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Comprehensive Dynamic Interaction Landscape of the Mammalian Hh Signaling Pathway

ABSTRACT: The Hedgehog (Hh) signaling pathway is essential for embryonic development and tissue homeostasis, and its dysregulation contributes to severe developmental disorders and various cancers. Despite its biological importance, a detailed understanding of the dynamic interactions and phosphorylation events that regulate this pathway remains incomplete. To address this gap, we employed a comprehensive systems-level approach combining proximity-dependent biotinylation (BioID), phosphoproteomics, and advanced computational analyses to generate an extensive and dynamic map of the mammalian Hh signaling pathway. Using stable NIH-3T3 and HEK293 cell lines expressing key Hh components, we systematically characterized protein-protein interactions (PPIs) and phosphorylation dynamics in response to pathway activation and during primary cilia progression. Our workflow identified numerous ciliary proteins, highlighting the essential role of primary cilia and phosphorylation in Hh signaling regulation. To further explore the contribution of primary cilia, we analyzed interaction networks during cilia absence, formation, and resorption. These analyses revealed that the mammalian Hh signaling network is modular, consisting of four distinct functional groups: core membrane/ciliary regulators, intracellular signaling regulators, trafficking/scaffolding regulators, and downstream transcriptional regulators. Each module displayed specialized roles within the signaling cascade, closely linked to cell cycle regulation.

INSTRUMENT(S): timsTOF Pro, Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606) Mus Musculus (ncbitaxon:10090)

SUBMITTER: Markku Varjosalo

PROVIDER: MSV000097352 | MassIVE | Mon Mar 17 22:19:00 GMT 2025

REPOSITORIES: MassIVE

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