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

Arveseth, Corvin D. and Happ, John T. and Hedeen, Danielle S. and Zhu, Ju-Fen and Capener, Jacob L. and Klatt Shaw, Dana and Deshpande, Ishan and Liang, Jiahao and Xu, Jiewei and Stubben, Sara L. and Nelson, Isaac B. and Walker, Madison F. and Kawakami, Kouki and Inoue, Asuka and Krogan, Nevan J. and Grunwald, David J. and Hüttenhain, Ruth and Manglik, Aashish and Myers, Benjamin R. and Basler, Konrad (2021) Smoothened transduces Hedgehog signals via activity-dependent sequestration of PKA catalytic subunits. PLOS Biology, 19 (4). e3001191. ISSN 1545-7885

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Abstract

The Hedgehog (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.

Item Type: Article
Subjects: Oalibrary Press > Biological Science
Depositing User: Managing Editor
Date Deposited: 03 Jan 2023 07:27
Last Modified: 24 Jul 2024 09:02
URI: http://asian.go4publish.com/id/eprint/851

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