INTRODUCTION
Chez les métazoaires, la disponibilité des nutriments et des facteurs de croissance contrôle le nombre de cellules, la taille et l’homéostasie métabolique. Nous étudions les programmes spécifiques qui sous-tendent ces réponses, et leur coordination par les mécanismes de transduction du signal.
Nous nous concentrons sur deux voies de transduction du signal nutritif, le mTOR (mammifère Target Of Rapamycin) et le complexe Vps15 / Vps34 (Vacuolar Protein Sorting15 / 34). Ces anciennes voies sont présentes dans toutes les cellules eucaryotes, des organismes unicellulaires comme la levure aux humains. Ils fonctionnent comme des mécanismes essentiels qui dirigent la façon dont la croissance et le métabolisme s’adaptent aux signaux nutritionnels.
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.
La recherche translationnelle se concentrera sur les maladies pédiatriques rares montrant une dérégulation des voies mTOR et PI3K de classe III. Cet aspect médical découle de deux considérations importantes. Premièrement, ces voies sont extrêmement bien conservées tout au long de l’évolution. Par exemple, les maladies humaines résultant de mutations dans les composants de la signalisation mTOR (par exemple Akt ou TSC) sont exactement ce que l’on aurait déduit de la génétique de la souris. Deuxièmement, cette direction bénéficiera d’une interaction étroite avec plusieurs départements médicaux de notre campus de recherche partagé de l’hôpital Necker pour enfants.
