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All rights reserved. http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/dc/elements/1.1/title BEL Framework Large Corpus Document http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/authoredBy http://www.tkuhn.ch/bel2nanopub/RA4fqkVMzZbxc4LnD75ulZGhNmVrHnlBCzMNULG0hZsjM#_8 http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/version 1.4 http://www.tkuhn.ch/bel2nanopub/RA4fqkVMzZbxc4LnD75ulZGhNmVrHnlBCzMNULG0hZsjM#_7 http://www.w3.org/ns/prov#value Involvement of Rheb in the insulin TOR S6K signaling pathway was further investigated in mammalian cells. Transient transfection of Rheb1 or Rheb2 in HEK293 cells results in the increase of the phosphorylation of ribosomal S6 kinase (S6K) 25,30-33. Increase of the phosphorylation of S6 as well as 4E-BP1 was observed 30,31,33. In contrast, Rheb did not stimulate Akt phosphorylation 30,33]. The increase of S6K activity by the transient expression of Rheb was inhibited by the addition of rapamycin but not by wortmannin, an inhibitor of PI3K This led to the activation of S6K as detected by its phosphorylation. However, expression of dominant negative Rheb mutant, Rheb1D60K, blocked serum-inducted activation of S6K The overall picture of the involvement of Rheb in the insulin mTOR S6K signaling pathway is shown in Fig. 3. During serum activation of this signaling pathway, insulin or IGF1 is received by their respective receptors at the cell surface. This results in the activation of PI3K, which then phosphorylates Akt. The activated Akt phosphorylates Tsc2 and inhibits the ability of Tsc1 Tsc2 to negatively regulate mTOR. The inhibition of Tsc1 Tsc2 leads to the activation of Rheb, which then causes activation of mTOR. 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