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

doi:10.1016/j.celrep.2022.111412

A nuclear cAMP microdomain suppresses tumor growth by Hippo pathway inactivation

Cell Rep. 2022 Sep 27;40(13):111412. doi: 10.1016/j.celrep.2022.111412.

Authors

Marek M Drozdz¹, Ashley S Doane², Rached Alkallas³, Garrett Desman⁴, Rohan Bareja⁵, Michael Reilly¹, Jakyung Bang¹, Maftuna Yusupova¹, Jaewon You¹, Zuhal Eraslan¹, Jenny Z Wang¹, Akanksha Verma², Kelsey Aguirre¹, Elsbeth Kane¹, Ian R Watson⁶, Olivier Elemento⁷, Elena Piskounova⁸, Taha Merghoub⁹, Jonathan H Zippin¹⁰

Affiliations

¹ Department of Dermatology, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY 10065, USA.
² Englander Institute for Precision Medicine, Joan and Sanford I. Weill Medical College of Cornell University, New York NY 10065, USA.
³ Rosalind and Morris Goodman Cancer Institute, Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada; McGill Genome Centre, McGill University, Montreal, QC H3A 0G1, Canada.
⁴ Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁵ Englander Institute for Precision Medicine, Joan and Sanford I. Weill Medical College of Cornell University, New York NY 10065, USA; Institute for Computational Biomedicine, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY 10065, USA.
⁶ Rosalind and Morris Goodman Cancer Institute, Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
⁷ Englander Institute for Precision Medicine, Joan and Sanford I. Weill Medical College of Cornell University, New York NY 10065, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10029, USA.
⁸ Department of Dermatology, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY 10065, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10029, USA.
⁹ Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10029, USA; Department of Pharmacology, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY 10065, USA.
¹⁰ Department of Dermatology, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY 10065, USA; Englander Institute for Precision Medicine, Joan and Sanford I. Weill Medical College of Cornell University, New York NY 10065, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10029, USA; Department of Pharmacology, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY 10065, USA. Electronic address: jhzippin@med.cornell.edu.

Abstract

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.

Keywords: CP: Molecular biology; Hippo pathway; PKA; YAP; cAMP; nucleus; sAC; tumor suppression.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Line
Cyclic AMP* / metabolism
Hippo Signaling Pathway
Humans
Neoplasms*
Phosphorylation
Protein Serine-Threonine Kinases
Serine / metabolism

Substances

Cyclic AMP
Protein Serine-Threonine Kinases
Serine

Abstract

Publication types

MeSH terms

Substances

Grants and funding