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Mol. Cell. Biol. 32 (12): 2268-2278

Copyright © 2012 by the American Society for Microbiology. All rights reserved.

PERK Utilizes Intrinsic Lipid Kinase Activity To Generate Phosphatidic Acid, Mediate Akt Activation, and Promote Adipocyte Differentiation

Ekaterina Bobrovnikova-Marjon,a,b Dariusz Pytel,a,b Matthew J. Riese,a,c Laura Pontano Vaites,a,b Nickpreet Singh,a Gary A. Koretzky,a,c Eric S. Witze,a,b, and J. Alan Diehla,b

The Leonard and Madlyn Abramson Family Cancer Research Institute,a Department of Cancer Biology,b Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA,c

Received for publication 12 January 2012. Revision received 29 January 2012. Accepted for publication 1 April 2012.

Abstract: The endoplasmic reticulum (ER) resident PKR-like kinase (PERK) is necessary for Akt activation in response to ER stress. We demonstrate that PERK harbors intrinsic lipid kinase, favoring diacylglycerol (DAG) as a substrate and generating phosphatidic acid (PA). This activity of PERK correlates with activation of mTOR and phosphorylation of Akt on Ser473. PERK lipid kinase activity is regulated in a phosphatidylinositol 3-kinase (PI3K) p85α-dependent manner. Moreover, PERK activity is essential during adipocyte differentiation. Because PA and Akt regulate many cellular functions, including cellular survival, proliferation, migratory responses, and metabolic adaptation, our findings suggest that PERK has a more extensive role in insulin signaling, insulin resistance, obesity, and tumorigenesis than previously thought.

Address correspondence to J. Alan Diehl, adiehl{at}

Published ahead of print 9 April 2012

E.B.-M. and D.P. contributed equally to the manuscript.

The {zeta} Isoform of Diacylglycerol Kinase Plays a Predominant Role in Regulatory T Cell Development and TCR-Mediated Ras Signaling.
R. P. Joshi, A. M. Schmidt, J. Das, D. Pytel, M. J. Riese, M. Lester, J. A. Diehl, E. M. Behrens, T. Kambayashi, and G. A. Koretzky (2013)
Science Signaling 6, ra102
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ER stress potentiates insulin resistance through PERK-mediated FOXO phosphorylation.
W. Zhang, V. Hietakangas, S. Wee, S. C. Lim, J. Gunaratne, and S. M. Cohen (2013)
Genes & Dev. 27, 441-449
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