TAILIEUCHUNG - Báo cáo khoa học: Nck-1 selectively modulates eIF2aSer51 phosphorylation by a subset of eIF2a-kinases

Phosphorylation of the a-subunit of the eukaryotic initiation factor 2 (eIF2) on Ser51 is an early event associated with the down-regulation of protein synthesis at the level of translation and initiation of a transcrip-tional program. This constitutes a potent mechanism to overcome various stress conditions. | ỊFEBS Journal Nck-1 selectively modulates eIF2aSer51 phosphorylation by a subset of eIF2a-kinases Eric Cardin Mathieu Latreille Chamel Khoury Michael T. Greenwood and Louise Larose Polypeptide Laboratory Department of ExperimentalMedicine McGillUniversity Montreal Canada Keywords adaptor proteins eIF2 eIF2a-kinases Nck stress Correspondence L. Larose Polypeptide Laboratory Department of Experimental Medicine McGillUniversity Strathcona Building 3640 University St. Rm W315 Montreal QC Canada H3A 2B2 Fax 1 514 398 3923 Tel 1 514 398 5844 E-mail Received 16 August 2007 accepted 19 September 2007 doi Phosphorylation of the a-subunit of the eukaryotic initiation factor 2 eIF2 on Ser51 is an early event associated with the down-regulation of protein synthesis at the level of translation and initiation of a transcriptional program. This constitutes a potent mechanism to overcome various stress conditions. In mammals four eIF2a-kinases PKR-like endoplasmic reticulum kinase PERK dsRNA-activated protein kinase PKR heme regulated inhibitor HRI and general control nonderepressible-2 GCN2 activated following specific stresses have been shown to be involved in this process. In this article we report that the ubiquitously expressed adaptor protein Nck composed only of Src homology domains and classically implicated in cell signaling by activated plasma membrane receptor tyrosine kinases modulates eIF2a-kinase-mediated eIF2aSer51 phosphorylation in a specific manner. Our results show that Nck not only prevents eIF2a phosphorylation upon PERK activation as reported previously but also reduces eIF2a phosphorylation in conditions leading to PKR and HRI activation. By contrast the overexpression of Nck in mammalian cells fails to attenuate eIF2aSer51 phosphorylation in response to amino acid starvation a stress well known to activate GCN2. This observation is further confirmed by showing that Nck fails to alter eIF2aSer51 .

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