Lewis C. Cantley
Co-discovered PI3K, the pathway that feeds into mTOR from growth factors
Professor of Cell Biology, Dana-Farber Cancer Institute & Harvard Medical School · director of the Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine (2012–2022) · co-discovered PI3K (1985) · PhD, Cornell
Cantley Lab, Dana-Farber (Boston, Massachusetts, USA) ↗ Lab lineage2 direct trainees → ORCID0000-0002-1298-7653 ↗
Lewis Cantley and colleagues discovered and characterized phosphoinositide 3-kinase (PI3K) in the 1980s, a lipid-signalling enzyme that turned out to sit at the top of one of the most frequently mutated pathways in human cancer. PI3K activation, through Akt, is a principal route by which growth factors and insulin switch on mTORC1, directly linking Cantley's discovery to the biology this Atlas documents.
Over a career spanning Harvard, Tufts, Beth Israel Deaconess, Weill Cornell Medicine (where he directed the Meyer Cancer Center, 2012–2022) and now Dana-Farber Cancer Institute, Cantley's lab has continued to map how PI3K signalling controls cell growth and metabolism, including work connecting LKB1, AMPK and TSC2 to the PI3K–mTOR network (SHAW2004). He has received the Breakthrough Prize and the Wolf Prize in Medicine, among many other honours.
The timeline below follows Cantley'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 |
|---|---|---|
| 2002 | R | The phosphoinositide 3-kinase pathway CAN2002 Reviews the phosphoinositide 3-kinase (PI3K) pathway that Cantley discovered, and its role in growth-factor signalling to mTOR. |
| 2002 | M | Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling TEE2002 Co-authors the study showing that TSC1 and TSC2 work together to inhibit mTOR signalling to S6K1 and 4E-BP1. |
| 2002 | M | Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway MAN2002 Senior author of the study identifying tuberin (TSC2) as an Akt substrate, wiring PI3K signalling to the TSC complex and S6K1. |
| 2003 | M | Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb TEE2003 TSC1-TSC2 acts as a GTPase-activating protein (GAP) for Rheb; when TSC is inactive, Rheb accumulates in its active GTP-bound form and activates mTOR signalling. |
| 2004 | M | The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress SHW2004 Co-authors one of the 2003–2004 studies showing that the LKB1 tumour suppressor directly activates AMPK, connecting energy stress to mTOR. |
| 2004 | M | The LKB1 tumor suppressor negatively regulates mTOR signaling SHAW2004 Senior author: LKB1 restrains mTOR signalling under low energy through AMPK and TSC2, with raised mTOR signalling in Lkb1 mutant mouse polyps. |
| 2008 | M | Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer CAR2008 mTORC1 inhibition activates the MAPK pathway via a PI3K-dependent feedback loop. Seen in tumour biopsies from patients with advanced solid tumours treated with RAD001 (everolimus), where the rise depended on the dosing schedule, and in a mouse prostate cancer model, xenografts and cell lines. |
| 2011 | M | Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size SAC2011 Co-author: Rac1 binds and regulates both mTORC1 and mTORC2 and controls cell size (cells). |
| 2011 | M | Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling YUX2011 Phosphoproteomics identify Grb10 as an mTORC1 substrate driving negative feedback on insulin/PI3K. |
| 2014 | M | Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome MEN2014 Spatial control of the TSC complex integrates insulin and nutrient inputs at the lysosome. |
| 2015 | M | PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex LIU2015 PIP3 relieves SIN1 PH-domain autoinhibition to activate the mTORC2 kinase complex. |
| 2015 | R | Regulation of mTORC1 by PI3K signaling DIB2015 Review of mTORC1 regulation by PI3K signalling. |
Co-authors in the Atlas 21
People with a profile here who share at least one study with Lewis C. Cantley.
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- Brendan D. Manning 5 shared studies Was among the groups that in 2002 identified TSC2 as a direct target of Akt (MAN2002), linking insulin and PI3K signalling to mTORC1, and later found TBC1D7 as the third subunit of the TSC complex. His lab has shown how mTORC1 turns growth signals into the synthesis of lipids and nucleotides
- John Blenis 5 shared studies Showed early on that rapamycin blocks S6 kinase, then worked out how mTORC1 drives cell growth through its two main translation targets, S6K1 and 4E-BP1. His lab also found, in parallel with the Sabatini lab, that mTORC1 phosphorylates Grb10, a feedback brake on insulin signalling
- Andrew R. Tee 3 shared studies First author of one of several 2003 papers showing that the TSC1–TSC2 complex acts as a GTPase-activating protein for Rheb
- Christian C. Dibble 2 shared studies Identified TBC1D7 as the third subunit of the TSC complex that controls mTORC1, as a Manning-lab graduate student. His lab at Beth Israel Deaconess studies how PI3K signalling and nutrient supply are integrated to control mTORC1 and cell metabolism
- Reuben J. Shaw 2 shared studies Showed, in parallel with two other groups, that the tumour suppressor LKB1 directly activates AMPK, and that AMPK brakes mTORC1 by phosphorylating raptor. His Salk lab also linked AMPK to autophagy through ULK1 and helped explain how metformin acts in the liver
- Abdelhafid Saci Cell biologist who, in Christopher Carpenter's lab at Beth Israel Deaconess, found that the small GTPase Rac1 binds mTOR and helps set the activity and location of both mTOR complexes
- Alexander J. Valvezan Showed as a Manning-lab postdoc that mTORC1 matches nucleotide production to demand, creating a weak point that can be targeted in tumours with TSC loss. His Rutgers lab found that mTORC1 activity rises and falls through the cell cycle and helps drive entry into mitosis
- Arkaitz Carracedo Cancer biologist who, as first author in 2008, showed that blocking mTORC1 can switch on the MAPK pathway through a PI3K-dependent feedback loop.
- Bing Su Immunologist who studies how mTOR and MAPK signaling shape immune regulation and vascular function, and senior author of the study showing that SIN1 is a core part of mTORC2.
- David J. Kwiatkowski Geneticist and physician who studies tuberous sclerosis complex (TSC) and the TSC1/TSC2 genes that restrain mTORC1.
- Diane C. Fingar Studies how mTORC1 and mTORC2 are regulated, especially through site-specific phosphorylation
- George Talbott Research assistant in Brendan Manning's mTOR lab at Harvard in 2013 and 2014, who contributed to studies on where the TSC complex sits in the cell and how metformin reaches mTORC1
- George Thomas Purified and cloned S6K1, the kinase that became the classic readout of mTORC1 activity. His lab later showed that mice lacking S6K1 resist diet-induced obesity, and that amino acids signal to mTORC1 through the lipid kinase hVps34 (GUL2008)
- Gerta Hoxhaj Studies how growth signalling through PI3K, AKT and mTOR rewires cell metabolism; as a Manning-lab postdoc she co-authored work on how metformin inhibits mTORC1 in the liver
- José Baselga Breast cancer oncologist who led the BOLERO-2 trial showing that the mTOR inhibitor everolimus added to hormone therapy lengthens progression-free survival
- Pier Paolo Pandolfi Showed that ERK directly phosphorylates and inactivates TSC2, wiring Ras/MAPK signalling into mTORC1 control, and that blocking mTORC1 in patients' tumours triggers a feedback rise in MAPK signalling
- Sara C. Kozma Studies the S6K/mTOR pathway and how it controls cell growth, ribosome production, diabetes and cancer, including mTOR signalling in liver cancer.
- Steven P. Gygi Mass-spectrometry scientist whose Harvard lab builds large-scale proteomics methods, including the BioPlex human protein-interaction map, and contributed proteomics to the discoveries of the CASTOR and SAMTOR nutrient sensors
- Sue Menon Showed insulin controls mTORC1 by moving the TSC complex on and off the lysosome
- Wenyi Wei Studies how protein stability and cell signalling, including the PI3K-mTOR-AKT network, are controlled in cancer cells.
- Yonghao Yu Used phosphoproteomics to show that mTORC1 phosphorylates and stabilises Grb10, which then acts as a feedback brake on insulin and IGF-1 signalling
Every researcher with a profile →
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