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The putative tumor suppressor gene PTPN13/PTPL1 induces apoptosis through insulin receptor substrate-1

Mathilde Dromard1, Guillaume Bompard, Murielle Glondu-Lassis

  • 1INSERM U826, Contrôle de la Progression des Cancers Hormono-Dépendants, Centre de Recherche en Cancérologie, Universite Montpellier I, CRLC Val d'Aurelle-Paul Lamarque, 34298 Montpellier, France.

Cancer Research
|July 20, 2007
PubMed

Insights

The tumor suppressor PTPL1 (protein tyrosine phosphatase like 1) directly dephosphorylates IRS-1, inhibiting the PI3K/Akt pathway and promoting apoptosis in cancer cells.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Signal Transduction

Background:

  • Protein tyrosine phosphatase PTPL1/PTPN13 is a candidate tumor suppressor.
  • PTPL1 activity is reduced in some tumors via mutations, loss, or methylation.
  • PTPL1 is crucial for antiestrogen-induced apoptosis by inhibiting Akt activation in breast cancer.

Purpose of the Study:

  • Determine if PTPL1 is sufficient to inhibit the PI3K/Akt pathway.
  • Identify a direct substrate of PTPL1 that triggers apoptosis.
  • Investigate PTPL1's role in cancer progression.

Main Methods:

  • In vitro and cellulo dephosphorylation assays.
  • Use of dominant-negative mutants and RNA interference.
  • Analysis of PTPL1's effect on the IRS-1/PI3K/Akt pathway and apoptosis.

Main Results:

  • PTPL1 specifically dephosphorylates insulin receptor substrate-1 (IRS-1).
  • PTPL1's role in IRS-1 dephosphorylation was confirmed using dominant-negative mutants and RNA interference.
  • PTPL1 expression inhibits the IRS-1/PI3K/Akt pathway, blocks IGF-I effects on survival, and induces apoptosis.

Conclusions:

  • PTPL1 directly dephosphorylates IRS-1, targeting the IRS-1/PI3K/Akt pathway.
  • PTPL1 acts as a positive regulator of apoptosis.
  • PTPL1 is sufficient to inhibit the PI3K/Akt pathway and induce apoptosis, supporting its role as a tumor suppressor.

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