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J. Biol. Chem., Vol. 283, Issue 1, 469-475, January 4, 2008

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Modulation of the Eukaryotic Initiation Factor 2 -Subunit Kinase PERK by Tyrosine Phosphorylation^*

Qiaozhu Su¹², Shuo Wang¹, Hong Qing Gao, Shirin Kazemi, Heather P. Harding, David Ron, and Antonis E. Koromilas³

From the Lady Davis Institute for Medical Research, McGiIl University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, H3T 1E2 Canada and Skirball Institute, New York University School of Medicine, New York, New York 10016

The endoplasmic reticulum (ER)-resident protein kinase PERK attenuates protein synthesis in response to ER stress through the phosphorylation of translation initiation factor eIF2 at serine 51. ER stress induces PERK autophosphorylation at several serine/threonine residues, a process that is required for kinase activation and phosphorylation of eIF2. Herein, we demonstrate that PERK also possesses tyrosine kinase activity. Specifically, we show that PERK is capable of autophosphorylating on tyrosine residues in vitro and in vivo. We further show that tyrosine 615, which is embedded in a highly conserved region of the kinase domain of PERK, is essential for autocatalytic activity. That is, mutation of Tyr-615 to phenylalanine compromises the autophosphorylation capacity of PERK and the phosphorylation of eIF2 in vitro and in vivo. The Y615F mutation also impairs the ability of PERK to induce translation of ATF4. Immunoblot analyses with a phosphospecific antibody confirm the phosphorylation of PERK at Tyr-615 both in vitro and in vivo. Thus, our data classify PERK as a dual specificity kinase whose regulation by tyrosine phosphorylation contributes to its optimal activation in response to ER stress.

Received for publication, June 5, 2007 , and in revised form, November 9, 2007.

^* This work was supported by a grant from the Cancer Research Society (to A. E. K.). 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.

¹ Both authors were equal contributors.

² Present address: Dept. of Molecular Structure and Function, Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1X8, Canada.

³ To whom correspondence should be addressed: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3999 Côte-Ste-Catherine St., Montreal, Quebec H3T 1E2, Canada. Tel.: 514-340-8260 (ext. 3697); Fax: 514-340-7576; E-mail: antonis.koromilas{at}mcgill.ca.

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