Journal
CELL
Volume 182, Issue 6, Pages 1531-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.07.043
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Funding
- National Science Foundation [DGE-1650112]
- Taiwan MOE scholarship
- AFOSR [FA9550-18-1-0051]
- NIH [R35 GM130389, R35 CA197622, R01 DK073368]
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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), RIa, 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 RIa LLPS and induces aberrant cAMP signaling. Loss of RIa 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.
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