A PKA Inhibitor Motif Within SMOOTHENED Controls Hedgehog Signal Transduction

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2022 Oct 6

PMID 36202993

Authors

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 Brockel

Lily Vu

C C King

Victor L Ruiz-Perez

Xuecai Ge

Gianluigi Veglia

Friedrich W Herberg

Susan S Taylor

Benjamin R Myers

Affiliations

Soon will be listed here.

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.

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