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J Physiol Volume 571, Number 3, 537-553, March 15, 2006 DOI: 10.1113/jphysiol.2005.102285
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Src family kinases play multiple roles in differentiation of trophoblasts from human term placenta

Georges Daoud1,2, Éric Rassart2, André Masse3 and Julie Lafond1,2

1 Laboratoire de Physiologie materno-foetale, Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, Québec, Canada, H3C 3P8
2 Centre de recherche Biomed, Université du Québec à Montréal, Montréal, Québec, Canada, H3C 3P8
3 Département d'Obstétrique-Gynécologie, Hôpital St-Luc, Université de Montréal, Montréal, Québec, Canada, H2L 4M1

Tyrosine phosphorylation plays a major role in controlling many biological processes in different cell types. Src family kinases (SFKs) are one of the most studied groups of tyrosine kinases and can mediate a variety of signalling pathways. However, little is known about the expression of SFKs in human term placenta and their implication in trophoblast differentiation. Therefore, we examined the expression profile of SFK members over time in culture and their implication in differentiation. In vitro, freshly isolated cytotrophoblast cells, cultured in 10% fetal bovine serum (FBS), spontaneously aggregate and fuse to form multinucleated cells that resemble phenotypically mature syncytiotrophoblasts, that concomitantly produce human chorionic gonadotropin (hCG) and human placental lactogen (hPL). In this study, we showed that trophoblasts expressed all SFK members and some of them are expressed as different splice variants. Moreover, using real-time PCR, this study showed two different expression profiles of SFKs in human trophoblasts during culture. In addition, the protein level and phosphorylation status of Src were evaluated using specific antibodies. Src was rapidly phosphorylated at Tyr-416 and dephosphorylated at Tyr-527 after FBS addition. Surprisingly, inhibition of SFKs by 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d] pyrimidine (PP2) or herbimycin A had different effects on trophoblast differentiation. While herbimycin A inhibited morphological and hormonal differentiation, PP2 stimulated hormonal differentiation and inhibited cell adhesion and spreading with no effect on cell fusion. In summary, this study showed that SFKs play different roles in trophoblast differentiation, probably depending on SFK members activated. Thus, this study increases our knowledge and understanding of pathology related to impaired trophoblast differentiation such as pre-eclampsia and trophoblast neoplasm.

(Received 23 November 2005; accepted after revision 11 January 2006; first published online 12 January 2006)
Corresponding author J. Lafond: Laboratoire de Physiologie materno-foetale, Université du Québec à Montréal, Département des Sciences Biologiques, C.P. 8888, Succursale Centre-ville, Montréal, Canada, H3C 3P8. Email: lafond.julie{at}uqam.ca






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