Alejo Efeyan has just gained an ERC Starting Grant for the proposal entitled The Physiology of Nutrient Sensing by mTOR (NutrientSensingVivo), which will be carried out at the Spanish National Cancer Research Centre (CNIO). Next is a brief description of his career and interests.
Since my early steps in scientific research, I have been interested in master regulators of fundamental biological processes. During my Ph.D., I studied how the tumor suppressor protein p53 exerts its cancer protection. In particular, by means of genetic engineered mice, I aimed to dissect the relative contribution of different inputs that activate p53 (DNA damage response and oncogenic signaling) to its ability to exert tumor suppression functions. Our results unequivocally showed the dramatic importance of oncogenic signaling, compared to that of the DNA damage response. I also performed a similar genetic approach to dissect the relevance of certain targets of p53 in p53-specific protection, which showed a moderate contribution of the cell cycle regulator p21.
For my postdoctoral studies, I switched to the study of a master regulator of cell growth: the mechanistic target of rapamycin (mTOR), involved in the pathogenesis of cancer and metabolic disorders. When part of mTOR complex 1 (mTORC1), this kinase drives cell growth by regulating every anabolic pathway in the cell. MTOR integrates signaling cues from the organismal nutritional state, elicited by growth factors and other hormones, and cues from local nutrient abundance. Unlike the growth factor signal transduction, our understanding of the nutrient-signaling pathway upstream of mTORC1 has just begun, triggered by the discovery of the family of Rag GTPases. Before my postdoctoral research, work on nutrient sensing by mTORC1 was restricted to cell culture studies, and whether this pathway had any function in the context of a mammalian organism was unknown. By means of generating novel genetically-engineered mouse models to study the function of the Rag GTPases, my postdoctoral work pushed forward this field by: 1) demonstrating that this nutrient sensing signaling pathway is essential for embryonic development and for adult life; 2) showing that the regulation of RagA activity is key for coordinating fasting responses, for the regulation of autophagy, and for enduring the neonatal starvation period; 3) demonstrating that the Rag GTPases work as multi-node nutrient sensors, signaling both amino acid and glucose sufficiency to mTORC1. I am currently investigating the impact of the nutrient sensing signaling pathway in adult mammalian physiology, in particular, in cancer and aging.