Activated α2-macroglobulin binding to cell surface GRP78 induces trophoblastic cell fusion

The villous cytotrophoblastic cells have the ability to fuse and differentiate, forming the syncytiotrophoblast (STB). The syncytialisation process is essential for placentation. Nevertheless, the mechanisms involved in cell fusion and differentiation are yet to be fully elucidated. It has been suggested that cell surface glucose-regulated protein 78 (GRP78) was involved in this process. In multiple cancer cells, cell membrane-located GRP78 has been reported to act as a receptor binding to the active form of alpha (2)-macroglobulin (alpha M-2*), activating thus several cellular signalling pathways implicated in cell growth and survival. We hypothesised that GRP78 interaction with alpha M-2* may also activate signalling pathways in trophoblastic cells, which, in turn, may promote cell fusion. Here, we observed that alpha M-2 mRNA is highly expressed in trophoblastic cells, whereas it is not expressed in the choriocarcinoma cell line BeWo. We thus took advantage of forskolin-induced syncytialisation of BeWo cells to study the effect of exogenous alpha M-2* on syncytialisation. We first demonstrated that alpha M-2* induced trophoblastic cell fusion. This effect is dependent on alpha M-2*-GRP78 interaction, ERK1/2 and CREB phosphorylation, and unfolded protein response (UPR) activation. Overall, these data provide novel insights into the signalling molecules and mechanisms regulating trophoblastic cell fusion.