Pyrazolo pyrimidine-type inhibitors of SRC family tyrosine kinases promote ovarian steroid-induced differentiation of human endometrial stromal cells in vitro.

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.

• Authors: Tetsuo Maruyama, Yurie Yamamoto, Aki Shimizu, Hirotaka Masuda, Nozomi Sakai, Rei Sakurai, Hironori Asada, Yasunori Yoshimura
• Journal: Biology of reproduction (Biol Reprod) Vol. 70 Issue 1 Pg. 214-21 (Jan 2004) ISSN: 0006-3363 [Print] United States
• PMID: 14522827 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine
• AG 1879
• Benzoquinones
• Biomarkers
• Enzyme Inhibitors
• Estrogens
• Insulin-Like Growth Factor Binding Protein 1
• Lactams, Macrocyclic
• Platelet-Derived Growth Factor
• Proto-Oncogene Proteins c-sis
• Pyrazoles
• Pyrimidines
• Quinones
• Becaplermin
• Rifabutin
• Progesterone
• herbimycin
• Prolactin
• src-Family Kinases
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Becaplermin
• Benzoquinones
• Biomarkers
• Cell Differentiation
• Decidua (cytology, metabolism)
• Endometrium (cytology, metabolism)
• Enzyme Inhibitors (pharmacology)
• Estrogens (pharmacology)
• Female
• Humans
• Insulin-Like Growth Factor Binding Protein 1 (genetics)
• Lactams, Macrocyclic
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• NIH 3T3 Cells
• Phosphorylation (drug effects)
• Platelet-Derived Growth Factor (pharmacology)
• Progesterone (pharmacology)
• Prolactin (genetics)
• Proto-Oncogene Proteins c-sis
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Quinones (pharmacology)
• Rifabutin (analogs & derivatives)
• Signal Transduction (drug effects, physiology)
• Stromal Cells (cytology, drug effects, metabolism)
• src-Family Kinases (antagonists & inhibitors, metabolism)