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Alejo Efeyan, PhD - "Nutrient Signaling in Health and Disease"

Group Leader, Spanish National Cancer Research Center, CNIO, Madrid, Spain
When May 14, 2019
from 12:00 PM to 01:30 PM
Where Tigem, Vesuvius Auditorium
Contact Name
Contact Phone 081-19230659
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Short CV

The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of growth via the control of most anabolic responses in the cell. MTORC1 integrates signals triggered by systemic availability of nutrients (via second messengers such as insulin), and from cellular nutrient sufficiency (amino acids, glucose). Growth factor signaling culminates in mTOR kinase activation by a signal transduction that involves Akt, TSC1/2 and a small GTPase called Rheb. Cellular nutrients activate the Rag family of GTPases, which recruit mTORC1 to the outer lysosomal surface, where Rheb resides. In this manner, maximal mTORC1 activity only takes place when cellular and system nutrient sufficiency exists, so as to drive cell growth only upon availability of the energy and the building blocks to execute and accomplish the anabolic processes. While well-defined at the biochemical level, the relevance of nutrient signaling for the physiological control of mTORC1 has been minimally explored.
We have generated a number of gain- and loss-of-function alleles to study, by means of genetically engineered mice, the impact nutrient signaling in mammals. Regulation of the nutrient signaling / Rag GTPase pathway resulted key to coordinate responses to fasting and to endure prolonged periods of nutrient limitation. Surprisingly, deregulated nutrient signaling has a deep impact in physiological and pathological B cell responses. We have studied the involvement of the RagC GTPase in B cell lymphomas, as 15% of follicular lymphomas harbor activating point mutations in RagC. Patient-derived RagC mutations, targeted to the endogenous locus in mice, conferred a partial insensitivity to nutrient deprivation, but strongly exacerbated B cell responses and accelerated experimental lymphomagenesis, while creating a selective vulnerability to pharmacological inhibition of mTORC1. The moderate increase in nutrient signaling conferred by point RagC mutants synergized with paracrine cues from the supportive T cell microenvironment to promote B cell activation. Our results support a model in which activating mutations in the nutrient signaling pathway foster lymphomagenesis by corrupting a nutrient-dependent control of mTORC1-activating paracrine signals from the T cell microenvironment.


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