Brendan D. Manning
Linked PI3K–AKT to mTOR and metabolism
PhD, Yale · postdoc with Lewis Cantley · Harvard T.H. Chan School of Public Health & Harvard Medical School
Manning Lab, Harvard Chan School ↗ Bluesky@bdmanning.bsky.social ↗
Brendan Manning studied at UMass Amherst and Yale, then joined Lewis Cantley's lab at Harvard for his postdoctoral work. There he made a defining discovery: the tuberous sclerosis (TSC) tumour-suppressor proteins are the missing link between the PI3K–AKT pathway — which is switched on in most human cancers — and the mTOR growth machine. This tied a major cancer-signalling network directly to a nutrient sensor.
Running his own lab at Harvard, Manning has shown how mTORC1 acts as a 'metabolic rheostat', switching on production of the building blocks a growing cell needs — nucleotides, lipids and proteins — and how drugs such as metformin act on this network. His work explains how cell growth and metabolism are wired together in health and in cancer.
Manning has received an Outstanding Investigator Award from the National Cancer Institute. The milestones below trace his contributions in this Atlas.
Milestones in the Atlas
| Year | Evidence | Study |
|---|---|---|
| 2012 | M | TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1 DIB2012 Completes the TSC complex by identifying TBC1D7 as its third subunit — the master off-switch upstream of mTORC1. |
| 2013 | M | Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1 BEN2013 mTORC1-S6K1 stimulates de novo pyrimidine synthesis by phosphorylating CAD. |
| 2013 | R | Signal integration by mTORC1 coordinates nutrient input with biosynthetic output DIB2013 Review: mTORC1 integrates nutrient input with biosynthetic output. |
| 2014 | M | Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome MEN2014 Shows insulin moves the TSC complex off the lysosome, releasing the brake on mTORC1. |
| 2016 | M | mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle BEN2016 Reveals how mTORC1 drives purine synthesis through the mitochondrial folate cycle. |
| 2017 | M | mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability VAL2017 Hyperactive mTORC1 couples nucleotide synthesis to demand; imbalance drives replication stress in these cells. |
| 2017 | M | Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex HOW2017 Pinned down HOW the diabetes drug metformin - a major longevity candidate - actually reaches mTOR. In the liver, metformin lowers cellular energy, and at low doses this shuts down mTORC1 specifically through AMPK and the TSC complex. Direct mechanistic bridge between a widely-used drug, energy sensing, and the mTOR pathway. |
| 2019 | R | Molecular logic of mTORC1 signalling as a metabolic rheostat VAL2019 Frames mTORC1 signalling as a metabolic rheostat coupling growth signals to biosynthesis. |
| 2019 | R | The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism HOX2019 Review of the PI3K-AKT-mTOR network at the interface of oncogenic signalling and metabolism. |
| 2026 | A | Feeding-Induced Muscle mTORC1 Signaling Regulates Postprandial Protein Synthesis and Endurance but Not Muscle Size LAP2026 Using a mouse model expressing an AKT-nonphosphorylatable TSC2 mutant specifically in skeletal muscle, the Manning lab genetically separated feeding-induced from contraction-induced mTORC1 activation. AKT-mediated TSC2 phosphorylation is required for feeding (but not contraction) to activate muscle mTORC1 and drive postprandial protein synthesis — yet mice lacking this feeding-induced signal have normal muscle mass and myofiber size, and instead show improved maximal endurance capacity with a modest rise in mitochondrial content. The finding dissociates mTORC1's role in postprandial anabolism from its role in maintaining steady-state muscle mass, and is a directly relevant data point for whether the pattern/source of mTORC1 activation (feeding vs. mechanical) — not just its average level — shapes downstream outcomes. |
On the programme
Meetings in the Atlas calendar where Brendan D. Manning is listed among the speakers or organisers.
- past Prague Metabolism and Signaling Symposium 2026 ↗ 24–27 Jun 2026 · Prague, Czech Republic · Tier 1