Mislocalization of protein kinase A drives pathology in Cushing's syndrome.
CP: Cell biology
CP: Metabolism
PRKACA
adrenal
anchoring
cortisol
photoactivation
proteomics
proximity biotinylation
scaffold
signaling
stress hormone
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
12 07 2022
12 07 2022
Historique:
received:
27
01
2022
revised:
20
04
2022
accepted:
17
06
2022
entrez:
13
7
2022
pubmed:
14
7
2022
medline:
16
7
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35830806
pii: S2211-1247(22)00871-3
doi: 10.1016/j.celrep.2022.111073
pmc: PMC9311266
mid: NIHMS1823265
pii:
doi:
Substances chimiques
Cyclic AMP-Dependent Protein Kinases
EC 2.7.11.11
Hydrocortisone
WI4X0X7BPJ
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
111073Subventions
Organisme : Cancer Research UK
ID : C1443/A22095
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R01 GM129090
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK119192
Pays : United States
Organisme : NIDDK NIH HHS
ID : F32 DK121415
Pays : United States
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/S018514/1
Pays : United Kingdom
Organisme : NIH HHS
ID : S10 OD021502
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK119186
Pays : United States
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/T018127/1
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : T32 GM007270
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK123694
Pays : United States
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
Science. 2014 May 23;344(6186):917-20
pubmed: 24855271
J Biol Chem. 2021 Jan-Jun;296:100445
pubmed: 33617877
Biochem J. 2003 Mar 1;370(Pt 2):361-71
pubmed: 12495431
Genes Dev. 2013 Feb 15;27(4):355-71
pubmed: 23431053
Physiol Rev. 2004 Jan;84(1):137-67
pubmed: 14715913
J Clin Endocrinol Metab. 2016 Sep;101(9):3526-38
pubmed: 27389594
J Cell Biol. 2018 Jun 4;217(6):2167-2184
pubmed: 29615473
Nat Rev Mol Cell Biol. 2015 Apr;16(4):232-44
pubmed: 25785716
Nat Rev Mol Cell Biol. 2004 Dec;5(12):959-70
pubmed: 15573134
J Pathol. 2018 Mar;244(3):257-259
pubmed: 29205368
Chem Rev. 2001 Aug;101(8):2381-411
pubmed: 11749379
J Proteome Res. 2017 Sep 1;16(9):3448-3459
pubmed: 28741359
Trends Pharmacol Sci. 2020 Dec;41(12):933-946
pubmed: 33082006
Sci Rep. 2017 May 19;7(1):2193
pubmed: 28526819
Nat Cell Biol. 2010 Dec;12(12):1242-9
pubmed: 21102438
Cells. 2019 Dec 07;8(12):
pubmed: 31817925
Trends Pharmacol Sci. 2018 Feb;39(2):209-222
pubmed: 29289379
Cell. 2021 May 13;184(10):2793
pubmed: 33989549
Biol Reprod. 2018 Jul 1;99(1):13-26
pubmed: 29718098
Genes Dev. 2016 Dec 15;30(24):2696-2709
pubmed: 28087714
Elife. 2013 Nov 05;2:e01319
pubmed: 24192038
Endocrinology. 2006 Apr;147(4):1805-18
pubmed: 16439455
Science. 2012 Feb 10;335(6069):712-6
pubmed: 22323819
Cells. 2020 Oct 12;9(10):
pubmed: 33053803
Nature. 2002 Jun 27;417(6892):949-54
pubmed: 12068308
Sci Signal. 2021 Jul 20;14(692):
pubmed: 34285132
Genesis. 2005 Nov;43(3):109-19
pubmed: 16155866
Sci Signal. 2021 Apr 13;14(678):
pubmed: 33850054
Nat Genet. 2014 Jun;46(6):613-7
pubmed: 24747643
Dev Cell. 2013 Sep 30;26(6):666-673
pubmed: 24035414
Medicine (Baltimore). 2019 Mar;98(11):e14866
pubmed: 30882689
J Cell Biochem. 2019 Jan;120(1):894-906
pubmed: 30256438
J Clin Endocrinol Metab. 2014 Oct;99(10):E2093-100
pubmed: 25057884
Proc Natl Acad Sci U S A. 2018 Dec 4;115(49):E11465-E11474
pubmed: 30455320
N Engl J Med. 2014 Mar 13;370(11):1019-28
pubmed: 24571724
Nat Commun. 2019 Jun 12;10(1):2572
pubmed: 31189917
Nat Rev Mol Cell Biol. 2012 Oct;13(10):646-58
pubmed: 22992589
Sci Adv. 2019 Aug 28;5(8):eaaw9298
pubmed: 31489371
Nucleic Acids Res. 2019 Jan 8;47(D1):D607-D613
pubmed: 30476243
Gene. 2016 Feb 15;577(2):101-8
pubmed: 26687711
J Biol Chem. 1990 Jun 25;265(18):10484-91
pubmed: 2162349
Science. 2017 Jun 23;356(6344):1288-1293
pubmed: 28642438
Nat Methods. 2014 Jun;11(6):603-4
pubmed: 24874572
FEBS Lett. 2017 Feb;591(3):459-467
pubmed: 28100013
Science. 2014 May 23;344(6186):913-7
pubmed: 24700472
Biochem J. 2016 Oct 1;473(19):3159-75
pubmed: 27444646
Elife. 2019 May 07;8:
pubmed: 31063128
JCI Insight. 2018 Jan 25;3(2):
pubmed: 29367455
Aging (Albany NY). 2019 Dec 18;11(24):12295-12314
pubmed: 31848326
Cells. 2021 Jul 31;10(8):
pubmed: 34440720
Ann N Y Acad Sci. 2002 Jun;968:65-74
pubmed: 12119268
Nat Biotechnol. 2018 Oct;36(9):880-887
pubmed: 30125270
Nat Methods. 2008 Apr;5(4):277-8
pubmed: 18376388
Biochem J. 1991 Oct 15;279 ( Pt 2):521-7
pubmed: 1659381
J Clin Endocrinol Metab. 2020 Dec 1;105(12):
pubmed: 32875319
Science. 2009 Nov 27;326(5957):1220-4
pubmed: 19965465
Endocrinology. 2019 Feb 1;160(2):447-459
pubmed: 30615103
Nat Rev Cancer. 2014 Jul;14(7):455-67
pubmed: 24957944
Am J Hum Genet. 2020 Nov 5;107(5):977-988
pubmed: 33058759
Lancet. 2015 Aug 29;386(9996):913-27
pubmed: 26004339
JCI Insight. 2018 Apr 19;3(8):
pubmed: 29669941
Endocrinol Metab Clin North Am. 2018 Jun;47(2):275-297
pubmed: 29754632
Mol Cell. 2006 Sep 15;23(6):925-31
pubmed: 16973443