Ultanir lab

Kinases and Brain Development Laboratory

: mTOR

Mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase which regulates cell growth downstream of nutrition availability and plays roles in neural stem cell proliferation and differentiation. Uncontrolled activation of mTOR, commonly by mutations in its inhibitor TSC1/2 complex, causes neurological diseases of epilepsy, brain tumours and focal cortical dysplasia.

Several mTOR effectors (e.g. ribosomal S6 kinase) are known. Surprisingly however, given the roles of mTOR in nervous system development and disease, substrates of mTOR in the nervous system are poorly characterized.

To identify novel mTORC1 substrates, we used brain specific Tsc1 knockout mice and compared these with littermate controls using quantitative mass spectrometry. We identified 25 novel mTORC1 substrate candidates in developing brain. These proteins have various cellular functions, and at least 7 of them have been implicated in neurodevelopmental disorders.

Our ongoing collaboration with Dr Joseph Bateman at King’s College London is focusing on determining the roles of these new mTOR downstream effectors in human iPSCs.