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Published on: July 17, 2020

Negative feedback regulation of the tumor suppressor PTEN by phosphoinositide-induced serine phosphorylation

Diana Birle1, Nunzio Bottini, Scott Williams

  • 1Program of Signal Transduction, Burnham Institute, La Jolla, CA 92037, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|June 22, 2002
PubMed

Insights

The phosphatase and tensin homolog (PTEN) protein is phosphorylated on its C-terminus, particularly at Serine 380, in T cells. This phosphorylation regulates PTEN levels, maintaining crucial D3-phosphoinositide homeostasis for T cell function.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Immunology

Background:

  • The PTEN tumor suppressor phosphatase inhibits phosphatidylinositol 3-kinase (PI3K) signaling by dephosphorylating phosphoinositides at the D3 position.
  • The Jurkat T cell line, common in lymphomas and leukemias, lacks functional PTEN due to mutations, contributing to its survival.
  • Phosphatidylinositol 3-kinase (PI3K) pathway is critical for T cell survival and activation.

Purpose of the Study:

  • To investigate the regulation of PTEN protein, particularly its phosphorylation and degradation.
  • To understand the role of PTEN phosphorylation in maintaining D3-phosphoinositide homeostasis in T cells.

Main Methods:

  • Reintroduction of PTEN into PTEN-deficient Jurkat T cells.
  • Analysis of PTEN phosphorylation at specific C-terminal serine residues (Ser380, Ser385).
  • Treatment of cells to alter D3-phospholipid levels and expression of protein kinase B (PKB/Akt).

Main Results:

  • Reintroduced PTEN in Jurkat cells was highly phosphorylated on Ser380 and Ser385.
  • Phosphorylation at Ser380 was also observed in normal human T cells.
  • Reduced D3-phospholipid levels led to decreased PTEN phosphorylation and faster degradation.
  • Inactive PTEN or active PKB/Akt increased PTEN phosphorylation and slowed its degradation.

Conclusions:

  • PTEN undergoes feedback regulation through C-terminal phosphorylation, particularly at Ser380.
  • This regulatory mechanism helps maintain homeostatic levels of D3-phosphoinositides.
  • Maintaining D3-phosphoinositide balance is essential for T cell survival and activation.

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