrumental in matrix assembly and remodeling. Calreticulin, a Ca2+-binding protein of the endoplasmic reticulum (ER), 3The abbreviations used are: ER, endoplasmic reticulum; [Ca2+]ER, concentration of Ca2+ within the endoplasmic reticulum; [Ca2+]c, concentration of calcium in the cytosol; ECM, extracellular matrix; FAK, focal adhesion kinase; MALDI-TOF MS, matrix-assisted laser desorption ionization time-of-flight mass spectrometry; PBS, phosphate-buffered saline; PIPES, 1,4-piperazinediethanesulfonic acid. has been shown to be involved in a great number of cellular processes (1.Bedard K. Szabo E. Michalak M. Opas M. Int. Rev. Cytol. 2005; 245: 91-121Crossref PubMed Scopus (126) Google Scholar). It is an important chaperone, working in conjunction with calnexin and protein disulfide isomerase; it affects intracellular Ca2+ homeostasis via its Ca2+ storage capacity and its effects on both the SERCA pumps and inositol 1,4,5-trisphosphate receptors (2.John L.M. Lechleiter J.D. Camacho P. J. Cell Biol. 1998; 142: 963-973Crossref PubMed Scopus (181) Google Scholar, 3.Camacho P. Lechleiter J.D. Cell. 1995; 82: 765-771Abstract Full Text PDF PubMed Scopus (200) Google Scholar). Calreticulin has been shown to affect cell adhesion via the induction of vinculin and N-cadherin expression and its involvement in β-catenin-associated pathways (4.Opas M. Szewczenko-Pawlikowski M. Jass G.K. Mesaeli N. Michalak M. J. Cell Biol. 1996; 135: 1913-1923Crossref PubMed Scopus (109) Google Scholar, 5.Fadel M.P. Dziak E. Lo C.M. Ferrier J. Mesaeli N. Michalak M. Opas M. J. Biol. Chem. 1999; 274: 15085-15094Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). Finally, calreticulin overexpression causes a decrease in total cellular tyrosine phosphorylation levels (5.Fadel M.P. Dziak E. Lo C.M. Ferrier J. Mesaeli N. Michalak M. Opas M. J. Biol. Chem. 1999; 274: 15085-15094Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 6.Fadel M.P. Szewczenko-Pawlikowski M. Leclerc P. Dziak E. Symonds J.M. Blaschuk O. Michalak M. Opas M. J. Biol. Chem. 2001; 276: 27083-27089Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). Fibronectin is a large glycoprotein which is secreted by the cell into the extracellular matrix (ECM) as a soluble dimer that, via cellular interactions, is deposited as a fibrillar meshwork that is bound to the surface of cells. Fibronectin affects the formation and the stability of cell-substratum adhesions, and conversely, cell-substratum adhesions may affect fibronectin matrix deposition (7.Katz B.Z. Zamir E. Bershadsky A. Kam Z. Yamada K.M. Geiger B. Mol. Biol. 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PubMed Scopus Google Scholar). a Ca2+-binding protein, influences cell fibronectin matrix deposition, and cell-substratum we the activity of c-Src in cells differentially expressing calreticulin on both and on the of calreticulin in fibronectin matrix deposition and the regulation of c-Src activity via its influence on releasable Ca2+ from the Cell in calreticulin expression used for this been and (4.Opas M. Szewczenko-Pawlikowski M. Jass G.K. Mesaeli N. Michalak M. J. Cell Biol. 1996; 135: 1913-1923Crossref PubMed Scopus (109) Google Scholar, 6.Fadel M.P. Szewczenko-Pawlikowski M. Leclerc P. Dziak E. Symonds J.M. Blaschuk O. Michalak M. Opas M. J. Biol. Chem. 2001; 276: 27083-27089Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, K. B. M. Michalak M. PubMed Scopus Google Scholar, Mesaeli N. Michalak M. Opas M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). and used to cell K. B. M. Michalak M. 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J. 1996; PubMed Scopus Google Scholar). the by with in in for in the presence of the to be and in and for to for of by protein by MALDI-TOF MS, the of from the and in acid. with in for and in for a the with for in the and in a the by for the in and for on and the to a for a the and by a with and by MALDI-TOF by the of the on the Cell with PBS, and with in for the cells in with for cells with and for with cells with PBS, and an Cell Fibronectin with fibronectin from in for and in surface with a to of fibronectin to and cells on in in for for in PBS, the cells for with in PIPES, and and for in and with for the in in PBS, the cells with in for the in which and in with a laser used for and and of cells and are that this and with for cells and for as c-Src inhibition cells with cells with and with for cells for and for used to the concentration of Ca2+ in the with for and for of of fibronectin and of fibronectin deposition, cells with for by in of intracellular in to with a concentration of for to a used to in intracellular on in in and to cells a concentration of to calcium from intracellular the cells on cells and in a and that with fibronectin and a the with cells Calreticulin in to cell of and (4.Opas M. Szewczenko-Pawlikowski M. Jass G.K. Mesaeli N. Michalak M. J. Cell Biol. 1996; 135: 1913-1923Crossref PubMed Scopus (109) Google Scholar, 6.Fadel M.P. Szewczenko-Pawlikowski M. Leclerc P. Dziak E. Symonds J.M. Blaschuk O. Michalak M. Opas M. J. Biol. Chem. 2001; 276: 27083-27089Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, K. B. M. Michalak M. PubMed Scopus Google Scholar, Mesaeli N. Michalak M. Opas M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). with calreticulin expression calreticulin cells with calreticulin as by K. B. M. Michalak M. PubMed Scopus Google Scholar), used in this that calreticulin influences the expression of an intracellular of focal we the extracellular of focal may be affected by calreticulin. on a of cell we that cells differentially expressing calreticulin in to of total cellular of for we that calreticulin levels of fibronectin in with calreticulin cells calreticulin the intracellular fibronectin protein, the the and cells fibronectin protein in calreticulin by an in the deposition of extracellular fibronectin into the matrix we effects for fibronectin the of from the cell and to by in the of from cells differentially expressing calreticulin and differences in the of a protein that the as such that in calreticulin and in calreticulin cells secreted an of this protein and this protein, the from the and by MALDI-TOF as a the protein from the with a mass of the in the with of from of to the of the secreted protein to be fibronectin these show that cells fibronectin and protein and which to a of it in the matrix. Importantly, this is in cells the calreticulin gene by a calreticulin as well as in embryonic cell with calreticulin levels with cells. M. P. and M. In is fibronectin expression in cells with calreticulin abundance. Calreticulin an Fibronectin Calreticulin Fibronectin the the of calreticulin expression and deposition of fibronectin into the to fibronectin matrix with on we that calreticulin an fibronectin matrix in fibronectin calreticulin a fibronectin which of a of and fibronectin matrix by cells that of and and of the Fibronectin in the deposition and of a fibronectin matrix is is by focal contacts, we the adhesive of cells. with to the and an to vinculin to show focal focal contact formation and a are in cells calreticulin are poorly and focal and of the number of focal cell a number of focal in calreticulin with cells Calreticulin a number of focal contacts, which are in cells fibronectin in is the and the extracellular of the is for (11.Wu C. Bauers R.L. Juliano R.L. McDonnell J.A. J. Biol. Chem. 1993; 268: 21883-21888Abstract Full Text PDF PubMed Google Scholar). We to the in fibronectin matrix assembly in cells to fibronectin expression the cell in calreticulin expression affect the total protein levels of in these cells (4.Opas M. Szewczenko-Pawlikowski M. Jass G.K. Mesaeli N. Michalak M. J. Cell Biol. 1996; 135: 1913-1923Crossref PubMed Scopus (109) Google Scholar, 6.Fadel M.P. Szewczenko-Pawlikowski M. Leclerc P. Dziak E. Symonds J.M. Blaschuk O. Michalak M. Opas M. J. Biol. 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Thus, we that this Ca2+ may be fibronectin gene expression and matrix Thus, we and of fibronectin by fibronectin levels which by fibronectin deposition and fibrillogenesis in cell Thus, has effects on both the expression and deposition of c-Src in to further the by which fibronectin and focal affected by calreticulin. We shown that poorly cells that calreticulin levels of total cellular in with well calreticulin M.P. Szewczenko-Pawlikowski M. Leclerc P. Dziak E. Symonds J.M. Blaschuk O. Michalak M. Opas M. J. Biol. 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