Quantitative Mass Spectrometry Identifies Insulin Signaling Targets in C. elegans

Meng-Qiu Dong,¹ John D. Venable,¹ Nora Au,^2,3 Tao Xu,¹ Sung Kyu Park,¹ Daniel Cociorva,¹ Jeffrey R. Johnson,¹ Andrew Dillin,² John R. Yates, III^1*

Abstract: DAF-2, an insulin receptor–like protein, regulates metabolism, development, and aging in Caenorhabditis elegans. In a quantitative proteomic study, we identified 86 proteins that were more or less abundant in long-lived daf-2 mutant worms than in wild-type worms. Genetic studies on a subset of these proteins indicated that they act in one or more processes regulated by DAF-2, including entry into the dauer developmental stage and aging. In particular, we discovered a compensatory mechanism activated in response to reduced DAF-2 signaling, which involves the protein phosphatase calcineurin.

¹ Scripps Research Institute, La Jolla, CA92037, USA.
² Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
³ University of California at San Diego, La Jolla, CA 92093, USA.

^* To whom correspondence should be addressed. E-mail: jyates{at}scripps.edu

Enhanced Energy Metabolism Contributes to the Extended Life Span of Calorie-restricted Caenorhabditis elegans.

Y. Yuan, C. S. Kadiyala, T.-T. Ching, P. Hakimi, S. Saha, H. Xu, C. Yuan, V. Mullangi, L. Wang, E. Fivenson, et al. (2012)
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LAAT-1 Is the Lysosomal Lysine/Arginine Transporter That Maintains Amino Acid Homeostasis.

B. Liu, H. Du, R. Rutkowski, A. Gartner, and X. Wang (2012)
Science 337, 351-354
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Aging as an Event of Proteostasis Collapse.

R. C. Taylor and A. Dillin (2011)
Cold Spring Harb Perspect Biol 3, a004440
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Proteomic Analysis of Integrin Adhesion Complexes.

A. Byron, J. D. Humphries, M. D. Bass, D. Knight, and M. J. Humphries (2011)
Science Signaling 4, pt2
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Two sides of lifespan regulating genes: pro-longevity or anti-longevity?.

S. Honjoh and E. Nishida (2011)
J. Biochem. 149, 381-388
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Computational biology for ageing.

D. Wieser, I. Papatheodorou, M. Ziehm, and J. M. Thornton (2011)
Phil Trans R Soc B 366, 51-63
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Long-lived mitochondrial (Mit) mutants of Caenorhabditis elegans utilize a novel metabolism.

J. A. Butler, N. Ventura, T. E. Johnson, and S. L. Rea (2010)
FASEB J 24, 4977-4988
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Regulation of Dauer Formation by O-GlcNAcylation in Caenorhabditis elegans.

J. Lee, K.-Y. Kim, J. Lee, and Y.-K. Paik (2010)
J. Biol. Chem. 285, 2930-2939
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Quantitative Proteomics by Metabolic Labeling of Model Organisms.

J. W. Gouw, J. Krijgsveld, and A. J. R. Heck (2010)
Mol. Cell. Proteomics 9, 11-24
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Discovery and validation of colonic tumor-associated proteins via metabolic labeling and stable isotopic dilution.

E. L. Huttlin, X. Chen, G. A. Barrett-Wilt, A. D. Hegeman, R. B. Halberg, A. C. Harms, M. A. Newton, W. F. Dove, and M. R. Sussman (2009)
PNAS 106, 17235-17240
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Proteomic Analysis of Integrin-Associated Complexes Identifies RCC2 as a Dual Regulator of Rac1 and Arf6.

J. D. Humphries, A. Byron, M. D. Bass, S. E. Craig, J. W. Pinney, D. Knight, and M. J. Humphries (2009)
Science Signaling 2, ra51
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The cellular geometry of growth drives the amino acid economy of Caenorhabditis elegans.

J. Swire, S. Fuchs, J. G. Bundy, and A. M. Leroi (2009)
Proc R Soc B 276, 2747-2754
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Excretory/Secretory Proteome of the Adult Developmental Stage of Human Blood Fluke, Schistosoma japonicum.

F. Liu, S.-J. Cui, W. Hu, Z. Feng, Z.-Q. Wang, and Z.-G. Han (2009)
Mol. Cell. Proteomics 8, 1236-1251
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Integrating siRNA and protein-protein interaction data to identify an expanded insulin signaling network.

Z. Tu, C. Argmann, K. K. Wong, L. J. Mitnaul, S. Edwards, I. C. Sach, J. Zhu, and E. E. Schadt (2009)
Genome Res. 19, 1057-1067
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Quantitative Proteomic Analysis of Bean Plants Infected by a Virulent and Avirulent Obligate Rust Fungus.

J. Lee, J. Feng, K. B. Campbell, B. E. Scheffler, W. M. Garrett, S. Thibivilliers, G. Stacey, D. Q. Naiman, M. L. Tucker, M. A. Pastor-Corrales, et al. (2009)
Mol. Cell. Proteomics 8, 19-31
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Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans.

R. Doonan, J. J. McElwee, F. Matthijssens, G. A. Walker, K. Houthoofd, P. Back, A. Matscheski, J. R. Vanfleteren, and D. Gems (2008)
Genes & Dev. 22, 3236-3241
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Quantitative mass spectrometry as a tool for nutritional proteomics.

J. J Moresco, M.-Q. Dong, and J. R Yates III (2008)
Am J Clin Nutr 88, 597-604
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Proteomics in Caenorhabditis elegans.

A. Audhya and A. Desai (2008)
Briefings in Functional Genomics 7, 205-210
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The Caenorhabditis elegans K10C2.4 Gene Encodes a Member of the Fumarylacetoacetate Hydrolase Family: A CAENORHABDITIS ELEGANS MODEL OF TYPE I TYROSINEMIA.

A. L. Fisher, K. E. Page, G. J. Lithgow, and L. Nash (2008)
J. Biol. Chem. 283, 9127-9135
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Distinct Activities of the Germline and Somatic Reproductive Tissues in the Regulation of Caenorhabditis elegans' Longevity.

T. M. Yamawaki, N. Arantes-Oliveira, J. R. Berman, P. Zhang, and C. Kenyon (2008)
Genetics 178, 513-526
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CELL BIOLOGY: Proteins That Promote Long Life.

S. K. Kim (2007)
Science 317, 603-604
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