Insulin-Like Growth Factor II Activates Phosphatidylinositol 3-Kinase-Protooncogenic Protein Kinase 1 and Mitogen-Activated Protein Kinase Cell Signaling Pathways, and Stimulates Migration of Ovine Trophectoderm Cells

• Published in: Endocrinology (Philadelphia) 2008-06, Vol.149 (6), p.3085-3094
• Main Authors: Kim, Jinyoung, Song, Gwonhwa, Gao, Haijun, Farmer, Jennifer L, Satterfield, M. Carey, Burghardt, Robert C, Wu, Guoyao, Johnson, Greg A, Spencer, Thomas E, Bazer, Fuller W
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Animals; Biological and medical sciences; Cell Differentiation; Cell Division; Cell migration; Cell proliferation; Cell signaling; Cell survival; Cloning, Molecular; Differentiation; Endometrium; Epithelium; Extracellular signal-regulated kinase; Female; Fundamental and applied biological sciences. Psychology; Glycogen; Glycogen synthase kinase 3; Glycogens; Growth factors; Hybridization; Insulin-like growth factor II; Insulin-Like Growth Factor II - genetics; Insulin-Like Growth Factor II - physiology; Insulin-like growth factors; Kinases; Male; MAP kinase; MAP Kinase Signaling System - physiology; mRNA; p38 Mitogen-Activated Protein Kinases - metabolism; Pregnancy; Protein kinase C; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pyruvic acid; Rapamycin; Ribosomal protein S6; Ribosomal protein S6 kinase; Ribosomal Protein S6 Kinases, 90-kDa - physiology; RNA, Messenger - genetics; Sheep; Signal transduction; Stimulators; Stroma; Tacrolimus; Tacrolimus-binding protein; Uterus - physiology; Vasectomy; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2007-1367

IGF-II, a potent stimulator of cellular proliferation, differentiation, and development, regulates uterine function and conceptus growth in several species. In situ hybridization analyses found that IGF-II mRNA was most abundant in the caruncular endometrial stroma of both cyclical and pregnant ewes. In the intercaruncular endometrium, IGF-II mRNA transitioned from stroma to luminal epithelium between d 14 and 20 of pregnancy. IGF-II mRNA was present in all cells of the conceptus but was particularly abundant in the yolk sac. Immunohistochemical analyses revealed that phosphorylated (p)-protooncogenic protein kinase 1, p-ribosomal protein S6 kinase, p-ERK1/2, and p-P38 MAPK proteins were present at low levels in a majority of endometrial cells but were most abundant in the nuclei of endometrial luminal epithelium and conceptus trophectoderm of pregnant ewes. In mononuclear trophectoderm cells isolated from d-15 conceptuses, IGF-II increased the abundance of p-pyruvate dehydrogenase kinase 1, p-protooncogenic protein kinase 1, p-glycogen synthase kinase 3B, p-FK506 binding protein 12-rapamycin associated protein 1, and p-ribosomal protein S6 kinase protein within 15 min, and the increase was maintained for 90 min. IGF-II also elicited a rapid increase in p-ERK1/2 and p-P38 MAPK proteins that was maximal at 15 or 30 min posttreatment. Moreover, IGF-II increased migration of trophectoderm cells. Collectively, these results support the hypothesis that IGF-II coordinately activates multiple cell signaling pathways critical to survival, growth, and differentiation of the ovine conceptus during early pregnancy.