Rictor is a novel target of p70 S6 kinase-1

Abstract

The rapamycin-insensitive companion of mammalian target of rapamycin (mTOR) (Rictor) is a key member of mTOR complex-2 (mTORC2), which phosphorylates the AGC kinases Akt/PKB, PKC and SGK1 at a C-terminal hydrophobic motif. We identified several novel sites on Rictor that are phosphorylated, including Thr1135, which is conserved across all vertebrates. Phosphorylation of this site on Rictor is stimulated by amino acids and growth factors through a rapamycin-sensitive signaling cascade. We demonstrate here that Rictor is a direct target of the ribosomal protein S6 kinase-1 (S6K1). Rictor phosphorylation at Thr1135 does not lead to major changes in mTORC2-kinase activity. However, phosphorylation of this site turns over rapidly and mediates 14-3-3 binding to Rictor and mTORC2, providing possibility for altered interactions of the complex. These findings reveal an unexpected signaling input into mTORC2, which is regulated by amino acids, growth factors and rapamycin.

Mammalian Target of Rapamycin (mTOR): Conducting the Cellular Signaling Symphony

“…Most recently, the mitotic kinase Cdc2 was reported to phosphorylate raptor Ser 696 and Thr 706 , with unknown functional significance (86). It is also clear that rictor experiences extensive phosphorylation at multiple sites, although the functional significance of almost all sites remains unknown (71)(72)(73). The phosphorylation of raptor and rictor at multiple sites may suggest that partner protein phosphorylation functions as a biochemical rheostat that fine-tunes mTORC1 and mTORC2 signaling in response to diverse environmental cues.…”

“…As the mTORC1/S6K1 feedback loop also generates a state of cellular insulin resistance and as S6K1 knock-out in the mouse increases whole body insulin sensitivity (69), it is possible that constitutive mTORC1 signaling promoted by excess nutrients (as in states of obesity) may contribute to insulin resistance and type II diabetes (67,70). Additionally, S6K1 phosphorylates rictor (at Thr 1135 ) to reduce mTORC2 signaling (71)(72)(73). Thus, the mTORC1/S6K1 axis operates in at least two negative feedback loops to suppress PI3K and mTORC2.…”

The Target of Rapamycin: Structure and Functions

“…This phosphorylation is mediated by S6K1 in an amino acid-and growth factor-dependent manner and is suggested to act as a feedback regulation of mTORC2 from mTORC1 signals (Dibble et al 2009;Julien et al 2010;Treins et al 2010). Its effect on the mTORC2-mediated Akt activation is very minimal if any (Boulbes et al 2010;Treins et al 2010). Moreover, in SIN1 -/-MEFs, in which mTORC2 complex integrity is disrupted, this phosphorylation is still detectable, suggesting that it might be involved in mTORC2-independent functions (Boulbes et al 2010).…”

“…Several studies have examined the function of rictor phosphorylation at Thr 1135 residue located in the Cterminal region. This phosphorylation is mediated by S6K1 in an amino acid-and growth factor-dependent manner and is suggested to act as a feedback regulation of mTORC2 from mTORC1 signals (Dibble et al 2009;Julien et al 2010;Treins et al 2010). Its effect on the mTORC2-mediated Akt activation is very minimal if any (Boulbes et al 2010;Treins et al 2010).…”

mTOR, la cible fonctionnelle de la rapamycine

“…En effet, la phosphorylation des protéines adaptatrices IRS (insulin receptor substrate 1) par mTORC1 et S6K a pour effet de diminuer leur stabilité et d'empêcher le recrutement de PI3K [25]. De plus, des étu-des plus récentes ont démontré que Rictor est phosphorylé par S6K1, ce qui inhibe l'activité de mTORC2 et diminue la phosphorylation et l'activation d'Akt [26][27][28].…”