Analysis of anti-growth properties of processed Follistatin proteins

Haerry, Theodor

Abstract

Members of the TGF-b family of growth factors (Activins/Inhibins/BMPs) are extracellular proteins that provide important signals during animal development. Mutations in many components of the TGF-b pathway have been linked to the loss of growth control and tumor formation in humans. In mice, the loss of Inhibin-a results in gonadal and adrenal tumors followed by a cancer cachexia-like wasting syndrome. These mice exhibit more than tenfold elevated levels of Activin in the blood suggesting that it may cause or facilitate the development or the progression of these cancers. It was found that ubiquitous over-expression of the Activin inhibitor Follistatin (FS) in inhibin-a mutant mice reduces Activin levels, alleviates cachexia, and prolongs survival. However, FS was not potent enough to prevent the formation of these tumors. Interestingly, we found that Drosophila Follistatin (dFS) is a stronger growth inhibitor than its vertebrate orthologues. Compared to vertebrate FS proteins, dFS is larger, more basic, and proteolytically processed. Our results suggest a model, where processed forms of dFS not only bind and inhibit ligands but also block signaling by allowing the formation of inactive complexes with type II receptors. To test this hypothesis, we will isolate, identify, and generate processed forms of dFS and analyze their biological activity. The final goal of the proposed work is to engineering modified FS proteins with greater anti-growth properties that could be used to combat cancers caused by mutations in Inhibin-a and other TGF-b signaling components. Follistatins are secreted proteins that bind members of the TGF-b family and inhibit cell proliferation. The final goal of the proposed work is to engineering modified FS proteins with greater anti-growth properties that could be used to combat cancers caused by mutations in TGF-b signaling components. ? ? ?