PP2 Regulates Human Trophoblast Cells Differentiation by Activating p38 and ERK1/2 and Inhibiting FAK Activation

ArticleinPlacenta 29(10):862-70 · October 2008with14 Reads
DOI: 10.1016/j.placenta.2008.07.011 · Source: PubMed
Throughout gestation, fetal growth and development depend, in part, on placental transfer of nutrients from the maternal circulation. This latter function depends on multinucleated, terminally differentiated syncytiotrophoblasts. In vitro, freshly isolated cytotrophoblast cells differentiate spontaneously into syncytiotrophoblast in the presence of fetal bovine serum (FBS). We have previously showed that trophoblast differentiation is regulated by ERK1/2 and p38. Moreover, we showed that PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3, 4-d]pyrimidine], a Src family kinase (SFK) specific inhibitor, stimulates biochemical trophoblast cells differentiation while it inhibits cell adhesion and spreading without affecting cell fusion. Therefore, we examined the mechanisms by which PP2 modulates trophoblast cells differentiation. This study shows that PP2 stimulates ERK1/2 and p38 activation after 24h of treatments and up to 3 days while it inhibits focal adhesion kinase (FAK) phosphorylation at many sites including Tyr-397, 407, 576 and 577. Furthermore, we showed that transient activation of ERK1/2 by FBS is independent of SFK and that PP2 induces rapid activation of p38. Moreover, the kinase activity of SFK is negatively regulated by the phosphorylation of their carboxy (C)-terminal regulatory tyrosines by specific proteins called carboxyl-terminal Src kinase (Csk) and Csk homologous kinase (CHK). We showed the expression of Csk and CHK in human trophoblast cells. In summary, this study showed that PP2 stimulates the biochemical differentiation of trophoblast cells by stimulating p38 and ERK1/2 while it inhibits the morphological differentiation by inhibiting FAK activation.
    • "Phosphorylated mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase 1/2 (ERK 1/2) also promote the syncytialization (Daoud et al., 2005 ). In fact, p38 phosphorylation mediates the EGF-induced syncytialization (Johnstone et al., 2005b) and phosphorylated p38 and ERK 1/2 mediated the induction of biochemical differentiation resulting from the inhibition of Src family kinases (SFKs) (Daoud et al., 2008). In relation to SFKs, a different inhibitor impairs CT differentiation, suggesting that different members of this family have distinct roles in syncytialization (Daoud et al., 2006). "
    [Show abstract] [Hide abstract] ABSTRACT: The placenta is important for the success of gestation and foetal development. In fact, this specialized pregnancy organ is essential for foetal nourishment, support, and protection. In the placenta, there are different cell populations, including four subtypes of trophoblasts. Cytotrophoblasts fuse and differentiate into the multinucleated syncytiotrophoblast (syncytialization). Syncytialization is a hallmark of placentation and is highly regulated by numerous molecules with distinct roles. Placentas from pregnancies complicated by preeclampsia, intrauterine growth restriction or trisomy 21 have been associated with a defective syncytialization and an altered expression of its modulators. This work proposes to review the molecules that promote or inhibit both fusion and biochemical differentiation of cytotrophoblasts. Moreover, it will also analyse the syncytialization modulators abnormally expressed in pathological placentas, highlighting the molecules that may contribute to the aetiology of these diseases.
    Full-text · Article · Nov 2015
    • "In addition, the ERK1/2 and p38 pathways are also involved in CXCL12-mediated trophoblast differentiation in the first trimester of pregnancy [17,59]. The CXCL12/ CXCR4 axis can induce cytotrophoblast differentiation into both invasive , proliferative and secretory phenotypes via EGFR/ERK and p38/PPARγ signaling [17,25,59]. Importantly, Tripathi et al. [14] recently demonstrated that the CXCL12/CXCR7 axis could also promote trophoblast differentiation and placental development via activation of Raf/MEK/ERK1/2 signaling (Fig. 1). "
    [Show abstract] [Hide abstract] ABSTRACT: The chemokine CXCL12 and its receptor CXCR4 are important signaling components required for human blastocyst implantation and the progression of pregnancy. Growing evidence indicates that the CXCL12/CXCR4 axis can regulate trophoblast function and uterine spiral artery remodeling, which plays a fundamental role in placentation and fetal outcome. The orphan receptor CXCR7 is also believed to partly regulate the function of the CXCL12/CXCR4 axis. Additionally, the CXCL12/CXCR4/CXCR7 axis can enhance the cross-talk between trophoblasts and decidual cells such as uterine natural killer cells and decidual stromal cells which are involved in regulation of trophoblast differentiation and invasion and placental angiogenesis. In addition, recent studies proved that CXCL12 expression is elevated in the placenta and mid-trimester amniotic fluid of pregnant women with preeclampsia, implying that dysregulation of CXCL12 plays a role in the pathogenesis of preeclampsia. Further understanding of the regulatory mechanisms of CXCL12-mediated signaling in trophoblast functions and placental angiogenesis may help to design novel therapeutic approaches for pregnancy-associated diseases.
    Article · Sep 2015
    • "The SFKs control multiple cellular events such as adhesion and spreading, migration, apoptosis , cell cycle progression and gene transcription [34]. SFKs have been shown to also be involved in the differentiation of different cell types such as T cells [12], myoblasts [13], trophoblasts [17,18], chondrocytes [14] and osteoclasts [10]. However, little is known regarding the role of SFKs in the regulation of differentiation in human intestinal epithelial cells. "
    [Show abstract] [Hide abstract] ABSTRACT: The proto-oncogene Src is an important protein tyrosine kinase involved in signaling pathways that control cell adhesion, growth, migration and survival. Here, we investigated the involvement of Src family kinases (SFKs) in human intestinal cell differentiation. We first observed that Src activity peaked in early stages of Caco-2/15 cell differentiation. Inhibition of SFKs with PP2, a selective SFK inhibitor, accelerated the overall differentiation program. Interestingly, all polarization and terminal differentiation markers tested, including sucrase-isomaltase, lactase-phlorizin hydrolase and E and LI-cadherins were found to be significantly up-regulated after only 3 days of treatment in the newly differentiating cells. Further investigation of the effects of PP2 revealed a significant up-regulation of the two main intestinal epithelial cell-specific transcription factors Cdx2 and HNF1α and a reduction of polycomb PRC2-related epigenetic repressing activity as measured by a decrease in H3K27me3, two events closely related to the control of cell terminal differentiation in the intestine. Taken together, these data suggest that SFKs play a key role in the control of intestinal epithelial cell terminal differentiation.
    Full-text · Article · Dec 2012
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