Bone morphogenetic protein antagonists: Mighty morphin small molecules
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A screen for chemical antagonists of the bone morphogenetic protein (BMP) pathway has identified dorsomorphin as a selective inhibitor of BMP receptor-mediated SMAD1/5/8 phosphorylation.
Chemical genetic screens to identify selective inhibitors of membrane receptor kinases are often complicated by the functional and structural similarities between receptors. When evaluated in vivo, prospective compounds that were identified in vitro often lack specificity or are not effective. In Nature Chemical Biology, Kenneth Bloch, Randall Peterson and colleagues employ an in vivo screening technique in zebrafish to identify dorsomorphin as a novel small molecule inhibitor of bone morphogenetic protein (BMP) signaling. Dorsomorphin is then used to establish a link between BMP signaling and iron homeostasis.
BMPs are members of the TGF-β family of cytokines and regulate development and differentiation. Dimeric BMP ligands stimulate the formation of an active heterotetrameric complex containing BMP type I and type II receptors, which phosphorylate SMAD1, SMAD5 and/or SMAD8. These SMADs then bind SMAD4 and translocate to the nucleus where they regulate gene transcription. Defects in the BMP pathway cause dorsalization of zebrafish embryos, so the authors screened a chemical library of over 7,500 small molecules in developing zebrafish to identify compounds that affect the dorsal-ventral axis. Dorsomorphin was identified as a specific BMP antagonist that phenocopied BMP type I receptor mutant zebrafish and inhibited BMP-mediated phosphorylation of SMAD1/5/8 in vitro. BMP type I receptors are the likely direct targets of dorsomorphin, as the compound specifically blocked the ability of constitutively active BMP type I receptors to phosphorylate SMAD1/5/8. Dorsomorphin did not affect the activity of the highly related BMPR-II or TGF-β receptors.
Previous studies have shown that BMP signaling regulates iron homeostasis by up-regulating hepcidin expression in a process that involves SMAD4. High iron levels stimulate hepcidin to inhibit the lone iron transporter ferroportin, thereby restricting the translocation of cellular stores of iron to the bloodstream. BMP clearly has a role in modulating the response to physiological levels of iron, but the molecular link between BMP and hepcidin had remained unclear. In this study, BMP2 in vitro and high systemic iron levels in vivo caused phosphorylation of SMAD1/5/8 and induced hepcidin expression. Dorsomorphin eliminated BMP2-mediated hepcidin expression in vitro, and iron-mediated hepcidin expression and SMAD activation in mice in vivo. Given that dorsomorphin selectively inhibits signaling via BMP type I receptors, this finding suggests that iron homeostasis and hepcidin expression are regulated by BMP type I receptor-mediated activation of SMAD1/5/8.
This elegant in vivo screening approach identifies a small molecule inhibitor of a receptor serine-threonine kinase based on its ability to phenocopy a receptor kinase mutation. Dorsomorphin selectively inhibits SMAD-dependent signaling downstream of BMP receptors in vivo and therefore provides a useful tool for further exploration of the physiological role of BMP signaling.
Emily J. Chenette Signaling Gateway
References
Yu, P. B., Hong, C. C., Sachidanandan, C. et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nature Chemical Biology4, 33-41 (2008) | Article | PubMed |
Anderson, G. J. & Darshan, D. Small-molecule dissection of BMP signaling. Nature Chemical Biology4, 15-16 (2008) | Article | PubMed |
