A novel receptor function for the heat shock protein Grp78: silencing of Grp78 gene expression attenuates alpha sub(2)M-induced signalling

• Published in: Cellular signalling 2004-08, Vol.16 (8), p.929-938
• Main Authors: Misra, U K, Gonzalez-Gronow, M, Gawdi, G, Wang, F, Pizzo, S V
• Format: Article
• Language: English
• ISSN: 0898-6568
• DOI: 10.1016/j.cellsig.2004.01.003

The activated proteinase inhibitor alpha sub(2)-macroglobulin ( alpha sub(2)M) binds to two receptors, the low density lipoprotein receptor- related protein (LRP-1) and the alpha sub(2)M signalling receptor ( alpha sub(2)MSR). Silencing LRP-1 gene expression in macrophages by RNA interference does not block alpha sub(2)M activation of signalling cascades. We now demonstrate that transfection of macrophages with a double-stranded RNA homologous in sequence to the Grp78 gene markedly decreased induction of inositol 1, 4, 5-trisphosphate (IP sub(3)) and subsequent IP sub(3)-dependent elevation of [Ca super(2+)] sub(i) induced by alpha sub(2)M. Concomitantly, alpha sub(2)M-induced increase in [ super(3)H]thymidine uptake was abolished in these transfected cells. Insulin treatment significantly upregulates alpha sub(2)MSR and it also caused a marked increase in Grp78 expression which could be blocked by RNA interference. alpha sub(2)M treatment of cells activates the Ras- and PI 3-kinase-dependent signalling pathways. Suppressing Grp78 expression leads to the loss of these activation events in transfected macrophages. We thus conclude that Grp78 is the alpha sub(2)M signalling receptor.