Proteasomal degradation of eukaryotic elongation factor-2 kinase (EF2K) is regulated by cAMP-PKA signaling and the SCFßTRCP ubiquitin E3 ligase.
J Biol Chem
; 288(24): 17803-11, 2013 Jun 14.
Article
em En
| MEDLINE
| ID: mdl-23640883
ABSTRACT
Protein translation and degradation are critical for proper protein homeostasis, yet it remains unclear how these processes are dynamically regulated, or how they may directly balance or synergize with each other. An important translational control mechanism is the Ca(2+)/calmodulin-dependent phosphorylation of eukaryotic elongation factor-2 (eEF-2) by eukaryotic elongation factor-2 kinase (EF2K), which inhibits elongation of nascent polypeptide chains during translation. We previously described a reduction of EF2K activity in PC12 cells treated with NGF or forskolin. Here, we show that both forskolin- and IGF-1-mediated reductions of EF2K activity in PC12 cells are due to decreased EF2K protein levels, and this is attenuated by application of the proteasome inhibitor, MG132. We further demonstrate that proteasome-mediated degradation of EF2K occurs in response to A2A-type adenosine receptor stimulation, and that activation of protein kinase A (PKA) or phospho-mimetic mutation of the previously characterized PKA site, Ser-499, were sufficient to induce EF2K turnover in PC12 cells. A similar EF2K degradation mechanism was observed in primary neurons and HEK cells. Expression of a dominant-negative form of Cul1 in HEK cells demonstrated that EF2K levels are regulated by an SCF-type ubiquitin E3 ligase. Specifically, EF2K binds to the F-box proteins, ßTRCP1 and ßTRCP2, and ßTRCP regulates EF2K levels and polyubiquitylation. We propose that the proteasomal degradation of EF2K provides a mechanistic link between activity-dependent protein synthesis and degradation.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sistemas do Segundo Mensageiro
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Proteínas Quinases Dependentes de AMP Cíclico
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AMP Cíclico
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Proteínas Ligases SKP Culina F-Box
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Quinase do Fator 2 de Elongação
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos