David M. Sabatini
Found mTOR in 1994, then took the machine apart: both complexes, the lysosomal docking system, and the sensors that read individual amino acids
Born 1968, New York, USA · Whitehead Institute & MIT (1997–2021) · Howard Hughes Medical Institute · now IOCB Prague
Portrait: video still via Wikimedia Commons
David Sabatini grew up in a family of scientists — his father is a well-known cell biologist — and trained as an MD–PhD at Johns Hopkins in the laboratory of Solomon Snyder. As a graduate student he became fascinated by rapamycin, a drug found in the soil of Easter Island that could stop cells from growing. Nobody knew what it actually hit inside mammalian cells. In 1994 Sabatini answered that question: using rapamycin bound to its partner protein FKBP12 as 'bait', he fished a giant protein out of rat brain and named it mTOR. That single discovery opened an entire field.
In 1997, still in his twenties, he started his own lab at the Whitehead Institute in Cambridge. Over the next two decades the Sabatini lab identified almost every core part of the mTOR machine: the two complexes mTORC1 and mTORC2, the Rag GTPases and Ragulator that dock mTORC1 onto the lysosome, and — most strikingly — the actual protein sensors (Sestrin2, CASTOR1, SLC38A9, SAMTOR) that let a cell literally taste individual amino acids such as leucine and arginine. Together this work explained how our cells decide, moment to moment, whether there is enough food to grow.
His discoveries earned major honours including the Louisa Gross Horwitz Prize and the BBVA Frontiers of Knowledge Award. In 2021–2022 he left MIT and the Whitehead Institute. Since late 2023 he has led a laboratory at the Institute of Organic Chemistry and Biochemistry (IOCB) in Prague. The timeline below traces his scientific path through the studies collected in this Atlas.
Milestones in the Atlas
| Year | Evidence | Study |
|---|---|---|
| 1994 | M | RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs SAB1994 The birth of the field: Sabatini purifies the Target Of Rapamycin (RAFT1/mTOR) from rat brain, proving it is the direct mammalian target of rapamycin and a cousin of the yeast TOR genes. |
| 1998 | M | RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1 BUR1998 RAFT1/mTOR directly phosphorylates p70 S6K (Thr389) and 4E-BP1, the two central translational effectors. |
| 2002 | M | mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery KIM2002 Defines mTOR Complex 1 by discovering raptor, the partner protein that makes mTOR sensitive to nutrients. |
| 2003 | M | GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR KIM2003 Discovered mLST8 (GbetaL), the third core subunit that clamps onto mTOR's kinase domain and stabilizes the complex. It fine-tunes how tightly Raptor holds mTOR in response to nutrients - a small but essential cog that later turned out to be especially critical for the mTORC2 complex. |
| 2004 | M | Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton SAR2004 Discovers mTOR Complex 2 (via rictor) — a second, rapamycin-insensitive mTOR machine that controls the cytoskeleton and Akt. |
| 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 LONG-term treatment also strips down mTORC2 in many cells, cutting Akt signaling. 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 | mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s FRI2006 mSin1 is required for mTORC2 assembly and Akt Ser473 phosphorylation; isoforms define distinct complexes. |
| 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. |
| 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. |
| 2007 | M | PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase SAN2007 Identified PRAS40 as the missing insulin-controlled brake INSIDE mTORC1. When insulin is absent PRAS40 clamps the complex shut; insulin makes Akt phosphorylate PRAS40, releasing the brake so Rheb can fully switch mTORC1 on. Explained how hormone signals set the exact strength of mTORC1 activity. |
| 2008 | M | The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1 SAN2008 Shows the Rag GTPases are the switch that relays the amino-acid signal to mTORC1. |
| 2009 | A | mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice GUE2009 mTORC2 is required for prostate cancer driven by Pten loss in mice. |
| 2009 | M | An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1 THO2009 Dropped a bombshell: rapamycin does NOT fully block mTORC1. Using Torin1 (which jams the active site directly), the authors showed rapamycin leaves important mTORC1 jobs running - notably 4E-BP1 phosphorylation and autophagy suppression. This reframed a decade of rapamycin experiments and launched the search for complete inhibitors. |
| 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. |
| 2010 | M | Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids SAN2010 Ragulator docks mTORC1 onto the surface of the lysosome — pinpointing where nutrient sensing physically happens. |
| 2010 | R | mTOR: from growth signal integration to cancer, diabetes and ageing ZON2010 Authoritative review of mTOR from growth-signal integration to disease. |
| 2010 | M | mTORC1 controls fasting-induced ketogenesis and its modulation by ageing SEN2010 mTORC1 controls fasting-induced hepatic ketogenesis via PPARalpha, and this is blunted with age. |
| 2011 | M | The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling HSU2011 mTOR-dependent phosphoproteomics reveal Grb10 as a substrate mediating feedback inhibition of PI3K. |
| 2011 | M | mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase ZON2011 Showed amino acid sensing starts INSIDE the lysosome: amino acids accumulate in the lumen and the v-ATPase relays that signal outward ('inside-out') to Ragulator-Rag. A surprising twist on where the cell measures its nutrient status. |
| 2011 | M | mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway PET2011 mTORC1 controls lipin-1 nuclear localization to regulate SREBP and lipid synthesis. |
| 2012 | A | Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival EFE2012 Rag-GTPase control of mTORC1 is essential for neonatal autophagy and survival to fasting. |
| 2012 | M | Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1 BAR2012 Ragulator is the guanine-nucleotide exchange factor activating the Rag GTPases on the lysosome. |
| 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 | A | Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity LAM2012 In mice, chronic rapamycin also disrupts mTORC2, causing insulin resistance; lifespan extension can be uncoupled from this side effect. |
| 2012 | M | A unifying model for mTORC1-mediated regulation of mRNA translation THO2012 Used ribosome profiling with the complete inhibitor Torin1 to address a long-standing debate: in these cells, mTORC1's translational control runs largely through the 4E-BP family acting on a specific class of mRNAs (TOP motifs). Losing just the 4E-BPs makes translation resistant to mTOR inhibition - naming them the master effectors. |
| 2013 | M | The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 TSU2013 Folliculin is a GAP for RagC/D that signals amino-acid sufficiency, activating mTORC1 substrate binding. |
| 2013 | M | A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1 BAR2013 Found the OFF switch for amino acid signaling: the GATOR1 complex is a GAP that shuts the Rag GTPases (and thus mTORC1) down when amino acids run low, while GATOR2 opposes it. GATOR1 genes are mutated in cancers, making those tumors 'blind' to starvation and hypersensitive to rapamycin. |
| 2014 | M | The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1 CHA2014 Sestrins bind GATOR2 to negatively regulate amino-acid signalling upstream of mTORC1. |
| 2014 | M | A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity GRA2014 A spectrum of cancer-associated MTOR mutations are hyperactivating and predict rapamycin sensitivity. |
| 2015 | M | Sestrin2 is a leucine sensor for the mTORC1 pathway WOL2015 Identifies Sestrin2 as a direct leucine sensor for the mTORC1 pathway. |
| 2015 | M | Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway SAX2015 Solves the crystal structure of Sestrin2 bound to leucine, revealing the molecular pocket that lets it act as mTORC1's dedicated leucine sensor. |
| 2015 | M | Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1 WAN2015 The lysosomal transporter SLC38A9 signals arginine sufficiency to mTORC1. |
| 2016 | M | Mechanism of arginine sensing by CASTOR1 upstream of mTORC1 SAX2016 CASTOR1 is a direct arginine sensor upstream of mTORC1; structure reveals the arginine-binding mechanism. |
| 2016 | M | The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway CHA2016 Identified CASTOR1 as the direct arginine sensor: when arginine binds CASTOR1, it lets go of GATOR2, switching mTORC1 on. Together with Sestrin2 (leucine) this built the picture of mTORC1 as a cell that literally tastes individual amino acids. |
| 2017 | R | mTOR Signaling in Growth, Metabolism, and Disease SAX2017 Comprehensive synthesis of mTORC1/mTORC2 signaling, growth regulation, metabolism, and disease relevance. |
| 2017 | R | Twenty-five years of mTOR: Uncovering the link from nutrients to growth SAB2017 Sabatini's own 25-year retrospective on mTOR: uncovering the link from nutrients to growth. |
| 2017 | M | KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1 WOL2017 KICSTOR tethers GATOR1 to the lysosome, required for nutrient control of mTORC1. |
| 2017 | M | mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient WYA2017 SLC38A9 effluxes essential amino acids (e.g. leucine) from lysosomes to activate mTORC1. |
| 2017 | R | The Dawn of the Age of Amino Acid Sensors for the mTORC1 Pathway WOLF2017 Review of the newly discovered amino-acid sensors feeding into mTORC1. |
| 2017 | M | SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway GU2017 Extended nutrient sensing beyond amino acids to METABOLITES: SAMTOR reads S-adenosylmethionine (SAM), the cell's methyl-donor currency, linking methionine and one-carbon metabolism to mTORC1. Relevant to why methionine restriction affects aging. |
| 2018 | M | Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes SHE2018 Cryo-EM structures of GATOR1 and GATOR1-Rag complexes reveal GAP and inhibitory-clamp mechanisms. |
| 2019 | M | Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex SHE2019 Cryo-EM structure of the human FLCN-FNIP2-Rag-Ragulator complex. |
| 2019 | M | Structural basis for the docking of mTORC1 on the lysosomal surface ROG2019 Structure shows how mTORC1 docks onto the Rag-Ragulator lysosomal scaffold. |
| 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. |
| 2021 | M | Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction CON2021 Genome-wide CRISPR screens reveal AMPK and HRI relay mitochondrial dysfunction to mTORC1. |
| 2022 | M | Structure of the nutrient-sensing hub GATOR2 VAL2022 Cryo-EM structure of human GATOR2: a 1.1 MDa, two-fold symmetric cage built on an octagonal scaffold decorated with eight pairs of WD40 beta-propellers, and a map of where Sestrin2 and CASTOR1 dock. It substantially advances the GATOR2 side of the sensor module, though how GATOR2 inhibits GATOR1 is still not fully settled. |
On the programme
Meetings in the Atlas calendar where David M. Sabatini is listed among the speakers or organisers.
- past Prague Metabolism and Signaling Symposium 2026 ↗ 24–27 Jun 2026 · Prague, Czech Republic · Tier 1