Phosphorylation and the control of protein synthesis

1983 ◽  
Vol 302 (1108) ◽  
pp. 127-134 ◽  
Keyword(s):  
Protein Synthesis ◽  
Protein Kinases ◽  
Molecular Mechanism ◽  
The Other ◽  
Initiation Factor ◽  
Reversible Phosphorylation ◽  
Double Stranded Rna ◽  
Inhibition Of Protein Synthesis ◽  
The One ◽  
Rabbit Reticulocytes

This paper reviews the evidence that protein synthesis in rabbit reticulocytes is regulated by the reversible phosphorylation of the initiation factor eIF-2 by protein kinases under the control of the cytoplasmic haemin concentration on the one hand, and double-stranded RNA on the other. A molecular mechanism is proposed to account for the observation that inhibition of protein synthesis occurs when considerably less than half the eIF-2 present has been phosphorylated. The question of whether phosphorylation regulates protein synthesis in other types of cell is discussed.

Regulation of protein synthesis in rabbit reticulocyte lysates: effect of of Ca2+, Mg2+, and Mn2+ on self-phosphorylation and heterophosphorylation catalyzed by the heme-regulated and double-stranded-RNA-activated protein kinases

1982 ◽  
Vol 2 (10) ◽  
pp. 813-817 ◽  
Author(s):  
Rajinder Singh Ranu
Keyword(s):  
Protein Synthesis ◽  
Cyclic Amp ◽  
Protein Kinases ◽  
Divalent Cations ◽  
The Other ◽  
Initiation Factor ◽  
Inhibitory Protein ◽  
Double Stranded Rna ◽  
Reticulocyte Lysates ◽  
Independent Protein

The influence of divalent cations Mg2+, Mn2+, and Ca2+ on the cyclic-AMP-independent protein kinases of the heine-regulated and double-stranded-RNA-activated translational inhibitory protein kinases on self-phosphorylation and heterophosphorylation of the substrate (the 38 000-dalton subunit of initiation factor eIF-2) has been examined, Results show that Mg2+, Mn2+, and Ca2+ affect the activities of these enzymes in the following fashion. Mg2+ supports both self-phosphorylation and heterophosphorylation efficiently. Mn2+ on the other hand supports self-phosphorylation but to a lesser degree the heterophosphorylation, Ca2+ promotes neither self-phosphorylation nor hetero-phosphorylation.

scholarly journals Ceramide Regulates Protein Synthesis by a Novel Mechanism Involving the Cellular PKR Activator RAX

2001 ◽  
Vol 276 (15) ◽  
pp. 11754-11758 ◽  
Author(s):  
Peter P. Ruvolo ◽  
Fengqin Gao ◽  
William L. Blalock ◽  
Xingming Deng ◽  
W. Stratford May
Keyword(s):  
Protein Synthesis ◽  
Kinase Inhibitor ◽  
Initiation Factor ◽  
Inhibit Protein Synthesis ◽  
Serine Threonine Kinase ◽  
Signal Molecule ◽  
Double Stranded Rna ◽  
Threonine Kinase ◽  
Universal Feature ◽  
Inhibition Of Protein Synthesis

The sphingolipid ceramide is an important second signal molecule and potent apoptotic agent. The production of ceramide is associated with virtually every known stress stimulus, and thus, generation of this sphingolipid has been suggested as a universal feature of apoptosis. Recent studies suggest that an important component of cell death following diverse stress stimuli (e.g. interleukin-3 withdrawal, sodium arsenite treatment, and peroxide treatment) is the activation of the double-stranded RNA-activable protein kinase, PKR, resulting in the inhibition of protein synthesis (Ito, T., Jagus, R., and May, W. S. (1994)Proc. Natl. Acad. Sci. U. S. A.91, 7455–7459). The recently discovered cellular PKR activator, RAX, is phosphorylated in association with PKR activation (Ito, T., Yang, M., and May, W. S. (1999)J. Biol. Chem.274, 15427–15432). Since RAX is phosphorylated by an as yet undetermined SAPK and ceramide is a potent activator of SAPKs such as JNK, a role for ceramide in the activation of RAX might be possible. Results indicate that overexpression of exogenous RAX potentiates ceramide-induced killing. Furthermore, ceramide can potently inhibit protein synthesis. Since ceramide potently promotes RAX and eukaryotic initiation factor-2α phosphorylation, a possible role for ceramide in this process may involve the activation of PKR by RAX. Since 2-aminopurine, a serine/threonine kinase inhibitor that has previously been shown to inhibit PKR, blocks both the potentiation of ceramide killing by RAX and ceramide-induced inhibition of protein synthesis, ceramide appears to promote PKR activation, at least indirectly. Collectively, these findings suggest a novel role for ceramide in the regulation of protein synthesis and apoptosis.

scholarly journals Protein synthesis persists during necrotic cell death

2005 ◽  
Vol 168 (4) ◽  
pp. 545-551 ◽  
Author(s):  
Xavier Saelens ◽  
Nele Festjens ◽  
Eef Parthoens ◽  
Isabel Vanoverberghe ◽  
Michael Kalai ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Synthesis ◽  
De Novo ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Proteolytic Activation ◽  
Double Stranded Rna ◽  
Molecular Events

Cell death is an intrinsic part of metazoan development and mammalian immune regulation. Whereas the molecular events orchestrating apoptosis have been characterized extensively, little is known about the biochemistry of necrotic cell death. Here, we show that, in contrast to apoptosis, the induction of necrosis does not lead to the shut down of protein synthesis. The rapid drop in protein synthesis observed in apoptosis correlates with caspase-dependent breakdown of eukaryotic translation initiation factor (eIF) 4G, activation of the double-stranded RNA-activated protein kinase PKR, and phosphorylation of its substrate eIF2-α. In necrosis induced by tumor necrosis factor, double-stranded RNA, or viral infection, de novo protein synthesis persists and 28S ribosomal RNA fragmentation, eIF2-α phosphorylation, and proteolytic activation of PKR are absent. Collectively, these results show that, in contrast to apoptotic cells, necrotic dying cells retain the opportunity to synthesize proteins.

scholarly journals The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bɛ at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase

2001 ◽  
Vol 355 (3) ◽  
pp. 609-615 ◽  
Author(s):  
Yvonne L. WOODS ◽  
Philip COHEN ◽  
Walter BECKER ◽  
Ross JAKES ◽  
Michel GOEDERT ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Kinases ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Initiation Factor ◽  
Glycogen Synthase Kinase 3 ◽  
General Role ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Protein Synthesis Initiation

The substrate specificity of glycogen synthase kinase 3 (GSK3) is unusual in that efficient phosphorylation only occurs if another phosphoserine or phosphothreonine residue is already present four residues C-terminal to the site of GSK3 phosphorylation. One such substrate is the ε-subunit of rat eukaryotic protein-synthesis initiation factor 2B (eIF2Bε), which is inhibited by the GSK3-catalysed phosphorylation of Ser535. There is evidence that GSK3 is only able to phosphorylate eIF2Bε at Ser535 if Ser539 is already phosphorylated by another protein kinase. However, no protein kinases capable of phosphorylating Ser539 have so far been identified. Here we show that Ser539 of eIF2Bε, which is followed by proline, is phosphorylated specifically by two isoforms of dual-specificity tyrosine phosphorylated and regulated kinase (DYRK2 and DYRK1A), but only weakly or not at all by other ‘proline-directed’ protein kinases tested. We also establish that phosphorylation of Ser539 permits GSK3 to phosphorylate Ser535in vitro and that eIF2Bε is highly phosphorylated at Ser539in vivo. The DYRK isoforms also phosphorylate human microtubule-associated protein tau at Thr212in vitro, a residue that is phosphorylated in foetal tau and hyperphosphorylated in filamentous tau from Alzheimer's-disease brain. Phosphorylation of Thr212 primes tau for phosphorylation by GSK3 at Ser208in vitro, suggesting a more general role for DYRK isoforms in priming phosphorylation of GSK3 substrates.

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