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Dev Cell DOI:10.1016/j.devcel.2014.03.017

RagA, but not RagB, is essential for embryonic development and adult mice.

Publication TypeJournal Article
Year of Publication2014
AuthorsEfeyan, A, Schweitzer, LD, Bilate, AM, Chang, S, Kirak, O, Lamming, DW, Sabatini, DM
JournalDev Cell
Volume29
Issue3
Pages321-9
Date Published2014 May 12
ISSN1878-1551
KeywordsAnimals, Cell Line, Embryo, Mammalian, Hepatocytes, Liver, Mice, Mice, Knockout, Monomeric GTP-Binding Proteins, Multiprotein Complexes, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Signal Transduction, TOR Serine-Threonine Kinases
Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) integrates cues from growth factors and nutrients to control metabolism. In contrast to the growth factor input, genetic disruption of nutrient-dependent activation of mTORC1 in mammals remains unexplored. We engineered mice lacking RagA and RagB genes, which encode the GTPases responsible for mTORC1 activation by nutrients. RagB has limited expression, and its loss shows no effects on mammalian physiology. RagA deficiency leads to E10.5 embryonic death, loss of mTORC1 activity, and severe growth defects. Primary cells derived from these mice exhibit no regulation of mTORC1 by nutrients and maintain high sensitivity to growth factors. Deletion of RagA in adult mice is lethal. Upon RagA loss, a myeloid population expands in peripheral tissues. RagA-specific deletion in liver increases cellular responses to growth factors. These results show the essentiality of nutrient sensing for mTORC1 activity in mice and its suppression of PI3K/Akt signaling.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S1534-5807(14)00169-5
DOI10.1016/j.devcel.2014.03.017
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24768164?dopt=Abstract

Alternate JournalDev. Cell
PubMed ID24768164
PubMed Central IDPMC4035553
Grant ListR01 AI047389 / AI / NIAID NIH HHS / United States
R01 CA103866 / CA / NCI NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
F31CA167872 / CA / NCI NIH HHS / United States
F31 CA167872 / CA / NCI NIH HHS / United States
R00 AG041765 / AG / NIA NIH HHS / United States
AI047389 / AI / NIAID NIH HHS / United States
CA103866 / CA / NCI NIH HHS / United States
R37 AI047389 / AI / NIAID NIH HHS / United States
R21 AG042876 / AG / NIA NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
AG041765 / AG / NIA NIH HHS / United States
R01 CA129105 / CA / NCI NIH HHS / United States
K99 AG041765 / AG / NIA NIH HHS / United States