Phase Separation of a PKA Regulatory Subunit Controls cAMP Compartmentation and Oncogenic Signaling.
Cell
; 182(6): 1531-1544.e15, 2020 09 17.
Article
in En
| MEDLINE
| ID: mdl-32846158
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
/
Cell Compartmentation
/
Cyclic AMP
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Carcinoma, Hepatocellular
/
HSP40 Heat-Shock Proteins
/
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
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Carcinogenesis
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Liver Neoplasms
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell
Year:
2020
Document type:
Article
Affiliation country:
Estados Unidos