GROWTH CONTROL The mTOR Signaling Complex

The protein kinase mTOR phosphorylates S6 kinase (S6K) and eIF-4E binding protein, two regulators of protein synthesis, and an mTOR signaling pathway has been implicated in controlling mammalian cell growth and cell size in response to nutrients and growth factors. The activity of mTOR is controlled in part by its association with raptor (regulatory associated protein of TOR), an interaction that seems to have both positive and negative effects on mTOR activity. For example, overexpression of raptor has been observed to both stimulate and inhibit mTOR activity. A nutrient-sensitive interaction between mTOR and raptor has also been unclear. Kim et al. now report that nutrient-sensitivity of the mTOR-raptor complex requires the interaction of mTOR with another protein called GßL (G protein ß subunit-like protein), a widely expressed protein of previously unknown function. An endogenous mTOR-GßL complex was detected in cultured mammalian cells and GßL bound to the kinase domain of mTOR. The mTOR-GßL interaction was more stable, and independent from, mTOR-raptor interaction. GßL appears to be a positive regulator of the mTOR signaling pathway, because overexpression of GßL stimulated mTOR kinase activity and decreased either GßL expression by small interfering RNA or expression of mutants that do not bind mTOR reduced phosphorylation of S6K. In addition, decreased GßL expression reduced raptor association with mTOR, implying that GßL stabilizes the mTOR-raptor complex. Furthermore, the mTOR-raptor complex was only nutrient-sensitive if GßL was expressed. The authors propose opposing actions of GßL and raptor on mTOR in which binding of raptor to a GßL-mTOR complex inhibits GßL-mediated activation of mTOR. Low nutrient conditions promote raptor association with mTOR only when GßL is also docked onto mTOR. Increased nutrients would weaken the raptor-mTOR interaction, allowing GßL to stimulate mTOR.

D.-H. Kim, D. D. Sarbassov, S. M. Ali, R. R. Latek, K. V. P. Guntur, H. Erdjument-Bromage, P. Tempst, D. M. Sabatini, GßL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell 11, 895-904 (2003). [Online Journal]

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