A PKA inhibitor motif within SMOOTHENED controls Hedgehog signal transduction

John T. Happ; Corvin D. Arveseth; Jessica Bruystens; Daniela Bertinetti; Isaac B. Nelson; Cristina Olivieri; Jingyi Zhang; Danielle S. Hedeen; Ju Fen Zhu; Jacob L. Capener; Jan W. Bröckel; Lily Vu; C. C. King; Victor L. Ruiz-Perez; Xuecai Ge; Gianluigi Veglia; Friedrich W. Herberg; Susan S. Taylor; Benjamin R. Myers

doi:10.1038/s41594-022-00838-z

A PKA inhibitor motif within SMOOTHENED controls Hedgehog signal transduction

John T. Happ, Corvin D. Arveseth, Jessica Bruystens, Daniela Bertinetti, Isaac B. Nelson, Cristina Olivieri, Jingyi Zhang, Danielle S. Hedeen, Ju Fen Zhu, Jacob L. Capener, Jan W. Bröckel, Lily Vu, C. C. King, Victor L. Ruiz-Perez, Xuecai Ge, Gianluigi Veglia, Friedrich W. Herberg, Susan S. Taylor, Benjamin R. Myers

Chemical and Structural Biology (TMED)

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

The Hedgehog (Hh) cascade is central to development, tissue homeostasis and cancer. A pivotal step in Hh signal transduction is the activation of glioma-associated (GLI) transcription factors by the atypical G protein-coupled receptor (GPCR) SMOOTHENED (SMO). How SMO activates GLI remains unclear. Here we show that SMO uses a decoy substrate sequence to physically block the active site of the cAMP-dependent protein kinase (PKA) catalytic subunit (PKA-C) and extinguish its enzymatic activity. As a result, GLI is released from phosphorylation-induced inhibition. Using a combination of in vitro, cellular and organismal models, we demonstrate that interfering with SMO-PKA pseudosubstrate interactions prevents Hh signal transduction. The mechanism uncovered echoes one used by the Wnt cascade, revealing an unexpected similarity in how these two essential developmental and cancer pathways signal intracellularly. More broadly, our findings define a mode of GPCR-PKA communication that may be harnessed by a range of membrane receptors and kinases.

Original language	English (US)
Pages (from-to)	990-999
Number of pages	10
Journal	Nature Structural and Molecular Biology
Volume	29
Issue number	10
DOIs	https://doi.org/10.1038/s41594-022-00838-z
State	Published - Oct 2022

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© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

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Happ, J. T., Arveseth, C. D., Bruystens, J., Bertinetti, D., Nelson, I. B., Olivieri, C., Zhang, J., Hedeen, D. S., Zhu, J. F., Capener, J. L., Bröckel, J. W., Vu, L., King, C. C., Ruiz-Perez, V. L., Ge, X., Veglia, G., Herberg, F. W., Taylor, S. S., & Myers, B. R. (2022). A PKA inhibitor motif within SMOOTHENED controls Hedgehog signal transduction. Nature Structural and Molecular Biology, 29(10), 990-999. https://doi.org/10.1038/s41594-022-00838-z

Happ, JT, Arveseth, CD, Bruystens, J, Bertinetti, D, Nelson, IB, Olivieri, C, Zhang, J, Hedeen, DS, Zhu, JF, Capener, JL, Bröckel, JW, Vu, L, King, CC, Ruiz-Perez, VL, Ge, X, Veglia, G, Herberg, FW, Taylor, SS & Myers, BR 2022, 'A PKA inhibitor motif within SMOOTHENED controls Hedgehog signal transduction', Nature Structural and Molecular Biology, vol. 29, no. 10, pp. 990-999. https://doi.org/10.1038/s41594-022-00838-z

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A PKA inhibitor motif within SMOOTHENED controls Hedgehog signal transduction

Abstract

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