Mutations in components of the Hedgehog (Hh) signal transduction pathway underlie a number of human developmental disorders, and contribute to a diverse array of tumors. Our long-term goals are to elucidate how this signal transduction pathway is usurped in these different human pathologies. To achieve this goal we first have to understand how this pathway functions in a physiological setting, using Drosophila melanogaster as a model system for the more complicated mammalian Hh pathway. All Hh signaling, in both developmental and pathological settings, goes through the seven-transmembrane protein Smoothened (Smo). Consistent with Smo's pivotal role in the Hh signal transduction pathway, a number of small-molecule Smo antagonists are currently undergoing clinical trials for the treatment of Hh-dependent tumors. Thus, understanding the signaling events immediately downstream of Smo will have an immediate relevance to human health. We have identified the only known direct Smo effectors, the kinesin-like protein Costal2 (Cos2) and the heterotrimeric guanine nucleotide binding protein (G-protein) Gi, which we speculate regulate overlapping branches of the Hh signaling pathway that combine to regulate the activity and levels of the transcription factor Cubitus interruptus (Ci). Thus the goal of the proposed research is to identify the molecular mechanisms by which Cos2 and Gi signaling combine to regulate Hh signal transduction. Such information is essential to establish how Ci is regulated by Hh, and to understanding how this mechanism is applicable to the regulation of Ci homologs during human development and in various human pathologies associated with dysfunctional Hh signaling.
Human components of the Hedgehog (HH) signaling pathway play an important role in both normal development and in various human pathologies. The long-term goal of our research is to elucidate how HH contributes to human development, and how this regulation is disrupted in various human pathologies. Prior to achieving these goals, we will have to understand the normal physiology of HH, how it is presented to receiving cells and how these cells interpret this signal. The knowledge gained as a result of this work could be used to design preventative or curative strategies for the different human pathologies that result from a deregulated HH pathway.
|Li, Bin; Orton, Darren; Neitzel, Leif R et al. (2017) Differential abundance of CK1? provides selectivity for pharmacological CK1? activators to target WNT-dependent tumors. Sci Signal 10:|
|Long, Jun; Li, Bin; Rodriguez-Blanco, Jezabel et al. (2014) The BET bromodomain inhibitor I-BET151 acts downstream of smoothened protein to abrogate the growth of hedgehog protein-driven cancers. J Biol Chem 289:35494-502|
|Li, Bin; Fei, Dennis Liang; Flaveny, Colin A et al. (2014) Pyrvinium attenuates Hedgehog signaling downstream of smoothened. Cancer Res 74:4811-21|
|Li, Bin; Flaveny, Colin A; Giambelli, Camilla et al. (2014) Repurposing the FDA-approved pinworm drug pyrvinium as a novel chemotherapeutic agent for intestinal polyposis. PLoS One 9:e101969|
|Robbins, David J; Fei, Dennis Liang; Riobo, Natalia A (2012) The Hedgehog signal transduction network. Sci Signal 5:re6|
|Singh, Samer; Wang, Zhiqiang; Liang Fei, Dennis et al. (2011) Hedgehog-producing cancer cells respond to and require autocrine Hedgehog activity. Cancer Res 71:4454-63|
|Farzan, Shohreh F; Stegman, Melanie A; Ogden, Stacey K et al. (2009) A quantification of pathway components supports a novel model of Hedgehog signal transduction. J Biol Chem 284:28874-84|
|Ogden, Stacey K; Fei, Dennis Liang; Schilling, Neal S et al. (2008) G protein Galphai functions immediately downstream of Smoothened in Hedgehog signalling. Nature 456:967-70|
|Farzan, Shohreh F; Singh, Samer; Schilling, Neal S et al. (2008) The adventures of sonic hedgehog in development and repair. III. Hedgehog processing and biological activity. Am J Physiol Gastrointest Liver Physiol 294:G844-9|
|Farzan, Shohreh F; Ascano Jr, Manuel; Ogden, Stacey K et al. (2008) Costal2 functions as a kinesin-like protein in the hedgehog signal transduction pathway. Curr Biol 18:1215-20|
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