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Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins

Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins
Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins
Signaling through the mammalian target of rapamycin (mTOR) controls cell size and growth as well as other functions, and it is a potential therapeutic target for graft rejection, certain cancers, and disorders characterized by inappropriate cell or tissue growth. mTOR signaling is positively regulated by hormones or growth factors and amino acids. mTOR signaling regulates the phosphorylation of several proteins, the best characterized being ones that control mRNA translation. Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) undergoes phosphorylation at multiple sites. Here we show that amino acids regulate the N-terminal phosphorylation sites in 4E-BP1 through the RAIP motif in a rapamycin-insensitive manner. Several criteria indicate this reflects a rapamycin-insensitive output from mTOR. In contrast, the insulin-stimulated phosphorylation of the C-terminal site Ser64/65 is generally sensitive to rapamycin, as is phosphorylation of another well-characterized target for mTOR signaling, S6K1. Our data imply that it is unlikely that mTOR directly phosphorylates Thr69/70 in 4E-BP1. Although 4E-BP1 and S6K1 bind the mTOR partner, raptor, our data indicate that the outputs from mTOR to 4E-BP1 and S6K1 are distinct. In cells, efficient phosphorylation of 4E-BP1 requires it to be able to bind to eIF4E, whereas phosphorylation of 4E-BP1 by mTOR in vitro shows no such preference. These data have important implications for understanding signaling downstream of mTOR and the development of new strategies to impair mTOR signaling.
0270-7306
2558-2572
Wang, Xuemin
d6bb4eb2-5687-46ed-b770-cceb22fd792e
Beugnet, Anne
78e2ba75-1730-4a12-bfdd-9e13903d19e2
Murakami, Mirei
5241d7dc-2c3e-46b2-9927-a2b8deceb94c
Yamanaka, Shinya
81e2757a-9f2c-41e7-af41-f1b9c02333ea
Proud, Christopher G.
59dabfc8-4b44-4be8-a17f-578a58550cb3
Wang, Xuemin
d6bb4eb2-5687-46ed-b770-cceb22fd792e
Beugnet, Anne
78e2ba75-1730-4a12-bfdd-9e13903d19e2
Murakami, Mirei
5241d7dc-2c3e-46b2-9927-a2b8deceb94c
Yamanaka, Shinya
81e2757a-9f2c-41e7-af41-f1b9c02333ea
Proud, Christopher G.
59dabfc8-4b44-4be8-a17f-578a58550cb3

Wang, Xuemin, Beugnet, Anne, Murakami, Mirei, Yamanaka, Shinya and Proud, Christopher G. (2005) Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins. Molecular and Cellular Biology, 25 (7), 2558-2572. (doi:10.1128/MCB.25.7.2558-2572.2005).

Record type: Article

Abstract

Signaling through the mammalian target of rapamycin (mTOR) controls cell size and growth as well as other functions, and it is a potential therapeutic target for graft rejection, certain cancers, and disorders characterized by inappropriate cell or tissue growth. mTOR signaling is positively regulated by hormones or growth factors and amino acids. mTOR signaling regulates the phosphorylation of several proteins, the best characterized being ones that control mRNA translation. Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) undergoes phosphorylation at multiple sites. Here we show that amino acids regulate the N-terminal phosphorylation sites in 4E-BP1 through the RAIP motif in a rapamycin-insensitive manner. Several criteria indicate this reflects a rapamycin-insensitive output from mTOR. In contrast, the insulin-stimulated phosphorylation of the C-terminal site Ser64/65 is generally sensitive to rapamycin, as is phosphorylation of another well-characterized target for mTOR signaling, S6K1. Our data imply that it is unlikely that mTOR directly phosphorylates Thr69/70 in 4E-BP1. Although 4E-BP1 and S6K1 bind the mTOR partner, raptor, our data indicate that the outputs from mTOR to 4E-BP1 and S6K1 are distinct. In cells, efficient phosphorylation of 4E-BP1 requires it to be able to bind to eIF4E, whereas phosphorylation of 4E-BP1 by mTOR in vitro shows no such preference. These data have important implications for understanding signaling downstream of mTOR and the development of new strategies to impair mTOR signaling.

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Published date: April 2005

Identifiers

Local EPrints ID: 56172
URI: https://eprints.soton.ac.uk/id/eprint/56172
ISSN: 0270-7306
PURE UUID: 86a1e586-bb8c-4baa-8508-f86b579cd7b8

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Date deposited: 07 Aug 2008
Last modified: 13 Mar 2019 20:35

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