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.

Sci. Signal., 26 January 2010
Vol. 3, Issue 106, p. ra7
[DOI: 10.1126/scisignal.2000514]

RESEARCH ARTICLES

A Crucial Role for RACK1 in the Regulation of Glucose-Stimulated IRE1{alpha} Activation in Pancreatic β Cells

Yifu Qiu1, Ting Mao1, Yongliang Zhang1, Mengle Shao1, Jia You1, Qiurong Ding1, Yan Chen1, Dongmei Wu1, Dong Xie1, Xu Lin1, Xiang Gao2, Randal J. Kaufman3, Wenjun Li1*, and Yong Liu1*

1 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China.
2 Model Animal Research Center, Nanjing University, Nanjing 210093, China.
3 Departments of Biological Chemistry and Internal Medicine, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48105, USA.

Abstract: Autophosphorylation of inositol-requiring enzyme 1{alpha} (IRE1{alpha}) is required for its activation, which elicits the cellular unfolded protein response (UPR) and is functionally connected with insulin biosynthesis in pancreatic β cells. We found that the scaffold protein receptor for activated C-kinase 1 (RACK1) interacted with IRE1{alpha} in a glucose-stimulated or endoplasmic reticulum (ER) stress–responsive manner in pancreatic β cells and primary islets. RACK1 mediated the glucose-inducible assembly of a complex containing IRE1{alpha}, RACK1, and protein phosphatase 2A (PP2A) to promote dephosphorylation of IRE1{alpha} by PP2A, thereby inhibiting glucose-stimulated IRE1{alpha} activation and attenuating IRE1{alpha}-dependent increases in insulin production. Moreover, IRE1{alpha} activation was increased and RACK1 abundance was decreased in a mouse model of diabetes. Thus, our findings demonstrate that RACK1 functions as a key component in regulating the IRE1{alpha} signaling pathway in pancreatic β cells.

* To whom correspondence should be addressed. E-mail: liuy{at}sibs.ac.cn (Y.L.) and wjli{at}sibs.ac.cn (W.L.)

Citation: Y. Qiu, T. Mao, Y. Zhang, M. Shao, J. You, Q. Ding, Y. Chen, D. Wu, D. Xie, X. Lin, X. Gao, R. J. Kaufman, W. Li, Y. Liu, A Crucial Role for RACK1 in the Regulation of Glucose-Stimulated IRE1{alpha} Activation in Pancreatic β Cells. Sci. Signal. 3, ra7 (2010).

Read the Full Text

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Phenobarbital Indirectly Activates the Constitutive Active Androstane Receptor (CAR) by Inhibition of Epidermal Growth Factor Receptor Signaling.
S. Mutoh, M. Sobhany, R. Moore, L. Perera, L. Pedersen, T. Sueyoshi, and M. Negishi (2013)
Science Signaling 6, ra31
   Abstract »    Full Text »    PDF »
Xenobiotic Perturbation of ER Stress and the Unfolded Protein Response.
M. A. Lafleur, J. L. Stevens, and J. W. Lawrence (2013)
Toxicol Pathol 41, 235-262
   Abstract »    Full Text »    PDF »
A Role for Protein Inhibitor of Activated STAT1 (PIAS1) in Lipogenic Regulation through SUMOylation-independent Suppression of Liver X Receptors.
Y. Zhang, Z. Gan, P. Huang, L. Zhou, T. Mao, M. Shao, X. Jiang, Y. Chen, H. Ying, M. Cao, et al. (2012)
J. Biol. Chem. 287, 37973-37985
   Abstract »    Full Text »    PDF »
Neuronal Cbl Controls Biosynthesis of Insulin-Like Peptides in Drosophila melanogaster.
Y. Yu, Y. Sun, S. He, C. Yan, L. Rui, W. Li, and Y. Liu (2012)
Mol. Cell. Biol. 32, 3610-3623
   Abstract »    Full Text »    PDF »
4-O-Carboxymethyl Ascochlorin Causes ER Stress and Induced Autophagy in Human Hepatocellular Carcinoma Cells.
J. H. Kang, Y.-C. Chang, and M. R. Maurizi (2012)
J. Biol. Chem. 287, 15661-15671
   Abstract »    Full Text »    PDF »
RACK1 Promotes Non-small-cell Lung Cancer Tumorigenicity through Activating Sonic Hedgehog Signaling Pathway.
S. Shi, Y.-Z. Deng, J.-S. Zhao, X.-D. Ji, J. Shi, Y.-X. Feng, G. Li, J.-J. Li, D. Zhu, H. P. Koeffler, et al. (2012)
J. Biol. Chem. 287, 7845-7858
   Abstract »    Full Text »    PDF »
Direct Interaction between Scaffolding Proteins RACK1 and 14-3-3{zeta} Regulates Brain-derived Neurotrophic Factor (BDNF) Transcription.
J. Neasta, P. A. Kiely, D.-Y. He, D. R. Adams, R. O'Connor, and D. Ron (2012)
J. Biol. Chem. 287, 322-336
   Abstract »    Full Text »    PDF »
The Unfolded Protein Response: Integrating Stress Signals Through the Stress Sensor IRE1{alpha}.
C. Hetz, F. Martinon, D. Rodriguez, and L. H. Glimcher (2011)
Physiol Rev 91, 1219-1243
   Abstract »    Full Text »    PDF »
PKA phosphorylation couples hepatic inositol-requiring enzyme 1{alpha} to glucagon signaling in glucose metabolism.
T. Mao, M. Shao, Y. Qiu, J. Huang, Y. Zhang, B. Song, Q. Wang, L. Jiang, Y. Liu, J.-D. J. Han, et al. (2011)
PNAS 108, 15852-15857
   Abstract »    Full Text »    PDF »
Membrane aberrancy and unfolded proteins activate the endoplasmic reticulum stress sensor Ire1 in different ways.
T. Promlek, Y. Ishiwata-Kimata, M. Shido, M. Sakuramoto, K. Kohno, and Y. Kimata (2011)
Mol. Biol. Cell 22, 3520-3532
   Abstract »    Full Text »    PDF »
Research Advances at the Institute for Nutritional Sciences at Shanghai, China.
Y. Chen, X. Lin, Y. Liu, D. Xie, J. Fang, Y. Le, Z. Ke, Q. Zhai, H. Wang, F. Guo, et al. (2011)
Adv Nutr 2, 428-439
   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 »
Mammalian endoplasmic reticulum stress sensor IRE1 signals by dynamic clustering.
H. Li, A. V. Korennykh, S. L. Behrman, and P. Walter (2010)
PNAS 107, 16113-16118
   Abstract »    Full Text »    PDF »
ER Stress in Pancreatic {beta} Cells: The Thin Red Line Between Adaptation and Failure.
D. L. Eizirik and M. Cnop (2010)
Science Signaling 3, pe7
   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