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TSC-insensitive Rheb mutations induce oncogenic transformation through a combination of constitutively active mTORC1

Jianling Xie1,2, Stuart P De Poi1,3, Sean J Humphrey4

  • 1Lifelong Health, South Australian Health and Medical Research Institute, Adelaide, SA, 5001, Australia.

Cellular and Molecular Life Sciences : CMLS
|April 9, 2021
PubMed

Insights

Mutations in Rheb, a key mTORC1 activator, can drive cancer by promoting cell growth and tumor formation. Different Rheb mutants activate distinct oncogenic pathways, suggesting personalized cancer therapies are needed.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Metabolism

Background:

  • Mechanistic target of rapamycin complex 1 (mTORC1) is a critical regulator of cellular metabolism frequently hyperactivated in cancer.
  • Ras-homolog enriched in brain (Rheb) is the primary activator of mTORC1, and mutations in Rheb are implicated as driver oncogenes.
  • Tuberous sclerosis complex (TSC) is the main negative regulator of Rheb activity.

Purpose of the Study:

  • To investigate how recurrent Rheb mutations contribute to mTORC1 hyperactivation and oncogenesis.
  • To elucidate the distinct molecular pathways driven by specific Rheb mutants.
  • To explore the therapeutic implications of Rheb mutations in cancer treatment.

Main Methods:

  • Analysis of Rheb mutants' sensitivity to tuberous sclerosis complex (TSC).
  • Assessment of cell growth, proliferation, and anchorage-independent growth in vitro.
  • In vivo tumor growth studies.
  • Proteomic analysis to identify downstream signaling pathways affected by Rheb mutations.
  • Investigation of interactions with 5' AMP-activated protein kinase (AMPK).

Main Results:

  • Recurrent Rheb mutants confer varying degrees of insensitivity to TSC, leading to mTORC1 hyperactivation.
  • Rheb-T23M and Rheb-E40K mutants significantly enhance cell growth, proliferation, and tumor formation in vivo.
  • Proteomic analysis revealed distinct oncogenic pathways: Rheb-T23M promotes anaerobic glycolysis, while Rheb-E40K affects translation factor eEF2 and autophagy.
  • Differential interactions with AMPK appear to mediate the distinct pathway activation by these mutants.

Conclusions:

  • Specific Rheb mutations drive cancer through distinct molecular mechanisms, impacting cellular metabolism and signaling.
  • Rheb-T23M and Rheb-E40K mutants represent distinct oncogenic drivers with unique pathway dependencies.
  • Understanding the specific Rheb mutant in a tumor could enable the development of personalized, combination therapies for cancer treatment.
Keywords:
AMPKPKMRhebTSCeEF2mTOR

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