RT Journal Article
SR Electronic
T1 Displacement of PKA catalytic subunit from AKAP signaling islands drives pathology in Cushing’s syndrome
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.10.18.464848
DO 10.1101/2021.10.18.464848
A1 Mitchell H. Omar
A1 Dominic P. Byrne
A1 Kiana N. Jones
A1 Tyler M. Lakey
A1 Kerrie B. Collins
A1 Kyung-Soon Lee
A1 Leonard A. Daly
A1 Katherine A. Forbush
A1 Ho-Tak Lau
A1 Martin Golkowski
A1 G. Stanley McKnight
A1 David T. Breault
A1 Anne-Marie Lefrançois-Martinez
A1 Antoine Martinez
A1 Claire E. Eyers
A1 Geoffrey S. Baird
A1 Shao-En Ong
A1 F. Donelson Smith
A1 Patrick A. Eyers
A1 John D. Scott
YR 2021
UL http://biorxiv.org/content/early/2021/10/19/2021.10.18.464848.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.