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Phosphorylation of Bone Morphogenetic Protein-15 and Growth and Differentiation Factor-9 Plays a Critical Role in Determining Agonistic or Antagonistic Functions

Department of Reproductive Medicine, University of California San Diego, School of Medicine, La Jolla, California 92093-0633

Two highly homologous oocyte-secreted growth factors, bone morphogenetic protein (BMP)-15 and growth and differentiation factor (GDF)-9, are known to control folliculogenesis and ovulation through direct effects on granulosa cells in the developing follicles. Although much is known about the expression and biology of these proteins, the impact of posttranslational modifications of BMP-15 and GDF-9 is unknown. Here, we report that: 1) recombinant human (rh) BMP-15 and rhGDF-9 are phosphorylated; 2) the phosphorylation is essential for bioactivity; and 3) the dephosphorylated forms of rhBMP-15 and rhGDF-9 can abolish the bioactivity of rhBMP-15, rhGDF-9, and rhBMP-7, but not rh activin A. These results indicate that the phosphorylation state of rhBMP-15 and rhGDF-9 is a determinant of their agonistic and antagonistic activities.