A nuclear cAMP microdomain suppresses tumor growth by Hippo pathway inactivation

Marek M. Drozdz, Ashley S. Doane, Rached Alkallas, Garrett Desman, Rohan Bareja, Michael Reilly, Jakyung Bang, Maftuna Yusupova, Jaewon You, Zuhal Eraslan, Jenny Z. Wang, Akanksha Verma, Kelsey Aguirre, Elsbeth Kane, Ian R. Watson, Olivier Elemento, Elena Piskounova, Taha Merghoub, Jonathan H. Zippin

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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.

Original languageEnglish
Article number111412
JournalCell Reports
Issue number13
StatePublished - 27 Sep 2022


  • CP: Molecular biology
  • Hippo pathway
  • PKA
  • YAP
  • cAMP
  • nucleus
  • sAC
  • tumor suppression


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