NDLI: Attenuation of Mammalian Target of Rapamycin Activity by Increased cAMP in 3T3-L1 Adipocytes

Content Provider	Journal of Biological Chemistry (JBC)
Author	Scott, Pamela H. Jr, John C. Lawrence Lawrence, John C.
Abstract	Incubating 3T3-L1 adipocytes with forskolin, which increases intracellular cAMP by activating adenylate cyclase, mimicked rapamycin by attenuating the effect of insulin on stimulating the phosphorylation of four (S/T)P sites in PHAS-I, a downstream target of the mammalian target of rapamycin (mTOR) signaling pathway. To investigate the hypothesis that increasing cAMP inhibits mTOR, the protein kinase activity of mTOR was measured in an immune complex assay with recombinant PHAS-I as substrate. Both forskolin and 8-(4-chlorophenylthio)adenosine 3′-5′-monophosphate (CPT-cAMP) prevented the activation of mTOR by insulin in adipocytes, but neither agent affected mTOR activity when added directly to the immunopurified protein. In contrast, the cAMP phosphodiesterase inhibitor, theophylline, inhibited mTOR activity not only when added to intact adipocytes but also when added to immunopurified mTOR in vitro, demonstrating that certain methylxanthines are able to inhibit mTOR independently of increasing cAMP. Forskolin and CPT-cAMP blocked the effect of insulin on increasing mTOR phosphorylation, which was assessed using mTAb1, an antibody whose binding is inhibited by phosphorylation of mTOR. Although the mTAb1 epitope contains a consensus site for protein kinase B, neither agent inhibited the activation of protein kinase B produced by insulin. These findings support the interpretation that increasing cAMP attenuates the effects of insulin on PHAS-I, p70S6K, and other downstream targets of the mTOR signaling pathway by inhibiting the phosphorylation and activation of mTOR.
Related Links	http://www.jbc.org/content/273/51/34496.abstract
Ending Page	34501
Starting Page	34496
Page Count	6
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	51
Volume Number	273
DOI	10.1074/jbc.273.51.34496
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	1998-12-18
Access Restriction	Open
Subject Keyword	Mammalian target of rapamycin (mTOR) 8-(4-chlorophenylthio)adenosine 3′-5′-monophosphate (CPT-cAMP) Eukaryotic initiation factor 4E (eIF4E) Eukaryotic initiation factor 4G (eIF4G) FK506-binding protein ofMr = 12,000 (FKBP12) High performance liquid chromatography (HPLC) Mitogen-activated protein kinase (MAP kinase) Polyacrylamide gel electrophoresis (PAGE) An eIF4E-binding protein also known as 4E-BP1 (PHAS-I) Phosphatidylinositol 3-kinase (PI 3-kinase) CAMP-dependent protein kinase (PKA) Protein kinase B (PKB) The Mr ≈ 70,000 ribosomal S6 protein kinase (p70S6K) MTOR kinase. (TORK) CELL BIOLOGY AND METABOLISM
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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