Molecular basis of bone morphogenetic protein-15 signaling in granulosa cells

R. Kelly Moore, Fumio Otsuka, Shunichi Shimasaki

Research output: Contribution to journalArticle

232 Citations (Scopus)

Abstract

Bone morphogenetic protein-15 (BMP-15), an oocyte growth factor belonging to the transforming growth factor-β superfamily, has recently been shown to be necessary for normal female fertility in mammals. We have previously demonstrated that BMP-15 regulates granulosa cell (GC) proliferation and differentiation; namely, BMP-15 promotes GC mitosis, suppresses follicle-stimulating hormone (FSH) receptor expression, and stimulates kit ligand expression. Although the role of BMP-15 in female reproduction has progressively deserved much attention, there is nothing known to date about the signaling pathway and receptors for BMP-15. Using rat primary GCs and a human GC cell line, COV434, we have now found that administration of BMP-15 causes a rapid and transient phosphorylation, thus activation, of the Smadl/5/8 pathway. BMP-15 also stimulated promoter activity of a selective BMP-responsive reporter construct, further demonstrating the stimulation of Smad1/5/8 signaling by BMP-15. In contrast, BMP-15 stimulation of Smad2 phosphorylation was very weak. To identify the receptors for BMP-15, we utilized recombinant extracellular domains of individual transforming growth factor-β superfamily receptors and found that activin receptor-like kinase-6 extracellular domain most effectively co-immunoprecipitates with BMP-15, whereas BMP receptor type II extracellular domain was most effective in inhibiting BMP-15 bioactivity on FSH-induced progesterone production and GC thymidine incorporation. We also investigated whether activation of the MAPK pathway is necessary for BMP-15 biological activity and found that the addition of U0126, an inhibitor of ERK1/2 phosphorylation, suppresses BMP-15 activity on GC mitotsis but not on FSH-induced progesterone production, suggesting a selective signaling cascade in GC proliferation and differentiation.

Original languageEnglish
Pages (from-to)304-310
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number1
DOIs
Publication statusPublished - Jan 3 2003
Externally publishedYes

Fingerprint

Bone Morphogenetic Protein 15
Granulosa Cells
Phosphorylation
Cell proliferation
Follicle Stimulating Hormone
Transforming Growth Factors
Bioactivity
Progesterone
Cell Differentiation
Type I Bone Morphogenetic Protein Receptors
Type II Bone Morphogenetic Protein Receptors
Chemical activation
Cells
Cell Proliferation
FSH Receptors
Stem Cell Factor
Mammals

ASJC Scopus subject areas

  • Biochemistry

Cite this

Molecular basis of bone morphogenetic protein-15 signaling in granulosa cells. / Moore, R. Kelly; Otsuka, Fumio; Shimasaki, Shunichi.

In: Journal of Biological Chemistry, Vol. 278, No. 1, 03.01.2003, p. 304-310.

Research output: Contribution to journalArticle

Moore, R. Kelly ; Otsuka, Fumio ; Shimasaki, Shunichi. / Molecular basis of bone morphogenetic protein-15 signaling in granulosa cells. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 1. pp. 304-310.
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