Mislocalization of protein kinase A drives pathology in Cushing?s syndrome



Omar, Mitchell H, Byrne, Dominic P, Jones, Kiana N, Lakey, Tyler M, Collins, Kerrie B, Lee, Kyung-Soon, Daly, Leonard A ORCID: 0000-0001-9712-9676, Forbush, Katherine A, Lau, Ho-Tak, Golkowski, Martin
et al (show 10 more authors) (2022) Mislocalization of protein kinase A drives pathology in Cushing?s syndrome. CELL REPORTS, 40 (2). 111073-.

[thumbnail of Omar Cell Reports 2022.pdf] Text
Omar Cell Reports 2022.pdf - Published version

Download (8MB) | Preview

Abstract

Mutations in the catalytic subunit of protein kinase A (PKAc) drive the stress hormone disorder adrenal Cushing's syndrome. We define mechanisms of action for the PKAc-L205R and W196R variants. Proximity proteomic techniques demonstrate that both Cushing's mutants are excluded from A kinase-anchoring protein (AKAP)-signaling islands, whereas live-cell photoactivation microscopy reveals that these kinase mutants indiscriminately diffuse throughout the cell. Only cAMP analog drugs that displace native PKAc from AKAPs enhance cortisol release. Rescue experiments that incorporate PKAc mutants into AKAP complexes abolish cortisol overproduction, indicating that kinase anchoring restores normal endocrine function. Analyses of adrenal-specific PKAc-W196R knockin mice and Cushing's syndrome patient tissue reveal defective signaling mechanisms of the disease. Surprisingly each Cushing's mutant engages a different mitogenic-signaling pathway, with upregulation of YAP/TAZ by PKAc-L205R and ERK kinase activation by PKAc-W196R. Thus, aberrant spatiotemporal regulation of each Cushing's variant promotes the transmission of distinct downstream pathogenic signals.

Item Type: Article
Additional Information: Source info: CELL-REPORTS-D-22-00511
Uncontrolled Keywords: Animals, Mice, Cushing Syndrome, Hydrocortisone, Cyclic AMP-Dependent Protein Kinases, Proteomics, Catalytic Domain
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 15 Jul 2022 10:00
Last Modified: 18 Jan 2023 20:56
DOI: 10.1016/j.celrep.2022.111073
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3158559