David A. Guertin
Built the mouse genetics that defined mTORC2's biological roles
Professor of Molecular Medicine, UMass Chan Medical School · postdoc, Whitehead Institute/MIT (Sabatini lab) · PhD, UMass Chan Medical School
Guertin Lab, UMass Chan (Worcester, Massachusetts, USA) ↗ Lab lineagetrained under David M. Sabatini →
Portrait: UMass Chan Medical School, Guertin Lab
David Guertin did his postdoctoral training in David Sabatini's lab, where he built mouse models lacking raptor, rictor or mLST8 (first in the whole animal, then in specific tissues such as the prostate) to work out which biological functions depend on mTORC1 versus mTORC2. This genetic dissection was essential to separating the two mTOR complexes' distinct roles in a living animal, not just in cultured cells.
Since joining the faculty at UMass Chan Medical School in 2009, Guertin has focused mTORC2 genetics on fat tissue and cancer, showing for instance that mTORC2 is required for prostate cancer driven by loss of the tumour suppressor Pten, and more recently studying how mTORC2 signalling shapes brown and white adipose tissue function.
The timeline below follows Guertin's contributions gathered in this Atlas.
Milestones in the Atlas
A selection, not a full bibliography: only papers that meet the Atlas inclusion criteria.
| Year | Evidence | Study |
|---|---|---|
| 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. |
| 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. |
| 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 Uses knockout mice lacking raptor, rictor or mLST8 to show that mTORC1 is essential in early development and that mTORC2 is required for signalling to Akt-FOXO and PKCalpha, but not S6K1. |
| 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. |
| 2009 | A | mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice GUE2009 Shows mTOR Complex 2 is required for prostate cancer driven by loss of the Pten tumour suppressor. |
| 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 | 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. |
Co-authors in the Atlas 15
People with a profile here who share at least one study with David A. Guertin.
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- David M. Sabatini 7 shared studies Identified mTOR (as RAFT1) in 1994. His lab then mapped much of the machinery around it: raptor and rictor at the core of mTORC1 and mTORC2, the Rag–Ragulator system that docks mTORC1 on the lysosome, and the sensors that detect leucine, arginine and SAM
- Dos D. Sarbassov 2 shared studies Discovered rictor as a Sabatini-lab postdoc, in parallel with Michael Hall's lab, defining mTOR Complex 2, and showed that this complex is the long-sought kinase that phosphorylates Akt on serine 473. He also found that prolonged rapamycin treatment can block mTORC2 assembly
- Siraj M. Ali 2 shared studies Worked in the Sabatini lab on the papers that discovered raptor, mLST8 and rictor, and on the finding that the rictor-mTOR complex phosphorylates Akt. He later moved into cancer genomics and clinical diagnostics
- Adam B. Salmon Biologist of aging at UT Health San Antonio whose work in this Atlas spans rapamycin in mice and in common marmosets. He is a co-author on the Interventions Testing Program reports from the San Antonio site and on the marmoset rapamycin studies on blood markers, epigenetic age and the salivary gland
- Arlan Richardson Studies how rapamycin slows ageing in mice, including the broad changes it causes in the liver, and co-authored early studies showing that rapamycin protects memory in Alzheimer's-model mice
- Carson C. Thoreen Used Torin1, one of the first ATP-competitive mTOR inhibitors, to reveal functions of mTORC1 that rapamycin cannot block. He then showed that mTORC1 controls translation of mRNAs for the protein-making machinery mainly through the 4E-BP proteins
- Do-Hyung Kim Co-discovered raptor, the defining partner of mTOR in mTORC1, and then mLST8 (GbetaL) as a Sabatini-lab postdoc. His Minnesota lab identified PRAS40 as an insulin-regulated link to mTORC1 and studies how mTORC1 controls autophagy
- Dudley W. Lamming Showed as a postdoc that rapamycin's harm to glucose metabolism comes largely from its effect on mTORC2, while the lifespan benefit tracks mTORC1. His Wisconsin lab studies intermittent rapamycin dosing and how restricting dietary protein or single amino acids affects metabolism and ageing
- Hediye Erdjument-Bromage Ran the mass-spectrometry analyses in Paul Tempst's lab at Memorial Sloan Kettering that identified the unknown proteins in the raptor, mLST8 and rictor purifications, and contributed the same approach to work on how ERK inactivates TSC2
- Joseph A. Baur Biologist of aging at the University of Pennsylvania whose lab showed that rapamycin's harm to glucose control comes from mTORC2 loss and studies how NAD levels shape health
- Nada Y. Kalaany Studies how a tumour's metabolism depends on the metabolic state of the whole body, and hunts for nutrient dependencies that can be turned into treatments
- Paul Tempst Developed mass-spectrometry methods for identifying proteins from tiny samples, and led the Memorial Sloan Kettering proteomics laboratory that identified the unknown partners of mTOR in the raptor, mLST8 and rictor purifications
- Robert R. Latek Bioinformatics scientist at the Whitehead Institute who worked on the Sabatini-lab papers that described raptor, mLST8 (GbetaL) and rictor (raptor and rictor were reported in parallel by other labs), the core partners of mTOR in its two complexes
- Seong A. Kang Contributed to the Sabatini-lab studies that identified PRAS40 and DEPTOR, two of the cell's own mTOR inhibitors, and to the first characterisation of the mTOR inhibitor Torin1
- Timothy R. Peterson Discovered DEPTOR, an inhibitor that binds mTOR in both complexes and is overexpressed in some multiple myelomas. He also showed that mTORC1 controls fat synthesis by regulating where the enzyme lipin 1 sits in the cell, and through it the SREBP pathway
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