FKBP12-Rapamycin-Associated Protein Associates with Mitochondria and Senses Osmotic Stress via Mitochondrial Dysfunction

FKBP12-rapamycin associated protein (FRAP, also known as mTOR or RAFT) is the founding member of the phosphatidylinositol kinase-related kinase family and functions as a sensor of physiological signals that regulate cell growth. Signals integrated by FRAP include nutrients, cAMP levels, and osmotic...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2002-04, Vol.99 (7), p.4319-4324
Main Authors: Desai, Bimal N., Myers, Benjamin R., Schreiber, Stuart L.
Format: Article
Language:English
Subjects:
3T3 Cells
Amino acids
Animals
Antibodies
Antigen-Antibody Complex - chemistry
Biological Sciences
Cell Division
Cell growth
Cell Membrane - chemistry
Cells
Cellular biology
Cyclooxygenase inhibitors
Humans
Jurkat Cells
Mice
Microscopy
Microscopy, Confocal
Mitochondria
Mitochondria - chemistry
Mitochondria - physiology
Osmosis
Osmotic Pressure
Phosphatases
Physiological regulation
Protein Kinases - analysis
Protein Kinases - physiology
Proteins
Sirolimus - pharmacology
T lymphocytes
TOR Serine-Threonine Kinases
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Summary:FKBP12-rapamycin associated protein (FRAP, also known as mTOR or RAFT) is the founding member of the phosphatidylinositol kinase-related kinase family and functions as a sensor of physiological signals that regulate cell growth. Signals integrated by FRAP include nutrients, cAMP levels, and osmotic stress, and cellular processes affected by FRAP include transcription, translation, and autophagy. The mechanisms underlying the integration of such diverse signals by FRAP are largely unknown. Recently, FRAP has been reported to be regulated by mitochondrial dysfunction and depletion of ATP levels. Here we show that exposure of cells to hyperosmotic conditions (and to glucose-deficient growth medium) results in rapid and reversible dissipation of the mitochondrial proton gradient. These results suggest that the ability of FRAP to mediate osmotic stress response (and glucose deprivation response) is by means of an intermediate mitochondrial dysfunction. We also show that in addition to cytosolic FRAP a large portion of FRAP associates with the mitochondrial outer membrane. The results support the existence of a stress-sensing module consisting of mitochondria and mitochondrial outer membrane-associated FRAP. This module allows the cell to integrate a variety of stress signals that affect mitochondrial function and regulate a growth checkpoint involving p70 S6 kinase.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.261702698