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Bypassing a Kinase Activity with an ATP-Competitive Drug
Feroz R. Papa,1,3*Chao Zhang,2Kevan Shokat,2Peter Walter3,4
Unfolded proteins in the endoplasmic reticulum cause trans-autophosphorylationof the bifunctional transmembrane kinase Ire1, which inducesits endoribonuclease activity. The endoribonuclease initiatesnonconventional splicing of HAC1 messenger RNAto trigger theunfolded-protein response (UPR). We explored the role of Ire1'skinase domain by sensitizing it through site-directed mutagenesisto the ATP-competitive inhibitor 1NM-PP1. Paradoxically, ratherthan being inhibited by 1NM-PP1, drug-sensitized Ire1 mutantsrequired 1NM-PP1 as a cofactor for activation. In the presenceof 1NM-PP1, drug-sensitized Ire1 bypassed mutations that inactivateits kinase activity and induced a full UPR. Thus, rather thanthrough phosphorylation per se, a conformational change in thekinase domain triggered by occupancy of the active site witha 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
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.
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.
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 »
Inaugural Article: 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 »
