Hussain S, Feldman AL, Das C, Ziesmer SC, Ansell SM, Galardy PJ

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates processes including mRNA translation, proliferation, and survival. By assembling with different cofactors, mTOR forms two complexes with distinct biological functions. Raptor-bound mTOR (mTORC1) governs cap-dependent mRNA translation, whereas mTOR, rictor, and mSin1 (mTORC2) activate the survival and proliferative ...

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kinase Akt. How the balance between the competing need for mTORC1 and 2 is controlled in normal cells and deregulated in disease is poorly understood. Here we show that the ubiquitin hydrolase UCH-L1 regulates the balance of mTOR signaling by disrupting mTORC1. We find that UCH-L1 impairs mTORC1 activity towards S6 kinase and 4EBP1 while increasing mTORC2 activity towards Akt. These effects are directly attributable to a dramatic rearrangement in mTOR complex assembly. UCH-L1 disrupts a complex between the DDB1-Cul4 ubiquitin ligase complex and raptor, and counteracts DDB1-Cul4 mediated raptor ubiquitination. These events lead to mTORC1 dissolution and a secondary increase in mTORC2. Experiments in Uchl1 deficient and transgenic mice suggest that the balance between these pathways is important for preventing neurodegeneration and the development of malignancy. These data establish UCH-L1 as a key regulator of the dichotomy between mTORC1 and mTORC2 signaling.

Date: Jan. 07, 2013

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