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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 \u03b1<jats:sub>2<\/jats:sub>-macroglobulin (\u03b1<jats:sub>2<\/jats:sub>M*), activating thus several cellular signalling pathways implicated in cell growth and survival. We hypothesised that GRP78 interaction with \u03b1<jats:sub>2<\/jats:sub>M* may also activate signalling pathways in trophoblastic cells, which, in turn, may promote cell fusion. Here, we observed that \u03b1<jats:sub>2<\/jats:sub>M 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 \u03b1<jats:sub>2<\/jats:sub>M* on syncytialisation. We first demonstrated that \u03b1<jats:sub>2<\/jats:sub>M* induced trophoblastic cell fusion. This effect is dependent on \u03b1<jats:sub>2<\/jats:sub>M*-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.<\/jats:p>","DOI":"10.1038\/s41598-020-66554-0","type":"journal-article","created":{"date-parts":[[2020,6,15]],"date-time":"2020-06-15T06:02:44Z","timestamp":1592200964000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Activated \u03b12-macroglobulin binding to cell surface GRP78 induces trophoblastic cell fusion"],"prefix":"10.1038","volume":"10","author":[{"given":"Daniel","family":"Bastida-Ruiz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Wuillemin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aude","family":"Pederencino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Yaron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bego\u00f1a","family":"Martinez de Tejada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore Vincent","family":"Pizzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,6,15]]},"reference":[{"key":"66554_CR1","unstructured":"Schoenwolf, G. 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