The mechanisms underlying the pro-aging consequences of mTOR activity are obscure. Deregulated mTOR activity leads to accelerated aging and upregulated mTORC1 activity occurs in aging organisms. We recently described the Rag family of proteins as key for mTORC1 activation by amino acids, through a mechanism that requires mTORC1 shuttling to the lysosomal surface. We have generated a series of immortalized cell lines derived from genetically-engineered mice that lack the RagA gene. Although mTORC1 activity is barely detectable in RagA-deficient embryos, cell lines derived from them have reactivated mTORC1 signaling, which is now insensitive to amino acids withdrawal, but sensitive to growth factors withdrawal. Intriguingly, in these lines mTORC1, although active, does not localize to lysosomes, indicating that an additional unknown mechanism of mTORC1 activation is at work. Based on a combination of transcriptional profiling and proteomic-based approaches, we plan to find the genes responsible for the lysosomal-independent activation of mTORC1 and to understand how this occurs. We will then take advantage of RagA-null livers to study in vivo the consequences of altering the expression of the candidates found. Further elucidation of the molecular mechanism leading to mTORC1 desensitization to amino acid withdrawal, together with the identification of druggable targets within this pathway, may pave the way for novel therapeutic approaches to aging and age-related diseases.
Deregulated cell growth signals arising from the mechanistic target of rapamycin (mTOR) protein kinase occur in diabetes, cancer and aging. Thus, understanding mTOR signaling pathway will enable the pursuit of improved therapies against these diseases. Taking advantage of novel mouse models of deregulated mTOR activity we have generated cell lines with a unique and intriguing regulation of mTOR activation, resistant to nutrient deprivation, which normally inactivates this signaling pathway. The identification of the responsible genes and the molecular mechanisms governing this particular signaling alteration that we plan to investigate in the present proposal will help understand deregulated cell growth states. The series of novel mouse models will also allow us to explore the consequences of this deregulated growth state in mammalian physiology, helping us to develop novel therapeutic avenues to manipulate the mTORC1 pathway in human disease.
|Efeyan, Alejo; Comb, William C; Sabatini, David M (2015) Nutrient-sensing mechanisms and pathways. Nature 517:302-10|
|Schweitzer, Lawrence D; Comb, William C; Bar-Peled, Liron et al. (2015) Disruption of the Rag-Ragulator Complex by c17orf59 Inhibits mTORC1. Cell Rep 12:1445-55|
|Efeyan, Alejo; Schweitzer, Lawrence D; Bilate, Angelina M et al. (2014) RagA, but not RagB, is essential for embryonic development and adult mice. Dev Cell 29:321-9|
|Efeyan, Alejo; Sabatini, David M (2013) Nutrients and growth factors in mTORC1 activation. Biochem Soc Trans 41:902-5|
|Liu, Qingsong; Chang, Jae Won; Wang, Jinhua et al. (2010) Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer. J Med Chem 53:7146-55|