mTOR Complex1–S6K1 signaling: at the crossroads of obesity, diabetes and cancer

Recent studies demonstrate that the mammalian target of rapamycin (mTOR) and its effector, S6 kinase 1 (S6K1), lie at the crossroads of a nutrient–hormonal signaling network that is involved in specific pathological responses, including obesity, diabetes and cancer. mTOR exists in two complexes: mTOR Complex1, which is rapamycin-sensitive and phosphorylates S6K1 and initiation factor 4E binding proteins (4E-BPs), and mTOR Complex2, which is rapamycin-insensitive and phosphorylates protein kinase B (PKB, also known as Akt). Both mTOR complexes are stimulated by mitogens, but only mTOR Complex1 is under the control of nutrient and energy inputs. Thus, to orchestrate the control of homeostatic responses, mTOR Complex1 must integrate signals from distinct cues. Here, we review recent findings concerning the regulation and pathophysiology associated with mTOR Complex1 and S6K1.

Introduction

The coordinated control of cell growth to produce a genetically predetermined cell size, organ shape or body plan is greatly influenced by mammalian target of rapamycin (mTOR) and its downstream effector S6 kinase 1 (S6K1), as first revealed by studies in mice and Drosophila [1]. In this context, S6K1 has emerged as a crucial effector of mTOR signaling. The ability of mTOR to phosphorylate and activate S6K1 depends on three associated proteins, the rapamycin-sensitive adaptor protein of mTOR (raptor), the G protein β-subunit-like protein (GβL) [2] and the proline-rich protein kinase B (PKB, also known as Akt) substrate 40 kDa (PRAS40) [3], which constitute mTOR Complex1 2, 4 (Box 1). However, although GβL was thought to be required for mTOR Complex1 signaling [2], this view has recently been questioned [5]. mTOR Complex1 interacts with downstream substrates through raptor, which recognizes mTOR substrates by their TOR signaling (TOS) motifs [6]. The anti-fungal macrolide rapamycin blocks mTOR Complex1 function by forming a gain-of-function inhibitory complex with the immunophilin FK506 binding protein 1A (FKBP12) [7]. This inhibitory complex binds to mTOR, thereby altering its ability to phosphorylate downstream substrates, including S6K1 [8]. Recent studies have shown that mTOR also occurs in a second complex, mTOR Complex2, which includes GβL, the adaptor protein rapamycin-insensitive companion of mTOR (rictor) and mammalian stress-activated protein kinase (SAPK)-interacting protein-1 (mSIN1) 9, 10, 11. mTOR Complex2 is the kinase responsible for phosphorylation of S473, one of the two key residues required for full activation of PKB/Akt. This second complex is largely insensitive to the rapamycin–FKBP12 complex in an acute setting, but in some conditions it might be inhibited by chronic exposure to rapamycin because nascent mTOR kinase binds to rapamycin before its assembly into mature mTOR Complex2 [12]. The importance of mTOR Complex1 in nutrient signaling has been underscored by observations of mice in which the gene that encodes mTOR has been deleted. Such mice die shortly after implantation due to impaired trophoblast differentiation and failure of embryonic stem cells to proliferate 13, 14. Exposure of early mouse embryos to rapamycin also arrests trophoblast differentiation and embryonic stem cell proliferation, indicating that it is the rapamycin-sensitive mTOR Complex1 function that is essential during this stage of development [1]. Consistent with this hypothesis, the effects of rapamycin on early development can be recapitulated by the withdrawal of amino acids [1], which specifically blocks mTOR Complex1 function, as judged by S6K1 T389 phosphorylation. Moreover, it has been recently shown that raptor-deficient mice are also embryonic lethal at day E5.5, whereas either rictor- or GβL-deficient mice live up to day E10.5 [5].

In contrast to mTOR^−/− mice, S6K1^−/− mice are viable, although they are retarded in development [i.e. they are 20% smaller at birth than wild-type (WT) mice] [1]. Such mice are also hypoinsulinemic, mildly glucose intolerant and have reduced β-cell size [1]. The pronounced reduction of β-cell size was suggested to account for the hypoinsulinemic phenotype of these mice [1]. Moreover, in recent studies it was demonstrated that S6K1^−/− mice also exhibit increased energy expenditure and lipolysis, and a reduction in adipose tissue mass, which could be accounted for by an apparent decrease in adipocyte-cell size [15]. It was also demonstrated that such mice remain exquisitely insulin sensitive on a high-fat diet (HFD), despite high levels of circulating free fatty acids [15]. This maintenance of insulin sensitivity was traced to the loss of a negative-feedback loop from S6K1 to the insulin receptor substrate 1 (IRS1) (see below). These phenotypes have underscored the importance of S6K1 as a downstream effector of mTOR Complex1 in several cellular processes, including transcription, translation, autophagy, insulin resistance, and tumorigenesis in regulating cell growth, metabolism and the oncogenic phenotype [8]. Thus, systemically, specific signals, including those of growth factors, hormones, nutrients and energy, converge at the level of mTOR Complex1–S6K1.