Abstract
Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum (ER) molecular chaperone that belongs to the heat shock protein 70 family. GRP78 is also present on the cell surface membrane of trophoblastic cells, where it is associated with invasive or fusion properties of these cells. Impaired mechanism of GRP78 relocation from ER to the cell surface was observed in preeclamptic cytotrophoblastic cells (CTB) and could take part in the pathogenesis of preeclampsia. In this study, we have investigated whether prostate apoptosis response 4 (Par-4), a protein identified as a partner of GRP78 relocation to the cell surface in prostate cancer cells, is present in trophoblastic cells and is involved in the translocation of GRP78 to the cell surface of CTB. Par-4 is indeed present in trophoblastic cells and its expression correlates with expression of membrane GRP78. Moreover, overexpression of Par-4 led to an increase of cell surface expression of GRP78 and decreased Par-4 gene expression reduced cell surface localization of GRP78 confirming a role of Par-4 in relocation of GRP78 from ER to the cell surface. Accordingly, invasive property was modified in these cells. In conclusion, we show that Par-4 is expressed in trophoblastic cells and is involved in transport of GRP78 to the cell surface and thus regulates invasive property of extravillous CTB.
Highlights
Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum (ER) molecular chaperone that belongs to the heat shock protein 70 family
Since mRNA of prostate apoptosis response 4 (Par-4) was found in placenta [27], we propose to evaluate the role of Par-4 in transport of GRP78 from the ER to the cell surface of extravillous cytotrophoblastic cells (evCTBs) and confirm the role of membrane GRP78 in trophoblastic cell invasion
To test the hypothesis that Par-4 is involved in the transport of GRP78 from the ER to the cell surface of trophoblastic cells, we first evaluated the presence of Par-4 in these cells
Summary
GRP78 is an ER molecular chaperone that belongs to the heat shock protein 70 family (for a review [1]). GRP78 is well-known to reside inside the ER lumen This chaperone is located at the cell surface of cancer cells and cells undergoing ER stress [5] [4]. It was hypothesized that overexpression of GRP78 observed under stress conditions may exceed the retention capacity of the KDEL retrieval system, resulting in relocation of GRP78 from the ER to the cell surface [7]. It was hypothesized that the masking of the KDEL may be implicated in GRP78 transport to the cell surface. On the outer plasma membrane, GRP78 functions as a receptor for a wide variety of ligands [2] and several small proteins can bind to surface GRP78 and modulate properties of cells [5]
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