Showalter Professor

Department of Biochemistry and Molecular Biology
Indiana University School of Medicine
John D. Van Nuys Medical Science Building
635 Barnhill Drive, Room 4067
Indianapolis, Indiana 46202-5122

Phone: (317) 274-0549
Facsimile: (317) 274-4686
E-mail: rwek@iupui.edu

Area of Study

Mechanisms for coping with cellular stress. Regulation of gene expression by eIF2 kinases.   More details...

Selected Recent Publications

Sood, R., Porter, A., Olsen, D.S., Cavener, D.R. and Wek, R.C. 2000. Mouse homologue for GCN2 protein kinase important for translation control by phosphorylation of eukaryotic initiation factor -2 (eIF-2). Genetics 154, 787-801.

Sood, R., Porter, A., Ma, K., Quilliam, L.A.. and Wek, R.C. 2000. Characterization of pancreatic eukaryotic initation factor -2a kinase, PEK, homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to ER stress. Biochemical Journal 346, 281-293.

Yang, R., Wek, S.A., Wek, R.C. 2000. Glucose limitation induces GCN4 translation by activation of Gcn2 protein kinase. Molecular and Cellular Biology 20, 2706-2717.

Harding, H.P, Novoa, I., Zhang, Y.Zeng, H, Wek, R., Schapira, M. and Ron, D. 2000. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Molecular Cell 6, 1099-1108.

Kimball, S.R., Clemens, M.J., Tilleray, V.J., Wek, R.C., Horetsky, R.L., and Jefferson, L.S. 2001. The Double-Stranded RNA-Activated Protein Kinase PKR is dispensable for regulation of translation Initiation in response to either calcium mobilization from the endoplasmic reticulum or essential amino acid starvation. Biochemical and Biophysical Research Communications, 280, 293-300.

Vattem, K.M., Staschke, K.A., Zhu, S. and Wek, R.C. 2001. Inhibitory sequences in the N-terminus of the double-stranded-RNA-dependent protein kinase, PKR, are important for regulating phosphorylation of eukaryotic initiation factor 2α (eIF2α). European Journal of Biochemistry 268, 1143-1153.

Vattem, K.M., Staschke, K.A. and Wek, R.C. 2001. Mechanism of activation of the double-stranded-RNA-dependent protein kinase, PKR: Role of dimerization and cellular localization in the stimulation of PKR phosphorylation of eukaryotic initiation factor 2α (eIF2α). European Journal of Biochemistry 268, 3674-3684.

Fernandez J.M., Yaman I., Merrick W.C., Koromilas A.E., Wek R.C., Sood R., Hensold J.O., Hatzoglou M. 2002. Regulation of internal ribosome entry site-mediated translation by eIF2α phosphorylation and translation of a small uORF. Journal of Biological Chemistry, 277, 2050-2058.

Ma, K., Vattem, K.M. and Wek, R.C. (2002) Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor -2 (eIF2) kinase in response to endoplasmic reticulum stress. Journal of Biological Chemistry, 277, 18728-18735.

Zhang P., McGrath B.C., Reinert J., Olsen D.S., Lei L., Gill S., Wek S.A., Vattem K.M., Wek R.C., Kimball S.R., Jefferson L.S. and Cavener D.R. 2002. The GCN2 eIF2alpha Kinase Is Required for Adaptation to Amino Acid Deprivation in Mice. Molecular and Cellular Biology 22, 6681-6688.

Zhan, K., Vattem, K.M., Bauer, B.N., Dever, T.E., Chen, J.-J. and Wek, R.C. 2002. Phosphorylation of eukaryotic initiation factor -2 by heme-regulated inhibitor kinase-related protein kinases in Schizosaccharomyces pombe is important for resistance to environmental stresses. Molecular and Cellular Biology 22, 7134-7146.

Jiang HY, Wek SA, McGrath BC, Scheuner D, Kaufman RJ, Cavener DR, Wek RC. 2003. Phosphorylation of the alpha Subunit of Eukaryotic Initiation Factor 2 Is Required for Activation of NF-kappaB in Response to Diverse Cellular Stresses. Molecular and Cellular Biology 23, 5651-5663.

Abe T, Lu X, Jiang Y, Boccone CE, Qian S, Vattem KM, Wek RC, Walsh JP. (2003) Site-Directed Mutagenesis of the Active Site of Diaclyglycerol Kinase alpha: Calcium and Phosphatidylserine Stimulate Enzyme Activity via Distinct Mechanisms. Biochemical Journal 375,673-80.

Jiang, H.Y., Wek, S.A., McGrath, B.C., Lu, D., Hai, T., Harding, H.P., Wang, X., Ron, D., Cavener, D.R., and Wek, R.C. (2004) Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Molecular and Cellular Biology 24, 1365-1377.

Wek, R.C., Staschke, K.A., and Narasimhan, J. (2004)  Regulation of the yeast general amino acid control pathway in response to nutrient stress.  In:  Nutrient-induced responses in eukaryotic cells.  Topics in Current Genetics Vol. 7.  Winderickx, J., and Taylor, P.M. editors.  Springer-Verlag, Berlin Heidelberg, Germany, Chapter 7, pp. 171-199.

Sullivan, W.J., Narasimhan, J., Bhatti, B.M., and Wek, R.C. (2004)  Parasite-specific eukaryotic initiation factor -2 (eIF2) kinase required for stress-induced translation control. Biochemical Journal 380, 523-531.

Narasimhan, J., Staschke, K.A., and Wek, R.C. (2004)  Dimerization is required for activation of eIF2 kinase Gcn2 in response to diverse environmental stress conditions.  Journal of Biological Chemistry, 279, 22820-22832.

Senée, V., Vattem, K.M., Delépine, M., Rainbow, L., Haton, C., Lecoq, A., Shaw, N., Robert, J.-J., Rooman, R., Diatloff-Zito, C.,  Michaud, J.L., Bin-Abbas, B., Taha, D., Zabel, B., Franceschini, P., Topaloglu, A.K., Lathrop, M., Barrett, T., Nicolino, M.,  Wek, R.C., Julier, C.  (2004) Wolcott-Rallison syndrome: clinical, genetic, and functional study of EIF2AK3 mutations, and suggestion of genetic heterogeneity. Diabetes, 53, 1876-1883.

Vattem,  K.M., and Wek, R.C. (2004)  Reinitiation involving upstream open reading frames regulates ATF4 mRNA translation in mammalian cells.  Proceedings of National Academy of Science, U.S.A.,  101. 11269-11274.

Anthony, T.G., McDaniel, B.J., Byerley, R.L., McGrath, B.C., Cavener, D.R., McNurlan, M.A., and Wek, R.C. (2004)  Preservation of liver protein synthesis during dietary leucine deprivation occurs at the expense of skeletal muscle mass in mice deleted for eIF2 kinase GCN2. Journal of Biological Chemistry, 279, 36553-36561.

Zhan, K., Narasimhan, J., Staschke, K.A., and Wek, R.C. (2004) Differential activation of eIF2 kinases in response to cellular stresses in Schizosaccharomyces pombe. Genetics, 168,1867-1875.

Jiang, H.Y., and Wek, R.C. (2005) Gcn2 phosphorylation of eIF2α activates NF-κB in response to UV irradiation. Biochemical Journal, 385, 371-380.

Jiang, H.Y., and Wek, R.C. (2005) Phosphorylation of eIF2α reduces protein synthesis and enhances apoptosis in response to proteasome inhibition. Journal of Biological Chemistry, 280, 14189-14202.

Hao, S., Sharp, J.W., Ross-Inta, C.M., McDaniel, B.J., Anthony, T.G., Wek, R.C., Cavener, D.R., McGrath, B.C., Rudell, J.B., Koehnle, T.J., and Gietzen, D.W. (2005) Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform cortex. Science 307, 1776-1778.

Pereira, C.M., Sattlegger, E., Jiang, H.Y., Longo, B.M., Jaqueta, C.B., Hinnebusch, A.G., Wek, R.C., Mello, L.E.A.M., and Castilho, B.A. (2005) IMPACT, a protein preferentially expressed in the mouse brain, binds GCN1 and inhibits GCN2 activation. Journal of Biological Chemistry 280, 28316-28323.

Dunand-Sauthier, I., Walker, C.A., Narasimhan, J., Pearce, A.K., Wek, R.C., and Humphrey, T.C. (2005) The SAPK pathway functions to support protein synthesis and translational adaptation in response to environmental stress in fission yeast.  Eukaryotic Cell 4, 1785-1793.

Wek, R.C., Jiang, H.T., and Anthony, T.G. (2006)  Coping with stress: eIF2 kinases and translational control. Biochemical Society Transactions 34, 7-11.

Joshi, M.A., Jeoung, N.H., Obayashi, M., Hattab, M.H., Brocken, E.G., Liechty, E.A., Kubek, M.J., Vattem, K.M., Wek, R.C, and Harris, R.A. (2006) Impaired growth and neurological abnormalities in branched-chain a-keto acid dehydrogenase kinase-deficient mice. Biochemical Journal 400, 153-162.

Reinert, R.B., Oberle, L.M., Wek. S., Gayheart, K., Miller, M., Aldrich, C.J., Durden, D.L., McNurlan, M.A., Wek, R.C. and Anthony, T.G. (2006) Role of glutamine depletion in directing tissue-specific stress responses to L-asparaginase. Journal of Biological Chemistry 281, 31222-31233.

Wek, R.C., and Anthony, T.G. (2006) EXtENDINg β cell survival by UPRegulating ATF4 translation. Cell Metabolism 4, 333-334.

Lopez, A.B., Wang, C., Huang, C.C., Yaman, I., Li, Y., Chakravarty, K., Johnson, P.F., Chiang, C.-M., Snider, M.D., Wek, R.C., and Hatzoglou, M. (2007) A feedback transcriptional mechanism controls the level of the arginine/lysine transporter cat-1 during amino acid starvation. Biochemical Journal 402,163-173.

Jiang, H.Y., Jiang, L., and Wek R.C. (2007) The eIF2 kinase pathway facilitates differential GADD45a expression in response to environmental stress. Journal of Biological Chemistry 282, 3755-3765.

Wek, R.C. and Cavener, D.R. (2007) Translational Control and the Unfolded Protein Response.  Antioxidants and Redox Signaling 9, 2357-2372.

Gass, J.N., Jiang, H.Y., Wek, R.C., and Brewer, J.W.(2008) The unfolded protein response of B-lymphocytes: PERK-independent development of antibody-secreting cells. Molecular Immunology 45, 1035-1043.

Chambers, K.T., Unverferth, J.A., Weber, X.M., Wek, R.C., Urano, F., Corbett, J.A. (2008) The Role of Nitric Oxide and the Unfolded Protein Response in Cytokine Induced {beta}-cell Death. Diabetes 57, 124-132.

Zhou, D., Palam, L.R., Jiang, L. Narasimhan, J., Staschke, K.A. and Wek, R.C. (2008)  Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions.  Journal of Biological Chemistry 283, 7064-7073.

Liang, F., Luo, Y., Dong, Y., Walls, C.D. Liang, J. Jiang, H.Y., Sanford, J.R., Wek, R.C. and Zhang, Z.Y. (2008) Translational control of Csk expression by PRL3 phosphatase.  Journal of Biological Chemistry 283 10339-10346.

Neznanov, N., Dragunsky, E.M., Chumakov, K.M., Neznanova, L., Wek, R.C., Gudkov, A.V., Banerjee, A.K. (2008)  Different Effect of Proteasome Inhibition on Vesicular Stomatitis Virus and Poliovirus Replication. PLoS ONE 3, e1887.

Narasimhan, J., Joyce, B.R., Naguleswaran, A., Smith, A.T., Livingston, M.R., Dixon, S.E., Coppens, I., Wek, R.C. and Sullivan, W.J. (2008) Translation regulation by eIF2 kinases in the development of latent cysts in Toxoplasma gondii.  Journal of Biological Chemistry 283 16591-16601.

Udagawa, T., Nemoto, N., Wilkinson, C.R., Narasimhan, J., Jiang, L. Watts, S., Zook, A. Jones, N., Wek, R.C., Bähler, J., and Asano, K. (2008) Int6/eIF3e promotes general translation and Atf1 abundance to modulate Sty1 map kinase-dependent stress response in fission yeast. Journal of Biological Chemistry 283 22063-22075.

Vonlaufen, N. Kanzok, S.M., Wek, R. C. and Sullivan, W.J. (2008) Stress response pathways in protozoan parasites. Cellular  Microbiology 10, 2387-2399.

Butler, J.S., Palam, L.R., Tate, C.M., Sanford, J.R., Wek, R.C., and Skalnik, D.G. (2009) DNA methyltransferase protein synthesis is reduced in CXXC finger protein 1-deficient embryonic stem cells. DNA and Cell Biology 28, 223-231.

Powley, I.R., Kondrashov, A., Young, L.A., Dobbyn, H.C., Hill, K., Cannel, I.G., Stoneley, M., Kong, Y.W., Cotes, J.A., Smith, G.C., Wek, R., Hayes, C., Gant, T.W., Spriggs, K.A., Bushell, M. and Willis, A.E. (2009) Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes. Genes and Development 23, 1207-1220.

Zaborske J.M., Narasimhan J., Jiang L., Wek S.A., Dittmar K.A., Freimoser F., Pan T., Wek R.C. (2009) Genome-wide analysis of tRNA charging and activation of the eIF2 kinase Gcn2p. Journal of Biological Chemistry 284, 25254-25267.

Wek, R.C., and Anthony, T.G. (2009)  Beta testing the antioxidant function of eIF2α phosphorylation in diabetes prevention.  Cell Metabolism, 10, 1-2. 

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Research Interests

Eukaryotic cells regulate their protein synthesis to accommodate a wide range of different environmental stresses. An important mechanism of protein synthesis control involves phosphorylation of eukaryotic initiation factor-2 (eIF2).

Research in my laboratory is focused on the mechanisms regulating a family of eIF2 protein kinases and the physiological advantages this altered pattern of gene expression provides for stressed cells. Currently, four family members have been identified. The first, RNA-dependent protein kinase, PKR, is an integral part of the anti-viral defense mechanism mediated by interferon and is thought to function in cell signaling, differentiation, cell growth and apoptosis. The GCN2 protein kinase is found from yeast to humans, and regulates general and gene-specific translation in response to nutrient deprivation. A third well studied eIF2 kinase, heme regulated inhibitor, HRI, functions principally in erythroid tissues and couples globin synthesis to iron availability.

Recently, we identified Pancreatic eIF-2 kinase, PEK, which is ubiquitously expressed, with highest levels in specialized secretory tissues. PEK, also designated PERK, controls translation in response to stress induced protein unfolding in the endoplasmic reticulum. PEK is associated with the membrane of the endoplasmic reticulum, with the amino regulatory sequences in the lumen of ER and the kinase domain in the cytoplasm. Deletion of PEK in humans has recently been found to be the underlying cause of an autosomal-recessive disorder, Wolcott-Rallison Syndrome, which is characterized by neonatal diabetes, bone deformations, heart and brain pathologies.

We are currently using a variety of molecular, biochemical and genetic tools to understand the mechanisms regulating these eIF2 kinases and the impact of stress-induced eIF2 phosphorylation on general and gene-specific translation. Additionally, we are exploiting the similarities between the eIF2 regulatory systems in human and yeast, to characterize different cellular and viral products that function to modulate each of the eIF2 kinases.