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Pré-Publication, Document De Travail Année : 2021

Displacement of PKA catalytic subunit from AKAP signaling islands drives pathology in Cushing’s syndrome

Mitchell Omar
Dominic Byrne
Leonard Daly
F. Donelson Smith
Patrick Eyers
John Scott

Résumé

Abstract Mutations in the catalytic subunit of protein kinase A (PKAc) drive the stress hormone disorder adrenal Cushing’s syndrome. Here we define mechanisms of action for the PKAc-L205R and W196R variants. Both Cushing’s mutants are excluded from A kinase anchoring protein (AKAP) signaling islands and consequently diffuse throughout the cell. Kinase-dead experiments show that PKA activity is required for cortisol hypersecretion. However, kinase activation is not sufficient, as only cAMP analog drugs that displace native PKAc from AKAPs enhance cortisol release. Rescue experiments that incorporate mutant PKAc into AKAP signaling islands abolish cortisol overproduction, indicating that kinase anchoring restores normal endocrine function. Phosphoproteomics show that PKAc-L205R and W196R engage different mitogenic signaling pathways. ERK activity is elevated in adrenal-specific PKAc-W196R knock-in mice. Conversely, PKAc-L205R attenuates Hippo signaling, thereby upregulating the YAP/TAZ transcriptional co-activators. Thus, aberrant localization of each Cushing’s variant promotes the transmission of a distinct downstream pathogenic signal.

Dates et versions

hal-03439134 , version 1 (22-11-2021)

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Citer

Mitchell Omar, Dominic Byrne, Kiana Jones, Tyler Lakey, Kerrie Collins, et al.. Displacement of PKA catalytic subunit from AKAP signaling islands drives pathology in Cushing’s syndrome. 2021. ⟨hal-03439134⟩
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