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1 Biochemistry & Molecular Biology, University of British Columbia, Vancouver, Canada
* To whom correspondence should be addressed. E-mail: cgpr{at}interchange.ubc.ca.
An important function of growth hormone (GH) is to promote cell and tissue growth, and a key component of these effects is the stimulation of protein synthesis. In this study, we demonstrate that, GH acutely activated protein synthesis through signaling via the mammalian target of rapamycin, mTOR, and specifically through the rapamycin-sensitive mTORC complex, mTORC1. GH treatment enhanced the phosphorylation of two targets of mTOR signaling, 4E-BP1 and ribosomal protein S6. Phosphorylation of S6 and 4E-BP1 was maximal at 30-45 min and 10-20 min after GH stimulation, respectively. The GH-induced phosphorylation of 4E-BP1 leaded to its dissociation from eIF4E and increased binding of eIF4E to eIF4G to form eIF4F complexes. The ability of GH to stimulate the phosphorylation of S6 and 4E-BP1 was blocked by rapamycin. GH also leaded to the dephosphorylation of a third translational component linked to mTORC1, the elongation factor eEF2. Its regulation followed complex biphasic kinetics, both phases of which required mTOR signaling. GH rapidly activated both the MAP kinase (ERK) and PI 3-kinase pathways. Signaling through PI 3-kinase, alone, was however, sufficient to activate the downstream mTORC1 pathway. Consistent with this, GH increased the phosphorylation of TSC2, an upstream regulator of mTORC1, at sites that are targets for Akt/ protein kinase B (PKB). Finally, the activation of overall protein synthesis by GH in H4IIE cells was essentially completely inhibited by wortmannin or rapamycin. These results demonstrated for the first time that mTORC1 plays a major role in the rapid activation of protein synthesis by GH.
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