A nuclear cAMP microdomain suppresses tumor growth by Hippo pathway inactivation.
CP: Molecular biology
Hippo pathway
PKA
YAP
cAMP
nucleus
sAC
tumor suppression
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
27 09 2022
27 09 2022
Historique:
received:
02
11
2020
revised:
19
07
2022
accepted:
01
09
2022
entrez:
28
9
2022
pubmed:
29
9
2022
medline:
1
10
2022
Statut:
ppublish
Résumé
Cyclic AMP (cAMP) signaling is localized to multiple spatially distinct microdomains, but the role of cAMP microdomains in cancer cell biology is poorly understood. Here, we present a tunable genetic system that allows us to activate cAMP signaling in specific microdomains. We uncover a nuclear cAMP microdomain that activates a tumor-suppressive pathway in a broad range of cancers by inhibiting YAP, a key effector protein of the Hippo pathway, inside the nucleus. We show that nuclear cAMP induces a LATS-dependent pathway leading to phosphorylation of nuclear YAP solely at serine 397 and export of YAP from the nucleus with no change in YAP protein stability. Thus, nuclear cAMP inhibition of nuclear YAP is distinct from other known mechanisms of Hippo regulation. Pharmacologic targeting of specific cAMP microdomains remains an untapped therapeutic approach for cancer; thus, drugs directed at the nuclear cAMP microdomain may provide avenues for the treatment of cancer.
Identifiants
pubmed: 36170819
pii: S2211-1247(22)01253-0
doi: 10.1016/j.celrep.2022.111412
pmc: PMC9549417
mid: NIHMS1839192
pii:
doi:
Substances chimiques
Cyclic AMP
E0399OZS9N
Protein Serine-Threonine Kinases
EC 2.7.11.1
Serine
452VLY9402
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
111412Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR077664
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA215136
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA220981
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA224391
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA194547
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA210989
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA211024
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA201228
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 J.H.Z. is a paid consultant and is on the medical advisory board of Hoth Therapeutics, is on the medical advisory board of SHADE, Inc., and is an inventor on US patent 8859213 on the use of antibodies directed against sACs for the diagnosis of melanocytic proliferations. O.E. is a cofounder and equity holder in Volastra Therapeutics and OneThree Biotech, an equity holder and SAB member in Owkin, Freenome, Genetic Intelligence, and Acuamark DX, and receives funding from Eli Lilly, Janssen, and Sanofi. T.M. is consultant for Leap Therapeutics, Immunos Therapeutics, and Pfizer, is a cofounder of Imvaq Therapeutics, has equity in Imvaq Therapeutics, reports grants from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmeceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea, and is an inventor on patent applications related to work on oncolytic viral therapy, alphavirus-based vaccines, neo-antigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4.
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