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

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Article numbere3001191
JournalPLoS Biology
Volume19
Issue number4
DOIs
Publication statusPublished - 2021 Apr

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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