Regulation of Interferon-Induced Protein Kinase PKR: Modulation of P58IPK Inhibitory Function by a Novel Protein, P52rIPK
| Autor: | Michael G. Katze, Patrick R. Romano, Michael Gale, Collin M. Blakely, Marlene Wambach, Deborah A. Hopkins, Mark W. Melville |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
DNA
Complementary viruses Molecular Sequence Data environment and public health Cell Line eIF-2 Kinase Yeasts Eukaryotic initiation factor Humans Amino Acid Sequence RNA Messenger Enzyme Inhibitors Protein kinase A Cell Growth and Development Molecular Biology Adaptor Proteins Signal Transducing EIF-2 kinase Base Sequence biology Kinase Cell Biology biochemical phenomena metabolism and nutrition HSP40 Heat-Shock Proteins Protein kinase R Repressor Proteins enzymes and coenzymes (carbohydrates) Tetratricopeptide Biochemistry biology.protein Phosphorylation Signal transduction Carrier Proteins Protein Binding |
| Zdroj: | Molecular and Cellular Biology. 18:859-871 |
| ISSN: | 1098-5549 |
| Popis: | The cellular response to environmental signals is largely dependent upon the induction of responsive protein kinase signaling pathways. Within these pathways, distinct protein-protein interactions play a role in determining the specificity of the response through regulation of kinase function. The interferon-induced serine/threonine protein kinase, PKR, is activated in response to various environmental stimuli. Like many protein kinases, PKR is regulated through direct interactions with activator and inhibitory molecules, including P58IPK, a cellular PKR inhibitor. P58IPK functions to represses PKR-mediated phosphorylation of the eukaryotic initiation factor 2alpha subunit (eIF-2alpha) through a direct interaction, thereby relieving the PKR-imposed block on mRNA translation and cell growth. To further define the molecular mechanism underlying regulation of PKR, we have utilized an interaction cloning strategy to identify a novel cDNA encoding a P58IPK-interacting protein. This protein, designated P52rIPK, possesses limited homology to the charged domain of Hsp90 and is expressed in a wide range of cell lines. P52rIPK and P58IPK interacted in a yeast two-hybrid assay and were recovered as a complex from mammalian cell extracts. When coexpressed with PKR in yeast, P58IPK repressed PKR-mediated eIF-2alpha phosphorylation, inhibiting the normally toxic and growth-suppressive effects associated with PKR function. Conversely, introduction of P52rIPK into these strains resulted in restoration of both PKR activity and eIF-2alpha phosphorylation, concomitant with growth suppression due to inhibition of P58IPK function. Furthermore, P52rIPK inhibited P58IPK function in a reconstituted in vitro PKR-regulatory assay. Our results demonstrate that P58IPK is inhibited through a direct interaction with P52rIPK which, in turn, results in upregulation of PKR activity. Taken together, our data describe a novel protein kinase-regulatory system which encompasses an intersection of interferon-, stress-, and growth-regulatory pathways. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|