Editors' ChoiceNeuroscience

Another mTOR complex?

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Science Signaling  12 Jul 2016:
Vol. 9, Issue 436, pp. ec160
DOI: 10.1126/scisignal.aah5207

The kinase mechanistic target of rapamycin (mTOR) forms two distinct protein complexes with different regulatory mechanisms and functions. These complexes mTORC1 and mTORC2 are defined by the presence of Raptor and PRAS40 or Rictor and mSIN1, respectively. Mutations in genes encoding proteins that limit mTOR activity, such as the GTPase-activating proteins NF1 and TSC1, cause neurological disorders with different cellular characteristics. For example, whereas loss of NF1 function in astrocytes results in increased proliferation, loss of TSC1 function results in increased cell size without an increase in proliferation. Smithson and Gutmann performed mass spectrometry analysis of the proteins that immunoprecipitated with mTOR in wild-type mouse astrocytes and identified G protein–coupled receptor kinase–interacting protein 1 (GIT1) as a binding partner. Unexpectedly, GIT1 immunoprecipitates contained mTOR, but not Raptor or Rictor, suggesting that the GIT1-bound mTOR complex may be distinct from mTORC1 and mTORC2. Less GIT1 coimmunoprecipitated with mTOR in astroctyes from Nf1−/− mice, and pharmacological inhibition of AKT activity increased the amount of GIT1 that coimmunoprecipitated with mTOR in the Nf1−/− astrocytes. Knocking down GIT1 in wild-type astrocytes had no effect on proliferation (determined by BrdU incorporation) but reduced proliferation and promoted apoptosis (determined by TUNEL staining) of Nf1−/− astrocytes. The identification of GIT1 as an mTOR-interacting protein that affects cell survival may provide a molecular explanation for the tumor-promoting effects of NF1 mutation and also suggests that the number of mTOR complexes may be greater than two.

L. J. Smithson, D. H. Gutmann, Proteomic analysis reveals GIT1 as a novel mTOR complex component critical for mediating astrocyte survival. Genes Dev. 30, 1383–1388 (2016). [PubMed]

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