Review Article A Novel Regulatory Mechanism of Apoptosis by Calreticulin, a Molecular Chaperone in the Endoplasmic Reticulum

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Calreticulin (CRT) is a Ca"--binding lectin-like molecular chaperone of the lumen of the endoplasmic reticulum. Recently, CRT has been revealed to be a multi-functional molecule related with glycoprotein maturation and chaperone function, Ca" homeostasis, cell adhesion, cell signaling, transcriptional regulation, and nuclear transporting mechanisms. CRT is also essential for cardiac and neural development in mice, suggesting an importance in the regulation of cell survival and death during development. To examine the role of CRT in cardiac differentiation, we established CRT-overexpressiog myocardiac H9c2 cells, and investigated the effect of the overexpression on cardiac differentiation in vitro. We found that the cells transfected with the CRT gene were highly susceptible to apoptosis compared with controls. In the gene-transfected cells, Akt/ protein kinase B signaling was significantly suppressed during the differentiation. Furthermore, PP2A, a Ser/Thr protein phosphatase, was significantly upregulated implying a suppression of Akt signaling due to dephosphorylation of Alit by the upregulated PP2A via the regulation of Ca` homeostasis. Thus, overexpression of CRT promotes differentiation- dependent apoptosis in H9c2 cells by suppressing the Akt signaling pathway. Our findings demonstrate a novel mechanism in which cytoplasmic Akt signaling is modulated to cause apoptosis by a resident protein of the endoplasmic reticulum, CRT.
長崎大学の論文