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Smoothened Signaling Through a G-Protein Effector Network

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Hedgehog signaling activation in human cancer and its clinical implications

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Abstract

Disruption of the Hedgehog (HH) signaling pathway underlies an increasingly large array of different human tumors. Consistent with the important role HH plays in cancer, the tumor burden of patients treated with a novel HH inhibitor was ­dramatically reduced in a recent clinical trial. This drug binds directly to and antagonizes activity of the seven-transmembrane protein Smoothened (SMO), attenuating downstream signaling events that remain largely unknown. While functional studies of SMO signaling have provided a basic roadmap of information flow following ligand stimulation, the exact routes of signaling, and how they communicate with each other and with other signaling pathways, are not well characterized. We recently demonstrated that one route of SMO-mediated signal transduction involves activation of the heterotrimeric guanine nucleotide binding protein (G-protein) Gαi, suggesting that SMO can signal, at least in part, as a canonical G-protein-coupled receptor (GPCR). In this chapter, we discuss structural, functional, and mechanistic aspects of SMO signaling that relate to its function as a GPCR, and provide insight into how G-protein-dependent signaling might impact HH pathway activity.

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Acknowledgments

We thank C. Carroll, D. Fei, S. Marada, and S. Singh for their comments on the manuscript. This work was supported by NIH grants 1RO1CA82628 and 1RO1GM064011 (DJR), March of Dimes MOD5-FY10-6 (SKO), and by the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children’s Research Hospital.

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  1. Department of Biochemistry, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, MS 340, Memphis, TN, 38105, USA

    Stacey K. Ogden

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  1. David J. Robbins
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  2. Stacey K. Ogden
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Correspondence to Stacey K. Ogden .

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  1. University of Texas Medical Branch, Galveston, 77555, Texas, USA

    Jingwu Xie

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Robbins, D.J., Ogden, S.K. (2011). Smoothened Signaling Through a G-Protein Effector Network. In: Xie, J. (eds) Hedgehog signaling activation in human cancer and its clinical implications. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-8435-7_3

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