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

Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo 160-8582, Japan

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.

¹ This study was supported, in part, by the Ministry of Education, Science, and Culture of Japan (grants B15390511 to T.M., B12470348 to Ya.Y., and A14207066 to Ya.Y.), by Keio Gijuku Academic Development Funds (to T.M.), by grants from the Keio Health Counseling Center (to T.M.), and by grants from Mitsukoshi Fund of Mitsukoshi Health and Welfare Foundation 2002 (to T.M.). Part of this work was presented at the 35th Annual Meeting of Society for the Study of Reproduction held in 2002, Baltimore, Maryland.

² Correspondence: Department of Obstetrics and Gynecology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. FAX: 81 3 3226 1667; tetsuo{at}sc.itc.keio.ac.jp

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