Smoothened transduces hedgehog signals via activity-dependent sequestration of PKA catalytic subunits

Corvin D. Arveseth; John T. Happ; Danielle S. Hedeen; Ju Fen Zhu; Jacob L. Capener; Dana Klatt Shaw; Ishan Deshpande; Jiahao Liang; Jiewei Xu; Sara L. Stubben; Isaac B. Nelson; Madison F. Walker; Kouki Kawakami; Asuka Inoue; Nevan J. Krogan; David J. Grunwald; Ruth Hüttenhain; Aashish Manglik; Benjamin R. Myers

doi:10.1371/journal.pbio.3001191

Smoothened transduces hedgehog signals via activity-dependent sequestration of PKA catalytic subunits

Corvin D. Arveseth, John T. Happ, Danielle S. Hedeen, Ju Fen Zhu, Jacob L. Capener, Dana Klatt Shaw, Ishan Deshpande, Jiahao Liang, Jiewei Xu, Sara L. Stubben, Isaac B. Nelson, Madison F. Walker, Kouki Kawakami, Asuka Inoue, Nevan J. Krogan, David J. Grunwald, Ruth Hüttenhain, Aashish Manglik, Benjamin R. Myers

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Abstract

The AUHedgehog: Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly (Hh) pathway is essential for organ development, : homeostasis, and regeneration. Dysfunction of this cascade drives several cancers. To control expression of pathway target genes, the G protein–coupled receptor (GPCR) Smoothened (SMO) activates glioma-associated (GLI) transcription factors via an unknown mechanism. Here, we show that, rather than conforming to traditional GPCR signaling paradigms, SMO activates GLI by binding and sequestering protein kinase A (PKA) catalytic subunits at the membrane. This sequestration, triggered by GPCR kinase (GRK)-mediated phosphorylation of SMO intracellular domains, prevents PKA from phosphorylating soluble substrates, releasing GLI from PKA-mediated inhibition. Our work provides a mechanism directly linking Hh signal transduction at the membrane to GLI transcription in the nucleus. This process is more fundamentally similar between species than prevailing hypotheses suggest. The mechanism described here may apply broadly to other GPCR- and PKA-containing cascades in diverse areas of biology.

Original language	English
Article number	e3001191
Journal	PLoS Biology
Volume	19
Issue number	4
DOIs	https://doi.org/10.1371/journal.pbio.3001191
State	Published - Apr 2021
Externally published	Yes

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Arveseth, C. D., Happ, J. T., Hedeen, D. S., Zhu, J. F., Capener, J. L., Shaw, D. K., Deshpande, I., Liang, J., Xu, J., Stubben, S. L., Nelson, I. B., Walker, M. F., Kawakami, K., Inoue, A., Krogan, N. J., Grunwald, D. J., Hüttenhain, R., Manglik, A., & Myers, B. R. (2021). Smoothened transduces hedgehog signals via activity-dependent sequestration of PKA catalytic subunits. PLoS Biology, 19(4), Article e3001191. https://doi.org/10.1371/journal.pbio.3001191

@article{01bb094235bb4186a316f722dde81456,

title = "Smoothened transduces hedgehog signals via activity-dependent sequestration of PKA catalytic subunits",

abstract = "The AUHedgehog: Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly (Hh) pathway is essential for organ development, : homeostasis, and regeneration. Dysfunction of this cascade drives several cancers. To control expression of pathway target genes, the G protein–coupled receptor (GPCR) Smoothened (SMO) activates glioma-associated (GLI) transcription factors via an unknown mechanism. Here, we show that, rather than conforming to traditional GPCR signaling paradigms, SMO activates GLI by binding and sequestering protein kinase A (PKA) catalytic subunits at the membrane. This sequestration, triggered by GPCR kinase (GRK)-mediated phosphorylation of SMO intracellular domains, prevents PKA from phosphorylating soluble substrates, releasing GLI from PKA-mediated inhibition. Our work provides a mechanism directly linking Hh signal transduction at the membrane to GLI transcription in the nucleus. This process is more fundamentally similar between species than prevailing hypotheses suggest. The mechanism described here may apply broadly to other GPCR- and PKA-containing cascades in diverse areas of biology.",

author = "Arveseth, {Corvin D.} and Happ, {John T.} and Hedeen, {Danielle S.} and Zhu, {Ju Fen} and Capener, {Jacob L.} and Shaw, {Dana Klatt} and Ishan Deshpande and Jiahao Liang and Jiewei Xu and Stubben, {Sara L.} and Nelson, {Isaac B.} and Walker, {Madison F.} and Kouki Kawakami and Asuka Inoue and Krogan, {Nevan J.} and Grunwald, {David J.} and Ruth H{\"u}ttenhain and Aashish Manglik and Myers, {Benjamin R.}",

note = "Publisher Copyright: Copyright: {\textcopyright} 2021 Arveseth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2021",

month = apr,

doi = "10.1371/journal.pbio.3001191",

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Arveseth, CD, Happ, JT, Hedeen, DS, Zhu, JF, Capener, JL, Shaw, DK, Deshpande, I, Liang, J, Xu, J, Stubben, SL, Nelson, IB, Walker, MF, Kawakami, K, Inoue, A, Krogan, NJ, Grunwald, DJ, Hüttenhain, R, Manglik, A & Myers, BR 2021, 'Smoothened transduces hedgehog signals via activity-dependent sequestration of PKA catalytic subunits', PLoS Biology, vol. 19, no. 4, e3001191. https://doi.org/10.1371/journal.pbio.3001191

TY - JOUR

T1 - Smoothened transduces hedgehog signals via activity-dependent sequestration of PKA catalytic subunits

AU - Arveseth, Corvin D.

AU - Happ, John T.

AU - Hedeen, Danielle S.

AU - Zhu, Ju Fen

AU - Capener, Jacob L.

AU - Shaw, Dana Klatt

AU - Deshpande, Ishan

AU - Liang, Jiahao

AU - Xu, Jiewei

AU - Stubben, Sara L.

AU - Nelson, Isaac B.

AU - Walker, Madison F.

AU - Kawakami, Kouki

AU - Inoue, Asuka

AU - Krogan, Nevan J.

AU - Grunwald, David J.

AU - Hüttenhain, Ruth

AU - Manglik, Aashish

AU - Myers, Benjamin R.

N1 - Publisher Copyright: Copyright: © 2021 Arveseth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2021/4

Y1 - 2021/4

N2 - The AUHedgehog: Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly (Hh) pathway is essential for organ development, : homeostasis, and regeneration. Dysfunction of this cascade drives several cancers. To control expression of pathway target genes, the G protein–coupled receptor (GPCR) Smoothened (SMO) activates glioma-associated (GLI) transcription factors via an unknown mechanism. Here, we show that, rather than conforming to traditional GPCR signaling paradigms, SMO activates GLI by binding and sequestering protein kinase A (PKA) catalytic subunits at the membrane. This sequestration, triggered by GPCR kinase (GRK)-mediated phosphorylation of SMO intracellular domains, prevents PKA from phosphorylating soluble substrates, releasing GLI from PKA-mediated inhibition. Our work provides a mechanism directly linking Hh signal transduction at the membrane to GLI transcription in the nucleus. This process is more fundamentally similar between species than prevailing hypotheses suggest. The mechanism described here may apply broadly to other GPCR- and PKA-containing cascades in diverse areas of biology.

AB - The AUHedgehog: Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly (Hh) pathway is essential for organ development, : homeostasis, and regeneration. Dysfunction of this cascade drives several cancers. To control expression of pathway target genes, the G protein–coupled receptor (GPCR) Smoothened (SMO) activates glioma-associated (GLI) transcription factors via an unknown mechanism. Here, we show that, rather than conforming to traditional GPCR signaling paradigms, SMO activates GLI by binding and sequestering protein kinase A (PKA) catalytic subunits at the membrane. This sequestration, triggered by GPCR kinase (GRK)-mediated phosphorylation of SMO intracellular domains, prevents PKA from phosphorylating soluble substrates, releasing GLI from PKA-mediated inhibition. Our work provides a mechanism directly linking Hh signal transduction at the membrane to GLI transcription in the nucleus. This process is more fundamentally similar between species than prevailing hypotheses suggest. The mechanism described here may apply broadly to other GPCR- and PKA-containing cascades in diverse areas of biology.

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U2 - 10.1371/journal.pbio.3001191

DO - 10.1371/journal.pbio.3001191

M3 - Article

C2 - 33886552

AN - SCOPUS:85104872415

SN - 1544-9173

VL - 19

JO - PLoS Biology

JF - PLoS Biology

IS - 4

M1 - e3001191

ER -

Smoothened transduces hedgehog signals via activity-dependent sequestration of PKA catalytic subunits

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