Pyrazolo Pyrimidine-Type Inhibitors of Src Family Tyrosine Kinases Promote Ovarian Steroid-Induced Differentiation of Human Endometrial Stromal Cells In Vitro1

Tetsuo Maruyama, Yurie Yamamoto, Aki Shimizu, Hirotaka Masuda, Nozomi Sakai, Rei Sakurai, Hironori Asada, Yasunori Yoshimura
In: Biology of Reproduction · 2004 · vol. 70(1) , pp. 214–221 · doi:10.1095/biolreprod.103.021527 · PMID:14522827 · W2121818595
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Pyrazolo[3,4-d]pyrimidine derivatives PP1 and PP2 unexpectedly enhanced ovarian steroid-induced human endometrial stromal cell differentiation by increasing c-Src kinase activity.

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Abstract

Reversible protein tyrosine phosphorylation, coordinately controlled by protein tyrosine kinases and phosphatases, is a critical element in signal transduction pathways regulating a wide variety of biological processes, including cell growth, differentiation, and tumorigenesis. We have previously reported that c-Src belonging to the Src family tyrosine kinase (SFK) becomes dephosphorylated at tyrosine 530 (Y530) and thereby activated during progestin-induced differentiation of human endometrial stromal cells (i.e., decidualization). In this study, to elucidate the role of decidual c-Src activation, we examined whether 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1) and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), both potent and selective SFK inhibitors, affected the ovarian steroid-induced decidualization in vitro. Unexpectedly, PP1 paradoxically increased the kinase activity of decidual c-Src together with dephosphorylation of Y530 in the presence of ovarian steroids. Concomitantly, PP1 enhanced morphological and functional decidualization, as determined by induction of decidualization markers, such as insulin-like growth factor binding protein-1 and prolactin. PP2 also advanced decidualization along with up-regulation of the active form of c-Src whose Y-530 was dephosphorylated. In contrast to PP1 and PP2, herbimycin A, a tyrosine kinase inhibitor with less specificity for SFKs, showed little enhancing effect on the expression of both IGFBP-1 and active c-Src. These results suggest that SFKs, including c-Src, may play a significant role in stromal cell differentiation, providing a clue for a possible therapeutic strategy to modulate endometrial function by targeting signaling pathway(s) involving SFKs.

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chemicals 12
pyrazolopyrimidine steroid tyrosine progestin amino oligosaccharide pyrazolopyrazole pyrimidine amino oligosaccharide steroid steroid pp2 elloramycin a
organisms 2
human human

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