Ken Inoki
Showed as a postdoc in Kun-Liang Guan's lab that Akt switches off TSC2, that TSC2 is the off-switch (GAP) for the small GTPase Rheb, and that AMPK and GSK3 feed energy and Wnt signals into the same brake. His Michigan lab studies mTOR signalling in metabolism and kidney disease
Roger C. Wiggins Collegiate Professor of the Life Sciences · Research Associate Professor, Life Sciences Institute · Professor of Internal Medicine (Nephrology) and of Molecular & Integrative Physiology, University of Michigan Medical School · MD, PhD
Inoki Lab, U. Michigan LSI (Ann Arbor, Michigan, USA) ↗
Portrait: University of Michigan Life Sciences Institute
Ken Inoki has focused his career on how the tuberous sclerosis complex proteins TSC1 and TSC2 control mTOR. Working in Kun-Liang Guan's lab and later independently, he showed that Akt directly phosphorylates and inhibits TSC2, wiring growth-factor signalling into the control of mTOR, and, as one of several groups reporting this in 2003, that TSC2 acts as a GTPase-activating protein (GAP) for the small GTPase Rheb, identifying Rheb as a direct, essential activator of mTORC1.
Inoki also showed that TSC2 integrates energy stress, via AMPK, and Wnt signalling into the same growth-control node, making the TSC–Rheb axis a central hub where nutrient, energy, growth-factor and developmental signals converge before reaching mTOR. His research at the University of Michigan continues to explore this axis in diabetes, aging and tuberous sclerosis, the inherited tumour disease caused by loss of TSC1 or TSC2.
The timeline below follows Inoki'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 | M | TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling INO2002 Shows, in parallel with other groups, that Akt phosphorylates and inhibits TSC2, linking growth-factor signalling to the control of mTOR. |
| 2003 | M | Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling INOK2003 One of several 2003 studies identifying Rheb as the direct target of TSC2's GAP activity and the essential activator of mTOR. |
| 2003 | M | TSC2 mediates cellular energy response to control cell growth and survival INO2003 Shows TSC2 mediates the cellular energy response, via AMPK, to control cell growth and survival. |
| 2004 | M | Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome COR2004 Co-authors the study placing LKB1 upstream of TSC2 through AMPK in the control of mTOR signalling (cells). |
| 2006 | M | Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity YAN2006 Identified Sin1 as an essential TORC2 component required for Akt phosphorylation. |
| 2006 | M | TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth INO2006 TSC2 integrates Wnt and energy signals through coordinated AMPK and GSK3 phosphorylation. |
| 2010 | M | ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS ALE2010 Co-authors a study showing that cytoplasmic ATM signals through LKB1, AMPK and TSC2 to repress mTORC1 when ROS rise. |
Co-authors in the Atlas 6
People with a profile here who share at least one study with Ken Inoki.
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- Kun-Liang Guan 7 shared studies Showed how growth-factor and energy signals reach mTORC1 through TSC2 and Rheb, and, in parallel with the Sabatini lab, that the Rag GTPases carry the amino-acid signal. His lab also found that AMPK and mTORC1 control autophagy by phosphorylating the kinase ULK1 at different sites
- Angela Alexander First author of the study showing that the DNA-damage kinase ATM also works in the cytoplasm, where it switches on TSC2 in response to reactive oxygen species and so turns mTORC1 down
- Cheryl Lyn Walker Cancer biologist and toxicologist who studies how environmental exposures reprogram the epigenome and target tumour suppressor genes; senior author of the study linking ATM to TSC2 and mTORC1 in the response to oxidative stress
- Michael N. Corradetti As an MD-PhD student at the University of Michigan, was first author on the 2004 study linking the LKB1 tumour suppressor to TSC2 through AMPK. He is now a radiation oncologist
- Qian Yang Researcher in Kun-Liang Guan's Michigan lab and first author of the 2006 study that identified Sin1 as an essential part of mTOR complex 2
- Tsuneo Ikenoue Gastroenterologist and cancer researcher at the University of Tokyo who trained in Kun-Liang Guan's mTOR lab and now builds mouse models of liver, bile duct and pancreatic cancer driven by the PI3K-Akt-mTOR pathway
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