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Updated: Aug 23, 2025

A Mass Spectrometry-Based Approach to Identify Phosphoprotein Phosphatases and their Interactors
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Phosphoproteomic Analysis Defines BABAM1 as mTORC2 Downstream Effector Promoting DNA Damage Response in Glioblastoma

Nuttiya Kalpongnukul1,2, Rungnapa Bootsri2,3, Piriya Wongkongkathep2,4

  • 1Interdisciplinary Program of Biomedical Sciences, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand.

Journal of Proteome Research
|October 31, 2022
PubMed

Insights

Mechanistic target of rapamycin complex 2 (mTORC2) regulates DNA repair in glioblastoma (GBM). Inhibiting mTORC2 impairs double-strand break repair and promotes cancer cell death, offering potential new brain cancer treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Glioblastoma (GBM) is an aggressive brain cancer with limited treatment options.
  • The mechanistic target of rapamycin (mTOR) pathway, including mTORC1 and mTORC2 complexes, is frequently dysregulated in GBM.
  • mTORC2 plays crucial roles in cell survival, metabolism, and DNA damage response.

Purpose of the Study:

  • To investigate the role of the aberrant mTORC2 signaling pathway in GBM.
  • To explore the functional link between mTORC2 and DNA double-strand break (DSB) repair mechanisms.
  • To identify potential therapeutic targets within the mTORC2 pathway for GBM treatment.

Main Methods:

  • Quantitative phosphoproteomic analysis of U87MG glioblastoma cells.
  • Investigation of mTORC2 regulation of DNA damage response proteins, including pBABAM1 and γH2AX.
  • Assessment of DNA repair activity and apoptosis following mTORC2 inhibition.

Main Results:

  • mTORC2 inhibition was associated with impaired double-strand break (DSB) repair.
  • Phosphorylation of BABAM1 at Ser29 (pBABAM1) is regulated by mTORC2 and is crucial for initiating DNA damage response.
  • mTORC2 controls histone H2AX phosphorylation at Ser139 (γH2AX), a marker of DNA damage, and its inactivation promotes cancer cell apoptosis.

Conclusions:

  • mTORC2 signaling is integral to DNA damage response and repair in glioblastoma cells.
  • Targeting mTORC2 may represent a novel therapeutic strategy for treating brain cancer.
  • Understanding mTORC2's role in DNA repair provides insights into GBM pathogenesis and treatment resistance.
Keywords:
BABAM1DNA damage responseglioblastomamTORC2phosphoproteomics

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