Pancreatic islet cells displaying TOR activation (brown staining) have a growth advantage
Food intake may dictate metabolic adaptations as well as the control of cell growth and proliferation. Mario Pende’s goal is to better understand the coordination of these responses. He and his team are stuyding the protein kinase Target Of Rapamycin (TOR) which has an evolutionary conserved role in the integration of nutritional cues. The pathophysiological impact of TOR activity will be analyzed in growth and metabolic diseases in mammals.
In metazoans, nutrient and growth factor availability control cell number, size and metabolic homeostasis. We investigate the specific programs underlying these responses, and their coordination by signal transduction mechanisms.
We focus on two nutrient signal transduction pathways, the mTOR (mammalian Target Of Rapamycin) and the Vps15/Vps34 complex (Vacuolar Protein Sorting15/34). These ancient pathways are present in every eukaryotic cell, from unicellular organisms like yeast to humans. They function as essential mechanisms that direct how growth and metabolism adapt to nutritional cues.
Both pathways were discovered in yeast by genetic screens. The Mike Hall lab was searching for the target of rapamycin, an antibiotic that inhibits cell growth and triggers autophagy. Scott Emr was looking at Vps mutants that mislocalize carbopeptidase from the lysosomes to the extracellular space. Yoshinori Ohsumi at the same time showed that Vps15/Vps34 mutants have impaired autophagy. mTOR is a Ser/Thr protein kinase, while the Vps15/Vps34 complex is a lipid kinase with phosphatidylinositol 3-kinase activity (class III PI3K). The transduction mechanisms triggered by mTOR and class III PI3K are complex. In mammalian cells, both kinases are engaged in multiple complexes that have different localization, targets and sensitivities to upstream signals, like nutrients and insulin.
We have contributed to demonstrate that this crosstalk and differential regulation may explain many physiological responses to nutrition. For instance, why nutrients and insulin are synergistic for cell growth, though nutrients cause resistance to the metabolic action of insulin. Or why insulin inhibits autophagy, though stimulates receptor trafficking.
RESEARCH ACHIEVEMENTS AND OBJECTIVES
During the past fifteen years we have generated and characterized a wide panel of mouse mutants in the mTOR and class III PI3K pathways. We were involved in revealing unique and interesting phenotypes that increased our knowledge of mTOR/class III PI3K roles in pathophysiology: mutants with small cells (Pende et al., Nature, 2000; Ohanna et al., Nature Cell Biol, 2005), mutants resistant to tumorigenesis in specific tissues and after specific oncogenic insults (Alliouachene et al., JCI, 2008; Panasyuk et al., Nature Comm., 2012; Patitucci et al., JCI, 2017), mutants with muscle disease (Risson et al., JCB, 2009; Nemazanyy et al., EMBO Mol Med, 2013), mutants mimicking caloric restriction and promoting longevity (Aguilar et al., Cell Metabolism, 2007; Barilari et al., EMBO J, 2017), mutants with altered insulin action (Nemazanyy et al., Nature Comm., 2015; Treins et al., Mol Cel Biol, 2012).
The overall goal of our research program for the next five years is threefold:
1) To investigate fundamental processes including cell size control and organismal longevity. To this end, we want to determine the molecular targets of the nutrient-activated mTORC1/S6 kinase cassette that may explain the alterations in cell size and lifespan when these kinases are deregulated.
2) To define how class III PI3K signaling integrates energy production and the circadian clock in the cell. To this end, we will study the regulation and novel downstream effectors of class III PI3K complexes.
3) To better understand human genetic diseases that arise from pathological changes in the activities of the mTOR/class III PI3K or that may benefit from therapeutical intervention on these pathways. These diseases include Tuberous Sclerosis Complex (TSC), metabolic diseases and lysosomal storage diseases.
The translational research will focus on rare pediatric diseases showing a deregulation of the mTOR and class III PI3K pathways. This medical aspect stems from two important considerations. First, these pathways are extremely well conserved throughout the evolution. For instance, the human diseases arising from mutations in the components of mTOR signaling (e.g. Akt or TSC) are exactly what one would have inferred from mouse genetics. Second, this direction will benefit of a close interaction with multiple Medical Departments in our shared research campus of the Necker Children Hospital.
• 2000 Ph. D. in Biochemistry, Friedrich Miescher Institute, University of Basel, Switzerland. George Thomas’ lab
• 2001 Appointed Group Leader at the Necker Institute, Paris, France
• Visiting professor, Nankai University, Tianjin, China, 2016
• Henri LABBÉ Prize (Integrative Biology), French Academy of Sciences, 2014
• Consolidator Grant, European Research Council (ERC), 2013
• Starting Grant, European Research Council (ERC), 2008
• G. B. Morgagni Silver medal Young Investigator Award, Servier, 2006
• Avenir Inserm Award, 2002
Fév 2012, Nat Commun
Jul 2011, J Clin Invest