Pyrazolo pyrimidine-type inhibitors of SRC family tyrosine kinases promote ovarian steroid-induced differentiation of human endometrial stromal cells in vitro.
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.
Maruyama
Tetsuo
T
Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo 160-8582, Japan. tetsuo@sc.itc.keio.ac.jp
Yamamoto
Yurie
Y
Shimizu
Aki
A
Masuda
Hirotaka
H
Sakai
Nozomi
N
Sakurai
Rei
R
Asada
Hironori
H
Yoshimura
Yasunori
Y
D000818:Animals; D000077214:Becaplermin; D016227:Benzoquinones; D015415:Biomarkers; D002454:Cell Differentiation; D003656:Decidua / Q000166:cytology / Q000378:metabolism; D004717:Endometrium / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics; D047029:Lactams, Macrocyclic; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology*; D011388:Prolactin / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; C412373:AG 1879; D016227:Benzoquinones; D015415:Biomarkers; D004791:Enzyme Inhibitors; D004967:Estrogens; D018970:Insulin-Like Growth Factor Binding Protein 1; D047029:Lactams, Macrocyclic; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011720:Pyrazoles; D011743:Pyrimidines; D011809:Quinones; D000077214:Becaplermin; D017828:Rifabutin; D011374:Progesterone; C020754:herbimycin; D011388:Prolactin; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases