In:
American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 298, No. 4 ( 2010-04), p. E761-E769
Abstract:
Like insulin, leucine stimulates the mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70 S6K ) axis in various organs. Insulin proceeds via the canonical association of phosphatidylinositol 3-kinase (PI3K), phosphoinositide-dependent protein kinase-1 (PDK1), and protein kinase B (PKB/Akt). The signaling involved in leucine effect, although known to implicate a PI3K mechanism independent of PKB/Akt, is more poorly understood. In this study, we investigated whether PDK1 could also participate in the events leading to mTOR/p70 S6K activation in response to leucine in the heart. In wild-type hearts, both leucine and insulin increased p70 S6K activity whereas, in contrast to insulin, leucine was unable to activate PKB/Akt. The changes in p70 S6K activity induced by insulin and leucine correlated with changes in phosphorylation of Thr 389 , the mTOR phosphorylation site on p70 S6K , and of Ser 2448 on mTOR, both related to mTOR activity. Leucine also triggered phosphorylation of the proline-rich Akt/PKB substrate of 40 kDa (PRAS40), a new pivotal mTOR regulator. In PDK1 knockout hearts, leucine, similarly to insulin, failed to induce the phosphorylation of mTOR and p70 S6K , leading to the absence of p70 S6K activation. The loss of leucine effect in absence of PDK1 correlated with the lack of PRAS40 phosphorylation. Moreover, the introduction in PDK1 of the L155E mutation, which is known to preserve the insulin-induced and PKB/Akt-dependent phosphorylation of mTOR/p70 S6K , suppressed all leucine effects, including phosphorylation of mTOR, PRAS40, and p70 S6K . We conclude that the leucine-induced stimulation of the cardiac PRAS40/mTOR/p70 S6K pathway requires PDK1 in a way that differs from that of insulin.
Type of Medium:
Online Resource
ISSN:
0193-1849
,
1522-1555
DOI:
10.1152/ajpendo.00421.2009
Language:
English
Publisher:
American Physiological Society
Publication Date:
2010
detail.hit.zdb_id:
1477331-4
SSG:
12
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