Ken Inoki

Showed TSC2 and Rheb form the master brake and throttle of mTOR

MD, PhD · Research Associate Professor, Life Sciences Institute · University of Michigan Medical School

Ken Inoki 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 that TSC2 acts as a GTPase-activating protein (GAP) for the small GTPase Rheb — identifying Rheb as the 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

Year	Evidence	Study
2002	M	TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling INO2002 Shows 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 Identifies 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.
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.

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