Smoothened Transduces Hedgehog Signals Via Activity-dependent Sequestration of PKA Catalytic Subunits

Overview

Journal PLoS Biol

Specialty Biology

Date 2021 Apr 22

PMID 33886552

Citations 32

Authors

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 Huttenhain

Aashish Manglik

Benjamin R Myers

Affiliations

Soon will be listed here.

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.

Citing Articles

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