Back to Search
Start Over
Phase Separation of a PKA Regulatory Subunit Controls cAMP Compartmentation and Oncogenic Signaling.
- Source :
-
Cell [Cell] 2020 Sep 17; Vol. 182 (6), pp. 1531-1544.e15. Date of Electronic Publication: 2020 Aug 25. - Publication Year :
- 2020
-
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.<br />Competing Interests: Declaration of Interests The authors declare no competing interests.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Carcinogenesis drug effects
Carcinogenesis genetics
Carcinoma, Hepatocellular metabolism
Cell Compartmentation drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Cell Proliferation genetics
Cyclic AMP pharmacology
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit genetics
Cyclic AMP-Dependent Protein Kinases genetics
Cyclic AMP-Dependent Protein Kinases metabolism
Cytoplasm metabolism
Humans
Liver Neoplasms metabolism
Mice
Oncogenes genetics
Protein Domains
Rats
Rats, Sprague-Dawley
Recombinant Fusion Proteins
Spectroscopy, Fourier Transform Infrared
Time-Lapse Imaging methods
Carcinogenesis metabolism
Carcinoma, Hepatocellular genetics
Cell Compartmentation genetics
Cyclic AMP metabolism
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit metabolism
HSP40 Heat-Shock Proteins genetics
Liver Neoplasms genetics
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4172
- Volume :
- 182
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 32846158
- Full Text :
- https://doi.org/10.1016/j.cell.2020.07.043