mTORC2
mTOR Complex 2; phosphorylates Akt/PKB, affects cell survival and glucose metabolism.
mTOR's second, less famous complex. The second, less-studied of the two mTOR complexes. It switches on Akt and affects cell survival and how cells handle sugar.
Largely plasma-membrane associated and PI3K-responsive via the SIN1 PH domain; acutely rapamycin-insensitive, which is the cleanest way to separate mTORC1 from mTORC2 biology experimentally.
TL;DR. mTORC2 appears in 41 curated studies in Oliver's mTOR Atlas: 1 in people (1 human study); 8 in animal models; 20 at the molecular level (cells, biochemistry, structure); 11 reviews; 1 preprint, not peer-reviewed. It has 15 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| mTORC2 activates Actin cytoskeleton mechanism: functional-consequence · this link in full · on the map table | mTORC2's first known job was shaping the cell's internal skeleton. It was found in yeast first, as the original TOR2 phenotype, and then in mammalian cells - where it stood out precisely because rapamycin didn't block it. Holds under: Mammalian cells, yeast, Drosophila and conditional Rictor-knockout mice (JAC2004, SAR2004, LOE2002, HUA2013). The cytoskeleton phenotype was defined in cell lines and yeast; its role in intact tissue is less tested. plausible in people, not shown directly · settled in the literature | A | JAC2004, SAR2004, LOE2002, HUA2013 |
| mTORC2 activates Akt/PKB mechanism: phosphorylation · this link in full · on the map table | mTORC2 adds the final activating tag to Akt – the same step that long-term use of the drug rapamycin eventually disrupts. In mice, that disruption is a major reason long-term rapamycin raises blood sugar. Holds under: Mammalian cell studies, cancer cells and one mouse and rat liver study (ARI2015). Ser473 phosphorylation is shown in cells. The glucose consequence of losing it comes from mouse work (LAM2012) and has not been measured in people. S473 contribution to Akt output is substrate-dependent: some Akt substrates are strongly mTORC2-dependent, others barely. plausible in people, not shown directly · settled in the literature | A | JAC2006, FRI2006, YAN2006, LIU2015, ROD2011, ARI2015, GAN2011, FAC2008, HAG2012 |
| mTORC2 inhibits Insulin resistance mechanism: functional-consequence · this link in full · on the map table | Losing mTORC2 disconnects Akt from insulin signalling and can cause blood-sugar problems – a separate effect from any lifespan benefit. Holds under: In mice, intermittent dosing largely spared glucose tolerance while keeping mTORC1 inhibition (ARR2015); not tested against this endpoint in humans. plausible in people, not shown directly · emerging, few independent studies | A | LAM2012, ARR2015 |
| mTORC2 activates Lipid synthesis mechanism: functional-consequence · this link in full · on the map table | mTORC2 also drives fat-making, which is one of the ways it is thought to help tumours grow. The cause-and-effect part was shown in mice; in people with liver cancer, the study only found that more fat-making went together with higher mTORC2 activity. Holds under: The causal part comes from mouse liver: one liver tumour model (GUR2017) that progresses from steatosis to hepatocellular carcinoma, and liver-specific Rictor knockout in otherwise normal mice (HAG2012), where loss of mTORC2 lowered lipogenesis through Akt and SREBP1c. GUR2017 also reports that in human HCC, increased lipogenesis correlated with elevated mTORC2 activity: correlative human data, not a test of this step. Not established as a general mTORC2 function outside liver. plausible in people, not shown directly · emerging, few independent studies | A | GUR2017, HAG2012 |
| mTORC2 required-for Prostate cancer mechanism: functional-consequence · this link in full · on the map table | Prostate tumours caused by losing a specific tumour-suppressor gene (Pten) need mTORC2 to develop – normal prostate tissue doesn't, at least in mice. Holds under: Single-study edge in this corpus (GUE2009). Shown in Pten-null mouse prostate only: mTORC2 (Rictor) is required for tumours to develop in that genetic background, while normal prostate epithelium is not dependent on it. Mouse only - not tested in another species in this corpus, and not shown in human prostate cancer. plausible in people, not shown directly · emerging, few independent studies | A | GUE2009 |
| mTORC2 activates SGK1 mechanism: phosphorylation · this link in full · on the map table | SGK1 is a second target of mTORC2 alongside Akt, and it shares some of Akt's jobs. Holds under: Single-study edge in this corpus. plausible in people, not shown directly · emerging, few independent studies | M | GAR2008 |
| mTORC2 activates MAM (ER–mitochondria contacts) mechanism: localisation · this link in full · on the map table | mTORC2 signalling also happens at a specific contact point between mitochondria and another cell structure - a sign that this pathway works at more than one location in the cell, not only on the lysosome. Holds under: Biochemical fractionation and imaging in cell lines; the functional contribution relative to plasma-membrane mTORC2 is not quantified. plausible in people, not shown directly · emerging, few independent studies | M | BET2013 |
| mLST8 required-for mTORC2 mechanism: complex-assembly · this link in full · on the map table | This protein isn't needed for mTORC1 in a living animal, but mTORC2 can't work without it – a clean genetic way to tell the two complexes apart. Holds under: Knockout mice (GUE2006) and human cell biochemistry (KIM2003). The separation of the two complexes is shown in mouse tissue; whether it holds in human tissue is not tested by these studies. plausible in people, not shown directly · settled in the literature | M | GUE2006, KIM2003 |
| mTOR required-for mTORC2 mechanism: complex-assembly · this link in full · on the map table | mTORC2 is built from the very same mTOR enzyme as mTORC1 – it's the partner proteins around it that make the two complexes different. Holds under: Cryo-EM structures of the complex from human cells and yeast (CHE2018, SCA2020, STU2018, KAR2017). Structural evidence shows how the complex is built, not how often or where it forms in living tissue. plausible in people, not shown directly · settled in the literature | M | CHE2018, SCA2020, STU2018, KAR2017 |
| PI3K activates mTORC2 mechanism: signal-relay · this link in full · on the map table | The same lipid signal that switches Akt on also switches mTORC2 on – so growth-factor signals hit both complexes. Holds under: Growth-factor dependence of mTORC2 assembly and activity, shown in mammalian cells. The ribosome requirement (ZIN2011) means the readout is not a clean separation of PI3K input from translational state. plausible in people, not shown directly · emerging, few independent studies | M | LIU2015, ZIN2011, DAL2012, GAN2011 |
| Rapamycin inhibits mTORC2 mechanism: complex-assembly · this link in full · on the map table | Rapamycin doesn't touch mTORC2 right away, but over days it stops new mTORC2 from being built. Holds under: Strictly time- and cell-type-dependent: absent acutely, present after prolonged exposure, and the sensitivity varies between cell lines. LAM2012 shows the same loss of mTORC2 signalling in mouse liver in vivo, so this is not a cell-culture-only phenomenon. Treating this edge as unconditional is a common error. plausible in people, not shown directly · settled in the literature | A | SAR2006, LAM2012 |
| Rictor required-for mTORC2 mechanism: complex-assembly · this link in full · on the map table | Rictor is what makes the second complex, mTORC2, distinct – and rapamycin doesn't block it right away. Holds under: Mammalian cells, Drosophila and conditional Rictor-knockout mice (SAR2004, JAC2004, HUA2013). Shows that the complex needs Rictor; relevance in human tissue is not tested by these studies. plausible in people, not shown directly · settled in the literature | A | SAR2004, JAC2004, HUA2013, POL2015 |
| SIN1 / MAPKAP1 required-for mTORC2 mechanism: complex-assembly · this link in full · on the map table | SIN1 holds mTORC2 together and positions its target – without it, mTORC2 can't switch Akt on. Holds under: Mammalian cell studies and a cryo-EM structure (JAC2006, FRI2006, YAN2006, STU2018). Cell and structural evidence; not tested in people by these sources. plausible in people, not shown directly · settled in the literature | M | JAC2006, FRI2006, YAN2006, STU2018 |
| ATP-competitive mTOR inhibitors inhibits mTORC2 mechanism: competitive-inhibition · this link in full · on the map table | mTORC1 and mTORC2 use the same ATP-binding pocket, so a drug that blocks the pocket hits both and cannot choose. That is thought to explain why this class of drugs causes more metabolic and immune side effects than rapamycin-type drugs, but the size of that effect has only been seen in cell studies and has not been measured in patients. Holds under: Explains the metabolic and immunological toxicity of this class relative to rapalogs; the magnitude in patients is not established from these cell-line studies. plausible in people, not shown directly · settled in the literature | M | THO2009, FEL2009, JAN2010, ROD2011, GAR2009 |
| PDCD4 inhibits mTORC2 mechanism: complex-assembly · this link in full · on the map table | PDCD4 grabs Rictor and keeps mTORC2 from working. Holds under: Human NSCLC cell lines and mouse xenografts; not shown in normal tissue. Single study. plausible in people, not shown directly · emerging, few independent studies | M | WANG2026B |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| H | Human study | 1 |
| A | Animal model | 8 |
| M | Molecular — cells, biochemistry, structure | 20 |
| PP | Preprint, not peer-reviewed | 1 |
| R | Review — secondary literature, not a new result | 11 |
Studies
| Year | Evidence | Study |
|---|---|---|
| 2025 | H | The Bi-steric, mTORC1-Selective Inhibitor, RMC-5552, in Advanced Solid Tumors: A Phase 1 Trial SCH2025 First-in-human, open-label dose-escalation trial (n=57, advanced solid tumors, no comparator arm) of a bi-steric mTORC1-selective inhibitor. Treatment-related hyperglycemia was low (4%) and not dose-limiting, alongside a 64% disease control rate. Because the trial was uncontrolled and made no head-to-head comparison against rapamycin or an ATP-site inhibitor, this is encouraging early clinical evidence consistent with the hypothesis that sparing mTORC2 reduces metabolic toxicity -- it does not establish mTORC2 sparing as the cause. |
| 2023 | A | A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer MEN2023 RMC-6272, a bi-steric molecule with >25-fold selectivity for mTORC1 over mTORC2, completely suppresses mTORC1 (hitting the rapamycin-resistant substrate 4E-BP1) and overcomes hormone- and CDK4/6-inhibitor resistance in breast cancer cell lines and PDX -- the preclinical basis for the RMC-5552 selective-inhibitor clinical program. |
| 2015 | A | mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation POL2015 By deleting Tsc2, Rheb or Rictor in T cells, this work split the CD8 response between the two mTOR complexes. Tsc2 loss left mTORC1 constitutively active: the cells were strongly glycolytic (high ECAR, high Slc2a1 and Pfk1, low spare respiratory capacity), made more IFN-gamma, TNF and granzyme B, cleared EL4 thymoma and slowed B16-OVA growth, but stayed terminally differentiated and were about two-fold fewer than wild type at day 30, with no memory. Rheb loss removed mTORC1 activity with mTORC2 intact: those cells failed as effectors but kept memory-like features and were about two-fold more numerous at day 30, yet did not respond to rechallenge, which the authors trace to metabolic defects. Rapamycin from day 5 (100 ug/kg daily) rescued survival of Tsc2-deficient cells, raised CD127 and Eomesodermin, lowered KLRG1 and T-bet and restored a recall response. Losing mTORC2 by Rictor deletion left effector function intact but increased memory cells that still responded 133 days after infection, and the Tsc2/Rictor double knockout showed that the hyperactive effector phenotype needs mTORC2. Boundary: mouse genetics with TCR-transgenic transfers and transplantable tumours; the comparison rests on genetic extremes (no TSC2, no Rheb, no Rictor) rather than graded physiological signalling, and nothing here is measured in people. |
| 2014 | A | The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells MAR2014 This study separated two arms of IL-15 signalling in NK cells by dose: low IL-15 mainly phosphorylated STAT5 (EC50 about 1.5 ng/ml), while higher IL-15 was needed to switch on mTOR (EC50 about 5.3 ng/ml for S6 phosphorylation), and IL-15 was the only one of many tested stimuli that strongly raised pS6. Deleting mTOR in NK cells left bone-marrow numbers normal but blocked the CD11b-low to double-positive transition, cut proliferation about three-fold and left almost no mature NK cells in the periphery, with lower CD71, glucose uptake and about half the surface CD122 and CD132, so the receptor feedback is itself mTOR-dependent. In activation, mTOR-deficient NK cells failed to grow or raise nutrient uptake after poly(I:C) and made about half as much granzyme B, while IFN-gamma production in response to IL-12 plus IL-18 stayed normal. Oral rapamycin lowered pS6 and granzyme B in vivo and made rejection of MHC-class-I-negative target cells significantly less efficient, and mTOR inhibitors also blocked IL-2-driven granzyme B induction in human NK cells. Boundary: mouse genetics and mouse in vivo pharmacology, with the human arm limited to healthy-donor NK cells stimulated in culture; the clinical implication for patients on rapalogs is inference, not a measured patient outcome. |
| 2013 | A | mTORC2 controls actin polymerization required for consolidation of long-term memory HUA2013 Conditional deletion of Rictor in the postnatal mouse forebrain reduced mTORC2 activity and selectively impaired long-term memory and the late phase of hippocampal LTP, with a comparable long-term-memory deficit in dTORC2-deficient flies. Hippocampal actin polymerisation was reduced, and restoring it rescued both L-LTP and long-term memory; a compound that raised mTORC2 activity converted early LTP into late LTP and enhanced memory. This is the loss-of-function AND rescue evidence that mTORC2 is required for memory consolidation - the arm chronic rapamycin also disrupts, and the study Open Question H8 needs for its mTORC2 liability leg, which until 2026-09-05 rested on no supporting study at all. |
| 2013 | A | Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression WUX2013 Genetically reduced mTOR increases mouse lifespan with tissue-specific slowing of aging. |
| 2012 | A | Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity LAM2012 Chronic rapamycin (about 2 mg/kg a day, close to the lifespan-extending dose) made mice glucose intolerant and insulin resistant. A clamp test placed the problem in the liver, which kept making glucose, while muscle and fat took up glucose normally. Removing mTORC1 from the liver did not cause this. Rapamycin did break up mTORC2 (it separated mTOR from Rictor) in liver, fat and muscle, and deleting Rictor in the liver alone reproduced the glucose problem. In the genetic part, female mice with one working copy each of mTOR and mLST8 had about 50% less mTORC1 signalling in the liver, normal mTORC2 signalling and normal glucose tolerance, and lived 14.4% longer on average (p = 0.046). Males did not. Boundary: mouse drug and genetics work, not people, and the lifespan gain is female-only. It supports separating the two effects, but the paper does not test a drug that blocks mTORC1 without touching mTORC2. |
| 2012 | A | Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c HAG2012 The authors deleted rictor, an essential mTORC2 component, only in mouse liver. In fed knockout mice the liver lost Akt Ser473 phosphorylation and had lower glucokinase and SREBP1c activity, so it kept making glucose (gluconeogenesis) while glycolysis and fat synthesis fell, as if it could not sense that the animal had eaten. The mice became hyperglycaemic and hyperinsulinaemic with low blood lipids. In mTORC2-deficient hepatocytes, constitutively active Akt2 restored both glucose flux and lipogenesis, while extra glucokinase restored glucose flux but not lipogenesis, placing Akt as the main route from hepatic mTORC2 to these outputs. Boundary: Mouse liver with lifelong genetic loss of mTORC2, plus cultured mouse hepatocytes. Not a drug study and not tested in people. Drafted from the abstract only. |
| 2011 | A | The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2 DEL2011 mTORC1 and mTORC2 selectively program distinct CD4 helper T-cell lineages. |
| 2026 | M | PTEN regulates microtubule polymerization via mTORC2, but not mTORC1, in peripheral sensory neurons EVA2026 Uses Raptor (mTORC1) versus Rictor (mTORC2) co-deletion on a Pten-knockout background to ask which complex carries the growth signal to the microtubule cytoskeleton. Suppressing mTORC2 — but not mTORC1 — returns the accelerated microtubule polymerisation and neuronal hypertrophy of Pten-KO neurons to wild-type levels, and the effect is confined to the axonal growth cone rather than the proximal axon shaft. A clean genetic dissection on the comparatively thin mTORC2 side of the pathway. |
| 2026 | M | ATF4 activates a transcriptional program that chronically suppresses mTOR activity and promotes neurodegeneration in Parkinson disease models DEMMINGS2026 Chronic integrated-stress-response signalling through ATF4 coordinately upregulates SESN2, DDIT4 and Trib3, which together suppress BOTH mTORC1 and mTORC2; this sustained mTOR inhibition drives dopaminergic neuron death via the pro-apoptotic BCL-2 family protein PUMA. Defines a maladaptive ISR/ATF4-to-mTOR axis in Parkinson disease models — a case where LESS mTOR activity is harmful, opposite to the usual longevity framing. |
| 2026 | M | Pdcd4-Rictor interaction suppresses mTORC2-PFKFB3 axis and tumorigenesis in NSCLC. WANG2026B Pdcd4 binds Rictor via residues R105/K108/R110 to disrupt mTORC2 assembly and kinase activity, lowering PFKFB3 levels and suppressing glycolysis and NSCLC tumour growth. |
| 2026 | R | The role of mTORC2/RICTOR in immune cells and inflammatory diseases. XU2026B mTORC2/RICTOR signaling (via AKT, SGK1, PKC) shapes Th1/Th2 differentiation, Treg stability, memory T cell formation, BCR signaling and plasma cell survival, and macrophage/DC/NK function; its role in tissue inflammation is context-dependent (exacerbating osteoarthritis and pancreatitis but restraining pro-inflammatory polarization in colorectal cancer), and dual mTORC1/2 inhibitors (e.g. AZD2014) show early but complicated promise. |
| 2022 | R | mTOR substrate phosphorylation in growth control BAT2022 Review cataloguing direct mTOR substrates and how mTORC1/2 achieve substrate specificity. |
| 2021 | R | Regulation and metabolic functions of mTORC1 and mTORC2 SZW2021 Comprehensive review of the regulation and metabolic functions of mTORC1 and mTORC2. |
| 2020 | R | mTOR at the nexus of nutrition, growth, ageing and disease LIU2020 The flagship modern review of the whole field, from Sabatini's own lab (Nature Reviews Molecular Cell Biology). Maps 25+ years of mTOR biology - how it senses nutrients, controls growth and autophagy, and goes wrong in cancer, neurodegeneration, metabolic disease and aging. The single best orientation document for the entire Atlas. |
| 2019 | R | mTOR as a central hub of nutrient signalling and cell growth KIM2019 Review: mTOR as a central hub of nutrient signalling and cell growth. |
| 2017 | R | mTOR Signaling in Growth, Metabolism, and Disease SAX2017 Comprehensive synthesis of mTORC1/mTORC2 signaling, growth regulation, metabolism, and disease relevance. |
| 2016 | M | A systems study reveals concurrent activation of AMPK and mTOR by amino acids DAL2016 Adding amino acids back to starved cells switched on AMPK, PI3K and mTORC2 acutely and independently of mTORC1, at the same time as mTOR. AMPK activation ran through CaMKK-beta and, under amino acid sufficiency, AMPK kept autophagy going via ULK1. So the textbook picture of AMPK and mTORC1 as simple opposites does not hold in the first minutes after feeding - which matters for how the AMPK-ULK1 feedback arm behaves over time. |
| 2015 | M | Lysosomal mTORC2/PHLPP1/Akt regulate chaperone-mediated autophagy ARI2015 Extends the mTOR-autophagy relationship to a third form of autophagy that the Atlas otherwise does not cover, and reverses two of its usual terms. Here it is mTORC2, not mTORC1, that sits on the lysosomal membrane, and it inhibits chaperone-mediated autophagy through Akt, while the phosphatase PHLPP1 counteracts it; the balance controls assembly and disassembly of the translocation complex that pulls single proteins into the lysosome. Boundary: mechanism in cells and rodent liver; the claim that restoring this axis helps in ageing or disease is proposed, not tested here. |
| 2014 | R | Mammalian target of rapamycin signaling in cardiac physiology and disease SCI2014 Review of mTOR signalling in cardiac physiology and disease. |
| 2012 | R | mTOR signaling in growth control and disease LAP2012 The classic 2012 Cell review that became the standard reference for mTOR signaling. Comprehensive yet readable synthesis of how mTOR integrates environmental cues to control growth, and how its deregulation drives cancer, obesity, diabetes and neurodegeneration. A perfect companion to the newer 2020 review. |
| 2012 | M | A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation DAL2012 A time-resolved, data-fitted model of the whole core insulin-mTOR network, including the mTORC1 negative feedback loop onto PI3K. Perturbing it in silico and in cells showed that TSC1-TSC2 is not a regulator of mTORC2, directly or through the feedback loop, and that mTORC2 activation runs through a PI3K variant insensitive to that loop. One of the few places where the feedback loops in the atlas are treated as a dynamical system rather than a diagram. |
| 2011 | M | Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size SAC2011 Rac1 binds and regulates both mTORC1 and mTORC2, controlling their localization and cell growth. |
| 2011 | M | mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling ROD2011 mTOR kinase inhibition triggers feedback-dependent biphasic AKT reactivation, informing resistance. |
| 2011 | M | Activation of mTORC2 by association with the ribosome ZIN2011 mTORC2 is activated by direct association with the ribosome downstream of PI3K. |
| 2011 | M | Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate GAN2011 PIP3 directly stimulates mTORC2 kinase activity, linking PI3K to mTORC2. |
| 2010 | M | Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor JAN2010 The ATP-competitive TORC1/2 inhibitor PP242 selectively kills leukemia cells, with much weaker effects on the proliferation and function of normal lymphocytes. |
| 2010 | R | mTOR: from growth signal integration to cancer, diabetes and ageing ZON2010 Authoritative review of mTOR from growth-signal integration to disease. |
| 2009 | M | The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment DEL2009 T cells lacking mTOR fail to become normal effector cells and default toward regulatory T cells, showing mTOR is a master switch for immune cell fate. |
| 2009 | M | DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival PET2009 Identified DEPTOR as a built-in brake on BOTH mTOR complexes. The twist: in some multiple myelomas DEPTOR is overexpressed, which by relieving a feedback loop actually keeps pro-survival Akt signaling ON - a neat example of how an 'inhibitor' can be co-opted by cancer. |
| 2009 | M | Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2 FEL2009 The parallel discovery to Thoreen 2009 (same year), from the Shokat lab. Their TORKinibs (PP242, PP30) block mTOR's active site, hitting both complexes and shutting down cap-dependent translation that rapamycin misses. Together these two papers established a whole new drug class beyond rapamycin. |
| 2009 | M | Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR) GAR2009 Ku-0063794 is a specific ATP-competitive mTOR inhibitor blocking mTORC1 and mTORC2. |
| 2008 | M | The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C FAC2008 Cells lacking the mTORC2 components mTOR, SIN1 or rictor lost phosphorylation of Akt and of conventional protein kinase C at the turn motif, a site near the end of the kinase domain. This phosphorylation did not depend on growth factors, and the authors reported the same function in yeast. Turn-motif phosphorylation helped newly made Akt and PKC fold correctly and stay stable; without it, Akt was held by the chaperone Hsp90 and protected from ubiquitin-mediated breakdown. mTORC2 controlled the Akt turn-motif and hydrophobic-motif (Ser473) sites independently in vivo and phosphorylated both directly in vitro. Boundary: Cell culture, yeast and in vitro kinase assays, with mouse tissue for the in vivo site analysis. Shows a protein-maturation role of mTORC2, not an organismal phenotype. Drafted from the abstract only. |
| 2007 | R | Defining the role of mTOR in cancer GUE2007 Comprehensive review arguing mTOR signaling is commonly deregulated in human cancers, laying out the rationale for rapalog trials in oncology. |
| 2006 | M | Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB SAR2006 The molecular explanation for rapamycin's dark side. Short-term rapamycin only hits mTORC1, but prolonged treatment can also inhibit the assembly of NEW mTORC2 in susceptible cell types, reducing mTORC2 abundance and cutting Akt signaling over time. The wording matters: this is prevention of new assembly, not the dismantling of complexes already built, and the response depends on cell context and length of exposure. This is the mechanistic root of the insulin-resistance side effect later shown in mice (see Lamming 2012) - crucial for anyone dosing rapamycin for longevity. |
| 2006 | M | Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1 GUE2006 The foundational genetic 'dissection' of the two complexes in living mice. Deleting Raptor was lethal early (mTORC1 essential); deleting Rictor or mLST8 selectively knocked out mTORC2 signaling to Akt and PKCalpha but spared S6K1. This cleanly assigned jobs to each complex and showed mLST8 is an mTORC2-specific requirement in mice. |
| 2006 | R | TOR signaling in growth and metabolism WUL2006 Landmark review synthesizing TOR signalling in growth and metabolism across organisms. |
| 2005 | M | Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex SAR2005 The rictor-mTOR complex (mTORC2) directly phosphorylates Akt/PKB on Ser473, regulating cell survival. |
| 2004 | M | Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton SAR2004 Discovery of Rictor and the SECOND mTOR complex, mTORC2. Crucially showed this complex is NOT blocked by rapamycin and does not use Raptor - it controls the cytoskeleton via PKC. This is the paper that split mTOR biology into 'two faces' at the molecular level. |
| 2025 | PP | The tumor suppressor CYLD acts as a deubiquitinase for mTOR to constrain its activity FER2025 An RNAi screen identified the tumor suppressor CYLD as a deubiquitinase that binds mTOR and removes non-degradative K63-linked ubiquitin chains from several of its residues, restraining both mTORC1 and mTORC2. Cells lacking CYLD show hyperactive mTORC1/2, higher protein synthesis, larger cell size and resistance to serum-starvation-induced cell death. In C. elegans, knocking down cyld-1 fully abolishes the extended lifespan of low-TORC1-activity mutants, and skin biopsies from CYLD cutaneous syndrome patients show mTORC1 hyperactivation. Preprint, not peer-reviewed. |
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