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Phase separation of a PKA regulatory subunit controls cAMP compartmentation and oncogenic signaling

Item Type:Article
Title:Phase separation of a PKA regulatory subunit controls cAMP compartmentation and oncogenic signaling
Creators Name:Zhang, J.Z. and Lu, T.W. and Stolerman, L.M. and Tenner, B. and Yang, J.R. and Zhang, J.F. and Falcke, M. and Rangamani, P. and Taylor, S.S. and Mehta, S. and Zhang, J.
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.
Keywords:Biosensor, FRET, Split GFP, Membraneless Organelle, FLC, Fibrolamellar Carcinoma, DnaJB1-PKA, Signal Transduction, Live Cell Imaging, Animals, Mice, Rats
Publisher:Cell Press
Page Range:1531-1544
Date:17 September 2020
Additional Information:Copyright © 2020 Elsevier Inc.
Official Publication:https://doi.org/10.1016/j.cell.2020.07.043
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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