Signal Transduction Mechanism in differentiation and Development of Follicular Granulosa Cells.

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Activin was originally isolated from mammalian ganads as a stimulator for FSH secretion by pituitary cells. the primary structures was found to be very similar to TGF-beta. Recent studies have verified that, like TGF-beta, mfivin has vadous fimctions in various biological reactions including development, differentiation and morphogenesis. In this project, we focused on elucidation of the mechanism for activin signal msduction.(1)We found in rat ovaly and bovine pituitary an activin-binding protein with a specific and high affinity for activin, and proved that it was identical to follistatin, which was initially obtained from pig ovary as an FSHsecretion suppressor. We also demonstrated that follistatin exerts a neutralizing effect on activin activity in various systems. These inhibitory effects of follistatin on activin actions can be explained by our finding that folhstatin binds directly to activin to form an inactive complex. Follistatin very likely plays a significant role in the regulation of various actions of activin. (2)Follistatin secreted by cultured rat granulosa cells was shown to associate with cell surface by affinity labeling with ^<125>I-activin. It bound to the heparan sulfate side chains of proteoglycans on the cell surface. Cell-bound follistatin may capture activin in the matrix and at the cell surface and regurate the various actions of activin. (3)An activin receptor protein was isolated by affinity chromatography on an activin-immobilizedcolumn from membrane fractions of several cell cultures including mouse Friend leukemia cell F5-5, human erythroleukemia cell K562 and mouse EC cell P19. SDS-PAGE of the prepretion showed one band of 70 kDa. The amino acid sequence of the first 18 residues revealed that the purified receptor is a member of the activin receptor family.