Phase Separation of a PKA Regulatory Subunit Controls cAMP Compartmentation and Oncogenic Signaling.
Cell
; 182(6): 1531-1544.e15, 2020 09 17.
Article
em 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.
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Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Compartimento Celular
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AMP Cíclico
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Carcinoma Hepatocelular
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Proteínas de Choque Térmico HSP40
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Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico
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Carcinogênese
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Neoplasias Hepáticas
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article