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Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
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Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors

Published on: July 17, 2020

5' phospholipid phosphatase SHIP-2 causes protein kinase B inactivation and cell cycle arrest in glioblastoma cells

V Taylor1, M Wong, C Brandts

  • 1Cancer Research Institute, University of California, San Francisco 94115, USA.

Molecular and Cellular Biology
|August 25, 2000
PubMed

Insights

The tumor suppressor PTEN is mutated in glioblastoma, affecting PI3K-PKB signaling. SHIP-2, like PTEN, inhibits PKB activity and causes cell cycle arrest, suggesting a negative regulatory role in this pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Glioblastoma multiforme (GBM) is characterized by PTEN mutations, leading to aberrant phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB) pathway signaling.
  • This pathway is crucial for cancer cell proliferation and survival, making it a key target for therapeutic intervention.

Purpose of the Study:

  • To investigate the distinct roles of phosphatidylinositol 3,4-biphosphate [PtdIns(3,4)P2] and phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3] in PKB regulation within PTEN-deficient glioblastoma cells.
  • To elucidate the function of SHIP-2, a phosphatase, in modulating PI3K-PKB signaling and its impact on glioblastoma cell behavior.

Main Methods:

  • Utilized glioblastoma cell lines with defective PTEN expression.
  • Manipulated PTEN and SHIP-2 levels through re-expression and antisense oligonucleotides.
  • Employed PI3K inhibitor LY294002 to assess pathway inhibition.
  • Measured levels of PtdIns(3,4)P2 and PtdIns(3,4,5)P3, PKB phosphorylation, PKB membrane association, and cell cycle progression.

Main Results:

  • Both PtdIns(3,4)P2 and PtdIns(3,4,5)P3 levels were reduced by PTEN re-expression or PI3K inhibition, decreasing PKB activity.
  • SHIP-2 overexpression reduced PtdIns(3,4,5)P3 but not PtdIns(3,4)P2, yet significantly inhibited PKB activity and membrane association, similar to PTEN.
  • SHIP-2 depletion increased PKB activity, and SHIP-2's phosphatase activity was not altered by growth factor-induced tyrosine phosphorylation.

Conclusions:

  • SHIP-2 acts as a negative regulator of the PI3K-PKB pathway in glioblastoma.
  • SHIP-2, akin to PTEN, induces G1 cell cycle arrest by stabilizing p27(KIP1) expression.
  • These findings highlight SHIP-2 as a potential therapeutic target in glioblastoma treatment.

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