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 GβL (G protein β subunit-like protein), a widely expressed protein of previously unknown function. An endogenous mTOR-GβL complex was detected in cultured mammalian cells and GβL bound to the kinase domain of mTOR. The mTOR-GβL interaction was more stable, and independent from, mTOR-raptor interaction. GβL appears to be a positive regulator of the mTOR signaling pathway, because overexpression of GβL stimulated mTOR kinase activity and decreased either GβL expression by small interfering RNA or expression of mutants that do not bind mTOR reduced phosphorylation of S6K. In addition, decreased GβL expression reduced raptor association with mTOR, implying that GβL stabilizes the mTOR-raptor complex. Furthermore, the mTOR-raptor complex was only nutrient-sensitive if GβL was expressed. The authors propose opposing actions of GβL and raptor on mTOR in which binding of raptor to a GβL-mTOR complex inhibits GβL-mediated activation of mTOR. Low nutrient conditions promote raptor association with mTOR only when GβL is also docked onto mTOR. Increased nutrients would weaken the raptor-mTOR interaction, allowing GβL 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, GβL, 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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