Identification and functional characterization of new components of TOR signalling in C. elegans

• Applicant: Professorin Elke Neumann-Haefelin
• Subject Area: Nephrology
• Term: from 2008 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 58488057

• Final Report Year: 2018

Final Report Abstract

mTOR holds a key position in an intricate signalling network with profound implications for cell metabolism, growth, and proliferation. Deregulation of mTOR plays an important role in the pathogenesis of polycystic kidney disease and in the progression of hereditary kidney diseases. However, the mechanisms causing mTOR dysregulation in kidney diseases remain incompletely understood. We established the nematode C. elegans as model organism in the clinical research unit and studied the genetic basis of mTOR signalling and related pathways. Ample molecular tools and evolutionary conservation have advanced C. elegans into a premiere model system for kidney and aging research. Despite having a simple body plan, C. elegans overcame many problems of studies in cell culture and mouse models and has proved to be a powerful tool in studying various aspects of renal research in the CRU. Using a multidisciplinary approach comprising C. elegans genetics, genome-wide screening, biochemical and human cell culture experiments we identified and characterized a guanine nucleotide exchange factor homologous to human Dbl that contributes to activation of mTORC1 signalling. These findings have important implications for mTOR functions and signalling mechanisms in kidney disease, aging and related diseases. We further elucidated how mTOR influences aging and stress response. We identified mechanisms of transcriptional regulation of fundamental importance in aging and mTOR effector functions. Protective mechanisms controlled by transcription factors may be of key importance for the balance between mTOR growth signals and longevity. We further characterized basic functions of mTORC2 operating in signaling pathways for growth, development and aging. Our molecular studies identified a crosstalk between growth factor signalling and TGF-ß signalling mediated by the tuberous sclerosis complex protein TSC1 for the regulation of cellular growth and tissue homeostasis. TSC1 promoted TGF-ß-induced growth arrest and this connection may limit cellular overgrowth. These findings may have implications for cancer treatments targeting growth factor signaling because they may impair tumor-suppressive cytostatic TGF-ß signaling. In summary, we provided considerable insights into the fundamental functions of mTOR and contributed to the understanding of the diverse roles of the two mTOR complexes in physiologic processes and pathogenic mechanisms of cystic kidney disease. It is hoped that a more thorough understanding of the genetics and signalling network of mTORC1 and mTORC2 will eventually help to design rationale therapeutic approaches.

Publications

• A model organism approach: defining the role of Neph proteins as regulators of neuron and kidney morphogenesis. Hum Mol Genet 19, 2347-2359 (2010)
  Neumann-Haefelin E, Kramer-Zucker A, Slanchev K, Hartleben B, Noutsou F, Martin K, Wanner N, Ritter A, Godel M, Pagel P, Fu X, Muller A, Baumeister R, Walz G, and Huber TB
  
• Functional and spatial analysis of C. elegans SYG-1 and SYG-2, orthologs of the Neph/nephrin cell adhesion module directing selective synaptogenesis. PLoS One 6, e23598 (2011)
  Wanner N, Noutsou F, Baumeister R, Walz G, Huber TB, and Neumann-Haefelin E
  
• A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Sci Signal 5, ra25 (2012)
  Dalle Pezze P, Sonntag AG, Thien A, Prentzell MT, Godel M, Fischer S, Neumann- Haefelin E, Huber TB, Baumeister R, Shanley DP, and Thedieck K
  
• TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab 15, 713-724 (2012)
  Robida-Stubbs S, Glover-Cutter K, Lamming DW, Mizunuma M, Narasimhan SD, Neumann- Haefelin E, Sabatini DM, and Blackwell TK
  
• TORC2 signaling antagonizes SKN-1 to induce C. elegans mesendodermal embryonic development. Dev Biol 384, 214-227 (2013)
  Ruf V, Holzem C, Peyman T, Walz G, Blackwell TK, and Neumann-Haefelin E.
  
• Hantavirus infection with massive proteinuria and podocyte foot process effacement. American Journal of Kidney Diseases 64(3): 452-456 (2014)
  Boehlke C., Hartleben B., Huber T.B., Hopfer H., Walz G., and Neumann-Haefelin E.
  
• mTORC2-SGK-1 acts in two environmentally responsive pathways with opposing effects on longevity. Aging Cell 13, 869-878 (2014)
  Mizunuma M, Neumann-Haefelin E, Moroz N, Li Y, and Blackwell TK
  
• Caenorhabditis elegans OSM-11 signaling regulates SKN-1/Nrf during embryonic development and adult longevity and stress response. Dev Biol 400, 118-131 (2015)
  Dresen A, Finkbeiner S, Dottermusch M, Beume JS, Li Y, Walz G, and Neumann-Haefelin E
  
• TSC1 activates TGF-beta-Smad2/3 signaling in growth arrest and epithelial-tomesenchymal transition. Dev Cell 32, 617-630 (2015)
  Thien A, Prentzell MT, Holzwarth B, Klasener K, Kuper I, Boehlke C, Sonntag AG, Ruf S, Maerz L, Nitschke R, Grellscheid SN, Reth M, Walz G, Baumeister R, Neumann-Haefelin E, and Thedieck K
  
• Cell cycle controls stress response and longevity in C. elegans. Aging 8, 2100-2126 (2016)
  Dottermusch M, Lakner T, Peyman T, Klein M, Walz G, and Neumann-Haefelin E
  
• CGEF-1 regulates mTORC1 signaling during adult longevity and stress response in C. elegans. Oncotarget (2018)
  Li Y.; Finkbeiner, S.; Ganner, A.; Gerber, J.; Klein, M.; Grafe, M.; Kandzia, J.; Thien, A.; Thedieck, K.; Breves, G.; Jank, T.; Baumeister, R.; Walz, G.; Neumann-Haefelin, E.
  
• Treating C3 glomerulopathy with eculizumab. BMC Nephrol 19, 7 (2018)
  Welte T, Arnold F, Kappes J, Seidl M, Haffner K, Bergmann C, Walz G, and Neumann-Haefelin E