Phase Separation of a PKA Regulatory Subunit Controls cAMP Compartmentation and Oncogenic Signaling

Jason Z Zhang1, Tsan-Wen Lu2, Lucas M Stolerman3, Brian Tenner4, Jessica R Yang5, Jin-Fan Zhang1, Martin Falcke6, Padmini Rangamani3, Susan S Taylor7, Sohum Mehta4, Jin Zhang8

  1. Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
  2. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
  3. Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, CA 92093, USA.
  4. Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
  5. Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  6. Mathematical Cell Physiology, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; Department of Physics, Humboldt University, 12489 Berlin, Germany.
  7. Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
  8. Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jzhang32@ucsd.edu.

Abstract

The fidelity of intracellular signaling hinges on the organization of dynamic activity architectures. Spatial compartmentation was first proposed over 30 years ago to explain how diverse G protein-coupled receptors achieve specificity despite converging on a ubiquitous messenger, cyclic adenosine monophosphate (cAMP). However, the mechanisms responsible for spatially constraining this diffusible messenger remain elusive. Here, we reveal that the type I regulatory subunit of cAMP-dependent protein kinase (PKA), RIα, undergoes liquid-liquid phase separation (LLPS) as a function of cAMP signaling to form biomolecular condensates enriched in cAMP and PKA activity, critical for effective cAMP compartmentation. We further show that a PKA fusion oncoprotein associated with an atypical liver cancer potently blocks RIα LLPS and induces aberrant cAMP signaling. Loss of RIα LLPS in normal cells increases cell proliferation and induces cell transformation. Our work reveals LLPS as a principal organizer of signaling compartments and highlights the pathological consequences of dysregulating this activity architecture.

Presented By Jason Zhang | ORCID iD

Cancer Biology, BiochemistryNicholas Liao2020-09 (Sep)