Published on Wed Jul 14 2021

Single Serine on TSC2 Exerts Biased Control over mTORC1 Activation by ERK1/2 but Not Akt

Dunkerly-Eyring, B. L., Pinilla-Vera, M., McKoy, D., Mishra, S., Grajeda Martinez, M. I., Oeing, C. U., Ranek, M. J., Kass, D. A.

The mammalian target of rapamycin complex 1 (mTORC1) is tightly controlled by tuberous sclerosis complex-2 (TSC2) Among these kinases is protein kinase G that modifies TSC2 at S1365 (S1364, human) This minimally affects basal m

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Abstract

The mammalian target of rapamycin complex 1 (mTORC1) is tightly controlled by tuberous sclerosis complex-2 (TSC2), itself regulated by kinase phosphorylation reflecting environmental cues. Among these kinases is protein kinase G that modifies TSC2 at S1365 (S1364, human). This minimally affects basal mTORC1 activity, but upon phosphorylation or with an SE mutation, it blocks mTORC1 co-activation by pathological stress. An SA (phospho-silenced) mutation does the opposite. Here we reveal S1365 exerts biased regulation over mTORC1 activity (S6K phosphorylation). In myocytes and fibroblasts, ERK1/2 stimulated mTORC1 via endothelin-1 (ET-1) is potently and bidirectionally regulated by S1365. By contrast, Akt stimulation of mTORC1 (insulin) is minimally impacted. S1365 phosphorylation rises with ET-1 but not insulin stimulation, supporting intrinsic engagement by one and not the other. Energy and nutrient modulation of mTORC1 are minimally influenced by S1365. Consistent with these findings, knock-in mice with SA or SE mutations develop identical obesity, glucose intolerance, and fatty liver disease. These results reveal an ERK1/2-biased TSC2 regulatory mechanism controlling mTORC1 activation, with implications for suppressing pathological but not physiological mTORC1 stimulation.