Crosstalk between Akt/GSK3ß signaling and dynamin-1 regulates clathrin-mediated endocytosis.
EMBO J
; 34(16): 2132-46, 2015 Aug 13.
Article
em En
| MEDLINE
| ID: mdl-26139537
ABSTRACT
Clathrin-mediated endocytosis (CME) regulates signaling from the plasma membrane. Analysis of clathrin-coated pit (CCP) dynamics led us to propose the existence of a rate-limiting, regulatory step(s) that monitor the fidelity of early stages in CCP maturation. Here we show that nascent endocytic vesicles formed in mutant cells displaying rapid, dysregulated CME are defective in early endosomal trafficking, maturation and acidification, confirming the importance of this "checkpoint." Dysregulated CME also alters EGF receptor signaling and leads to constitutive activation of the protein kinase Akt. Dynamin-1, which was thought to be neuron specific, is activated by the Akt/GSK3ß signaling cascade in non-neuronal cells to trigger rapid, dysregulated CME. Acute activation of dynamin-1 in RPE cells by inhibition of GSK3ß accelerates CME, alters CCP dynamics and, unexpectedly, increases the rate of CCP initiation. CRISPR-Cas9n-mediated knockout and reconstitution studies establish that dynamin-1 is activated by Akt/GSK3ß signaling in H1299 non-small lung cancer cells. These findings provide direct evidence for an isoform-specific role for dynamin in regulating CME and reveal a feed-forward pathway that could link signaling from cell surface receptors to the regulation of CME.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Dinamina I
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Quinase 3 da Glicogênio Sintase
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Endocitose
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Células Epiteliais
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Proteínas Proto-Oncogênicas c-akt
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Mapas de Interação de Proteínas
Limite:
Humans
Idioma:
En
Revista:
EMBO J
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Estados Unidos