mTORC1 activation by nutrients and growth factors. mTOR is found in two distinct protein complexes. mTORC1 (mTOR, Raptor, PRAS40, mLST8) is acutely rapamycin sensitive and is regulated by both growth factors and nutrient cues. By contrast, mTORC2 (mTOR, Rictor, Sin1, Protor, mLST8) is not acutely regulated by rapamycin nor is it nutrient-sensitive. Growth factors stimulate mTORC1 via activating PI3-kinase downstream of growth-factor-binding receptor tyrosine kinases (RTKs), such as the insulin receptor. PI3-kinase stimulates phosphatidylinositol (3,4,5)-triphosphate [PtdIns(3,4,5)P₃] production, which recruits Akt to the plasma membrane and results in its activation through phosphoinositide-dependent kinase 1 (PDK1)-mediated activation loop phosphorylation and hydrophobic motif phosphorylation by the mTORC2 complex. Akt and other growth-factor-dependent kinases not depicted converge to phosphorylate several residues in the TSC2 tumor suppressor, resulting in its inactivation. TSC2 and TSC1 form an obligate heterodimer that functions as a GAP for the Rheb GTPase. Hence, activation of PI3-kinase or Ras results in TSC complex inactivation and an increase in GTP-bound Rheb, which then binds mTORC1, stimulating its kinase activity. Glucose stimulates mTORC1, at least in part, through its inactivation of AMPK. Under conditions of low intracellular ATP, such as during glucose- or oxygen-deprived conditions, AMPK is activated in a manner dependent on both its direct binding to AMP and phosphorylation by its upstream kinase LKB1. AMPK in turn inhibits mTORC1 by directly phosphorylating both TSC2 and Raptor, thereby decreasing mTORC1 kinase activity. Two new studies identified the Rag GTPases as crucial mediators of amino acid signaling to the mTORC1 complex. The addition of amino acids to starved cells increases the levels of GTP-bound RagB, which increases its affinity for Raptor. The Rag-bound mTORC1 complex then relocalizes to Rab7-positive perinuclear vesicular structures in the cell (also the site of Rheb localization). Localized recruitment of Rag-bound mTORC1 enables Rheb to associate with mTORC1 and stimulate its kinase activity. Active mTORC1 then phosphorylates its downstream substrates 4EBP1 and S6K1, thus, stimulating protein synthesis and cell growth. The Vps34 class III PtdIns-3 kinase and its binding partners Vps15 and Beclin were previously reported to modulate Rab7 vesicle trafficking; this finding could provide an explanation for previous studies that identified Vps34 as a component of the pathway from amino acids to mTORC1 activation. Further studies are needed to validate several different aspects of the model. The crucial role this pathway has in human cancer is underscored by the fact that several human tumor suppressors (blue with red text) that are inactivated in a variety of human cancers are found in this pathway. In addition, four different human oncoproteins (yellow) are found bearing activating mutations in a wide variety of human cancers. In addition, mTORC1 hyperactivation occurs in patients with metabolic syndrome. Color code: AMPK, pink; mLST8, brown; mSin1, mid blue; mTOR, green; Rag proteins, red; Raptor, purple; Rheb, orange; PRAS40, beige; Protor, dark blue; Rictor, bright pink; S6K1, gold; Vps proteins, gray; 4E-BP1, light blue.