Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 302 (5650): 1533-1537

Copyright © 2003 by the American Association for the Advancement of Science

Bypassing a Kinase Activity with an ATP-Competitive Drug

Feroz R. Papa,1,3* Chao Zhang,2 Kevan Shokat,2 Peter Walter3,4

Abstract: Unfolded proteins in the endoplasmic reticulum cause trans-autophosphorylation of the bifunctional transmembrane kinase Ire1, which induces its endoribonuclease activity. The endoribonuclease initiates nonconventional splicing of HAC1 messenger RNAto trigger the unfolded-protein response (UPR). We explored the role of Ire1's kinase domain by sensitizing it through site-directed mutagenesis to the ATP-competitive inhibitor 1NM-PP1. Paradoxically, rather than being inhibited by 1NM-PP1, drug-sensitized Ire1 mutants required 1NM-PP1 as a cofactor for activation. In the presence of 1NM-PP1, drug-sensitized Ire1 bypassed mutations that inactivate its kinase activity and induced a full UPR. Thus, rather than through phosphorylation per se, a conformational change in the kinase domain triggered by occupancy of the active site with a ligand leads to activation of all known downstream functions.

1 Department of Medicine, University of California, San Francisco, CA 94143–2200, USA.
2 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143–2200, USA.
3 Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143–2200, USA.
4 Howard Hughes Medical Institute, University of California, San Francisco, CA 94143–2200, USA.

* To whom correspondence should be addressed. E-mail: frpapa{at}medicine.ucsf.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Endoplasmic Reticulum Stress Sensing in the Unfolded Protein Response.
B. M. Gardner, D. Pincus, K. Gotthardt, C. M. Gallagher, and P. Walter (2013)
Cold Spring Harb Perspect Biol 5, a013169
   Abstract »    Full Text »    PDF »
IRE1{alpha} Cleaves Select microRNAs During ER Stress to Derepress Translation of Proapoptotic Caspase-2.
J.-P. Upton, L. Wang, D. Han, E. S. Wang, N. E. Huskey, L. Lim, M. Truitt, M. T. McManus, D. Ruggero, A. Goga, et al. (2012)
Science 338, 818-822
   Abstract »    Full Text »    PDF »
Endoplasmic Reticulum Stress, Pancreatic {beta}-Cell Degeneration, and Diabetes.
F. R. Papa (2012)
Cold Spring Harb Perspect Med 2, a007666
   Abstract »    Full Text »    PDF »
Islet Autoantigens: Structure, Function, Localization, and Regulation.
P. Arvan, M. Pietropaolo, D. Ostrov, and C. J. Rhodes (2012)
Cold Spring Harb Perspect Med 2, a007658
   Abstract »    Full Text »    PDF »
Profile of Kevan M. Shokat.
N. Zeliadt (2012)
PNAS 109, 11057-11059
   Full Text »    PDF »
New insights on stress-induced epithelial phenotypic changes.
N. Pallet (2012)
Nephrol. Dial. Transplant. 27, 483-485
   Full Text »    PDF »
A Conserved Structural Determinant Located at the Interdomain Region of Mammalian Inositol-requiring Enzyme 1{alpha}.
Z. Xue, Y. He, K. Ye, Z. Gu, Y. Mao, and L. Qi (2011)
J. Biol. Chem. 286, 30859-30866
   Abstract »    Full Text »    PDF »
Peptides derived from the bifunctional kinase/RNase enzyme IRE1{alpha} modulate IRE1{alpha} activity and protect cells from endoplasmic reticulum stress.
M. Bouchecareilh, A. Higa, S. Fribourg, M. Moenner, and E. Chevet (2011)
FASEB J 25, 3115-3129
   Abstract »    Full Text »    PDF »
Condensin phosphorylated by the Aurora-B-like kinase Ark1 is continuously required until telophase in a mode distinct from Top2.
N. Nakazawa, R. Mehrotra, M. Ebe, and M. Yanagida (2011)
J. Cell Sci. 124, 1795-1807
   Abstract »    Full Text »    PDF »
Potent and Selective Inhibitors of the Inositol-requiring Enzyme 1 Endoribonuclease.
K. Volkmann, J. L. Lucas, D. Vuga, X. Wang, D. Brumm, C. Stiles, D. Kriebel, A. Der-Sarkissian, K. Krishnan, C. Schweitzer, et al. (2011)
J. Biol. Chem. 286, 12743-12755
   Abstract »    Full Text »    PDF »
Attenuation of yeast UPR is essential for survival and is mediated by IRE1 kinase.
A. Chawla, S. Chakrabarti, G. Ghosh, and M. Niwa (2011)
J. Cell Biol. 193, 41-50
   Abstract »    Full Text »    PDF »
Putting the brakes on the unfolded protein response.
F. Sicheri and R. H. Silverman (2011)
J. Cell Biol. 193, 17-19
   Abstract »    Full Text »    PDF »
Homeostatic adaptation to endoplasmic reticulum stress depends on Ire1 kinase activity.
C. Rubio, D. Pincus, A. Korennykh, S. Schuck, H. El-Samad, and P. Walter (2011)
J. Cell Biol. 193, 171-184
   Abstract »    Full Text »    PDF »
Adenylate Kinase 2 Links Mitochondrial Energy Metabolism to the Induction of the Unfolded Protein Response.
A. Burkart, X. Shi, M. Chouinard, and S. Corvera (2011)
J. Biol. Chem. 286, 4081-4089
   Abstract »    Full Text »    PDF »
Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma.
I. Papandreou, N. C. Denko, M. Olson, H. Van Melckebeke, S. Lust, A. Tam, D. E. Solow-Cordero, D. M. Bouley, F. Offner, M. Niwa, et al. (2011)
Blood 117, 1311-1314
   Abstract »    Full Text »    PDF »
Dual Functions of Yeast tRNA Ligase in the Unfolded Protein Response: Unconventional Cytoplasmic Splicing of HAC1 Pre-mRNA Is Not Sufficient to Release Translational Attenuation.
T. Mori, C. Ogasawara, T. Inada, M. Englert, H. Beier, M. Takezawa, T. Endo, and T. Yoshihisa (2010)
Mol. Biol. Cell 21, 3722-3734
   Abstract »    Full Text »    PDF »
Regulation of basal cellular physiology by the homeostatic unfolded protein response.
D. T. Rutkowski and R. S. Hegde (2010)
J. Cell Biol. 189, 783-794
   Abstract »    Full Text »    PDF »
A Trojan Horse for Parkinson's Disease.
Y. Hu and Y. Tong (2010)
Science Signaling 3, pe13
   Abstract »    Full Text »    PDF »
AlphaScreen(R)-Based Characterization of the Bifunctional Kinase/RNase IRE1{alpha}: A Novel and Atypical Drug Target.
M. Bouchecareilh, M. E. Caruso, P. Roby, S. Parent, N. Rouleau, S. Taouji, O. Pluquet, R. Bosse, M. Moenner, and E. Chevet (2010)
J Biomol Screen 15, 406-417
   Abstract »    Full Text »    PDF »
Regulated Ire1-dependent decay of messenger RNAs in mammalian cells.
J. Hollien, J. H. Lin, H. Li, N. Stevens, P. Walter, and J. S. Weissman (2009)
J. Cell Biol. 186, 323-331
   Abstract »    Full Text »    PDF »
Bypassing Kinase Activity of the Tomato Pto Resistance Protein with Small Molecule Ligands.
D. Salomon, A. Bonshtien, M. Mayrose, C. Zhang, K. M. Shokat, and G. Sessa (2009)
J. Biol. Chem. 284, 15289-15298
   Abstract »    Full Text »    PDF »
Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity.
M. L. Duennwald and S. Lindquist (2008)
Genes & Dev. 22, 3308-3319
   Abstract »    Full Text »    PDF »
IRE1 Signaling Affects Cell Fate During the Unfolded Protein Response.
J. H. Lin, H. Li, D. Yasumura, H. R. Cohen, C. Zhang, B. Panning, K. M. Shokat, M. M. LaVail, and P. Walter (2007)
Science 318, 944-949
   Abstract »    Full Text »    PDF »
Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins.
Y. Kimata, Y. Ishiwata-Kimata, T. Ito, A. Hirata, T. Suzuki, D. Oikawa, M. Takeuchi, and K. Kohno (2007)
J. Cell Biol. 179, 75-86
   Abstract »    Full Text »    PDF »
Self-association and BiP dissociation are not sufficient for activation of the ER stress sensor Ire1.
D. Oikawa, Y. Kimata, and K. Kohno (2007)
J. Cell Sci. 120, 1681-1688
   Abstract »    Full Text »    PDF »
The Golgi-resident protease Kex2 acts in conjunction with Prm1 to facilitate cell fusion during yeast mating.
M. G. Heiman, A. Engel, and P. Walter (2007)
J. Cell Biol. 176, 209-222
   Abstract »    Full Text »    PDF »
The Last 10 Amino Acid Residues beyond the Hydrophobic Motif Are Critical for the Catalytic Competence and Function of Protein Kinase C{alpha}.
S. S. Yeong, Y. Zhu, D. Smith, C. Verma, W. G. Lim, B. J. Tan, Q. T. Li, N. S. Cheung, M. Cai, Y.-Z. Zhu, et al. (2006)
J. Biol. Chem. 281, 30768-30781
   Abstract »    Full Text »    PDF »
Multiple Endoplasmic Reticulum-to-Nucleus Signaling Pathways Coordinate Phospholipid Metabolism with Gene Expression by Distinct Mechanisms.
S. A. Jesch, P. Liu, X. Zhao, M. T. Wells, and S. A. Henry (2006)
J. Biol. Chem. 281, 24070-24083
   Abstract »    Full Text »    PDF »
Intrinsic Capacities of Molecular Sensors of the Unfolded Protein Response to Sense Alternate Forms of Endoplasmic Reticulum Stress.
J. B. DuRose, A. B. Tam, and M. Niwa (2006)
Mol. Biol. Cell 17, 3095-3107
   Abstract »    Full Text »    PDF »
Rapid Turnover of Unspliced Xbp-1 as a Factor That Modulates the Unfolded Protein Response.
B. Tirosh, N. N. Iwakoshi, L. H. Glimcher, and H. L. Ploegh (2006)
J. Biol. Chem. 281, 5852-5860
   Abstract »    Full Text »    PDF »
On the mechanism of sensing unfolded protein in the endoplasmic reticulum.
J. J. Credle, J. S. Finer-Moore, F. R. Papa, R. M. Stroud, and P. Walter (2005)
PNAS 102, 18773-18784
   Abstract »    Full Text »    PDF »
Genome-wide Analysis Reveals Inositol, Not Choline, as the Major Effector of Ino2p-Ino4p and Unfolded Protein Response Target Gene Expression in Yeast.
S. A. Jesch, X. Zhao, M. T. Wells, and S. A. Henry (2005)
J. Biol. Chem. 280, 9106-9118
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882