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Tyrosine phosphatase inhibition triggers sustained canonical serine-dependent NFkappaB activation via Src-dependent

Sandra Barisic1, Claudia Schmidt, Henning Walczak

  • 1Institute of Cell Biology and Immunology, University of Stuttgart, Germany. Sandra.Barisic@izi.uni-stuttgart.de

Biochemical Pharmacology
|May 11, 2010
PubMed

Insights

This study reveals how Src kinase influences cancer by linking tyrosine and serine phosphorylation. It shows Src-mediated inhibition of PP2A phosphatase leads to sustained NFkappaB activation, promoting tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Src kinase and NFkappaB are crucial in cancer development and radio-resistance.
  • NFkappaB activation depends on the serine phosphorylation of its inhibitor, IkappaBalpha.
  • Constitutive NFkappaB activation is linked to tumor maintenance, necessitating strict regulation.

Purpose of the Study:

  • To investigate the molecular mechanisms linking tyrosine and serine phosphorylation in cellular signaling.
  • To elucidate the role of Src kinase and PP2A phosphatase in regulating NFkappaB activation.
  • To understand how these pathways contribute to cancer progression and tumorigenic effects.

Main Methods:

  • Utilized orthovanadate to inhibit pan-tyrosine phosphatase activity.
  • Investigated molecular interactions using IL-1 stimulation.
  • Analyzed phosphorylation events on Src, IkappaBalpha, and IKKbeta.
  • Identified PP2A as a Src substrate and assessed its catalytic activity.

Main Results:

  • Inhibition of tyrosine phosphatase activity via Src leads to the inhibition of serine phosphatase PP2A.
  • Src-mediated phosphorylation of PP2Ac at Tyr307 inhibits its catalytic activity.
  • Src links initial Tyr416 phosphorylation to sustained Ser177/181 phosphorylation of IKKbeta.
  • This results in chronic IkappaBalpha degradation and constitutive NFkappaB activation, enhancing tumorigenic effects.

Conclusions:

  • PP2A phosphatase acts as a critical mediator translating tyrosine to serine phosphorylation.
  • Src-mediated activation of NFkappaB contributes significantly to its tumorigenic potential.
  • Targeting the Src-PP2A-NFkappaB axis may offer new therapeutic strategies for cancer treatment.

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