Abstract
The hedgehog (Hh) and Wnt pathways, crucial for the embryonic development and stem cell proliferation of Metazoa, have long been known to have similarities that argue for their common evolutionary origin. A surprising additional similarity of the two pathways came with the discovery that WIF1 proteins are involved in the regulation of both the Wnt and Hh pathways. Originally, WIF1 (Wnt Inhibitory Factor 1) was identified as a Wnt antagonist of vertebrates, but subsequent studies have shown that in Drosophila, the WIF1 ortholog serves primarily to control the distribution of Hh. In the present, work we have characterized the interaction of the human WIF1 protein with human sonic hedgehog (Shh) using Surface Plasmon Resonance spectroscopy and reporter assays monitoring the signaling activity of human Shh. Our studies have shown that human WIF1 protein binds human Shh with high affinity and inhibits its signaling activity efficiently. Our observation that the human WIF1 protein is a potent antagonist of human Shh suggests that the known tumor suppressor activity of WIF1 may not be ascribed only to its role as a Wnt inhibitor.
Highlights
Wnt and hedgehog (Hh) signaling play essential roles in the control of cell proliferation and development [1,2]
SAhnha-lWysIeFs1ocfothmepSlePxRhraesspaoKnsdeocfu2r.v06es±o0f.9thneMse e(Txapbelreim1)e.nts have revealed that the sonic hedgehog (Shh)-Wnt Inhibitory Factor 1 (WIF1) compDleoxseh-adsepaeKnddeonf t2.S0P6R±si0g.9nanlMs w(Teareblaels1o).observed when we studied the interaction of human Shh with immobilized human WIF domain (Figure 3)
Since WIF1 and WIF domain cause the near-complete inhibition of Gli1-activity (Figures 4 and 5), we may conclude that the WIF1 and WIF domain inhibit Gli1–activity elicited by Shh signaling
Summary
Wnt and hedgehog (Hh) signaling play essential roles in the control of cell proliferation and development [1,2]. Full-length vertebrate WIF1 affected the distribution and signaling of Hh in D. melanogaster, suggesting a possible role for WIF1 as a modulator of vertebrate Hh signaling [27] These studies have led to the conclusion that vertebrate WIF1 serves primarily as a negative regulator of the Wnt pathway, whereas the Drosophila ortholog Shf serves as a positive regulator of the Hh pathway. It remained unclear, whether the human WIF1 protein is highly specific for human Wnts or if it has a significant influence on the signaling activity of human Hhs. In the present work, we have characterized the interaction of the human WIF1 protein with human sonic hedgehog (Shh) using Surface Plasmon Resonance spectroscopy and. This finding cautions that the loss of WIF1 activity might promote carcinogenesis through the aberrant activation of the Hh pathway and that the therapeutic targeting of WIF1 might have effects on both the Wnt and Hh pathways
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