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

Tetsuo Maruyama, Yurie Yamamoto, Aki Shimizu, Hirotaka Masuda, Nozomi Sakai, Rei Sakurai, Hironori Asada, Yasunori Yoshimura

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)214-221
Number of pages8
JournalBiology of Reproduction
Volume70
Issue number1
DOIs
Publication statusPublished - 2004 Jan

Fingerprint

Insulin-Like Growth Factor Binding Protein 1
src-Family Kinases
Stromal Cells
Protein-Tyrosine Kinases
Tyrosine
Cell Differentiation
Steroids
Biological Phenomena
Protein Tyrosine Phosphatases
Progestins
Prolactin
Signal Transduction
Carcinogenesis
Phosphotransferases
Up-Regulation
Phosphorylation
Growth
Proteins
pyrimidine
In Vitro Techniques

Keywords

  • Decidua
  • Female reproductive tract
  • Kinases
  • Progesterone
  • Signal transduction

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Embryology

Cite this

Pyrazolo Pyrimidine-Type Inhibitors of Src Family Tyrosine Kinases Promote Ovarian Steroid-Induced Differentiation of Human Endometrial Stromal Cells in Vitro. / Maruyama, Tetsuo; Yamamoto, Yurie; Shimizu, Aki; Masuda, Hirotaka; Sakai, Nozomi; Sakurai, Rei; Asada, Hironori; Yoshimura, Yasunori.

In: Biology of Reproduction, Vol. 70, No. 1, 01.2004, p. 214-221.

Research output: Contribution to journalArticle

Maruyama, Tetsuo ; Yamamoto, Yurie ; Shimizu, Aki ; Masuda, Hirotaka ; Sakai, Nozomi ; Sakurai, Rei ; Asada, Hironori ; Yoshimura, Yasunori. / Pyrazolo Pyrimidine-Type Inhibitors of Src Family Tyrosine Kinases Promote Ovarian Steroid-Induced Differentiation of Human Endometrial Stromal Cells in Vitro. In: Biology of Reproduction. 2004 ; Vol. 70, No. 1. pp. 214-221.
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