PP2 Regulates Human Trophoblast Cells Differentiation by Activating p38 and ERK1/2 and Inhibiting FAK Activation
Laboratoire de Physiologie Materno-Foetale, Département des Sciences Biologiques, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montréal, Québec, Canada. Placenta
(Impact Factor: 2.71).
10/2008; 29(10):862-70. DOI: 10.1016/j.placenta.2008.07.011
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.
Available from: Amel Guezguez
- "The SFKs control multiple cellular events such as adhesion and spreading, migration, apoptosis , cell cycle progression and gene transcription . SFKs have been shown to also be involved in the differentiation of different cell types such as T cells , myoblasts , trophoblasts  , chondrocytes  and osteoclasts . However, little is known regarding the role of SFKs in the regulation of differentiation in human intestinal epithelial cells. "
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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.
Available from: Duangmani Thanapprapasr
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ABSTRACT: Gynecologic cancer is a major health burden in women across the world. Almost a half million mortalities from gynecologic cancer were reported every year. Knowledge in molecular biology research on cancer could lead to develope novel therapeutic options in gynecologic cancer. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase which plays an essential role in cancer cells survival, migration, invasion, metastasis and also tumor angiogenesis. Various human cancerous tissues were demonstrated over expression of FAK which were correlated to the survival. There were evidences showed that FAK involved in molecular pathways of ovarian cancer, endometrial cancer and cervical cancer. In the light of this review, FAK has been a promising mediator that regulates cancer growth and metastasis. Therefore, molecular therapies targeted FAK may be beneficial for patients with gynecologic cancer in the near future.
Available from: Harold M Marsh
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ABSTRACT: Repetitive deformation enhances intestinal epithelial migration across tissue fibronectin (tFN) via Src but inhibits migration across collagen. Since cell spreading generally precedes motility, we compared the effects of cyclic strain on Caco-2 spreading and migration on tFN, collagen-I, and plasma fibronectin (pFN), and investigated the role of Src in deformation-influenced spreading and migration.
Human Caco-2 intestinal epithelial cells on tFN, collagen-I or pFN were subjected to an average 10% strain at 10 cycles/min for 2 h. Src was inhibited with 10muM PP2 or Src was reduced with siRNA. Parallel studies assessed deformation effects on monolayer wound closure.
Deformation, Src-inhibition or reduction each inhibited spreading on tFN but Src-inhibition or reduction prevented further inhibition of spreading by deformation without preventing further inhibition of motility. Deformation did not alter spreading on collagen-I or pFN, but inhibited wound closure.
Although cell spreading generally precedes and parallels motility, repetitive deformation regulates motility independently of spreading. Since deformation activates Src, the ability of Src blockade to mimic strain-associated inhibition of spreading on tFN suggests that this effect occurs by a separate mechanism that may also require basal Src activity. Further delineation of the mechanisms by which strain disparately modulates spreading and motility may permit acceleration of mucosal healing by targeted interventions to separately promote spreading and epithelial motility.
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