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J. Biol. Chem., Vol. 279, Issue 41, 42687-42693, October 8, 2004

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Serine 18 Phosphorylation of RAX, the PKR Activator, Is Required for PKR Activation and Consequent Translation Inhibition^*

Richard L. Bennett, William L. Blalock, and W. Stratford May¶

From the University of Florida College of Medicine, Shands Cancer Center, Gainesville, Florida 32610

It is now apparent that the double-stranded (ds)RNA-dependent protein kinase, PKR, is a regulator of diverse cellular responses to stress. Recently, the murine dsRNA-binding protein RAX and its human ortholog PACT were identified as cellular activators of PKR. Previous reports demonstrate that following stress, RAX/PACT associates with and activates PKR resulting in eIF2 phosphorylation, consequent translation inhibition, and cell death via apoptosis. Although RAX/PACT is phosphorylated during stress, any regulatory role for this post-translational modification has been uncertain. Now we have discovered that RAX is phosphorylated on serine 18 in both human and mouse cells. The non-phosphorylatable form of RAX, RAX(S18A), although still able to bind dsRNA and associate with PKR, fails to activate PKR following stress. Furthermore, stable expression of RAX(S18A) results in a dominant-negative effect characterized by deficiency of eukaryotic initiation factor 2 subunit phosphorylation, delay of translation inhibition, and failure to undergo rapid apoptosis following removal of interleukin-3. We propose that the ability of RAX to activate PKR is regulated by a sequential mechanism featuring RAX association with PKR, RAX phosphorylation at serine 18, and activation of PKR.

Received for publication, March 25, 2004 , and in revised form, August 6, 2004.

^* This work was supported by National Institutes of Health Grant 5R01HL054083-8. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of National Research Service Award CA09126-27.

Supported by Leukemia and Lymphoma Society Fellow Award 5510-02.

^¶ To whom correspondence should be addressed: 1600 SW Archer Rd. Box 100232 Gainesville, FL 32610. E-mail: smay{at}ufscc.ufl.edu.

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