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PTPH1 dephosphorylates and cooperates with p38gamma MAPK to increase ras oncogenesis through PDZ-mediated interaction

Song-Wang Hou1, Hui-Ying Zhi, Nicole Pohl

  • 1Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

Cancer Research
|March 25, 2010
PubMed

Insights

Protein tyrosine phosphatase H1 (PTPH1) directly binds and dephosphorylates p38gamma mitogen-activated protein kinase (MAPK), revealing a cooperative mechanism driving Ras-dependent oncogenic activity and suggesting a novel therapeutic target.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Oncology

Background:

  • Protein phosphatases and kinases coordinate biological functions, but integrated examples are scarce.
  • p38gamma mitogen-activated protein kinase (MAPK) is a Ras effector involved in transformation.
  • The specific phosphatase for p38gamma and its role in oncogenesis remain largely uncharacterized.

Purpose of the Study:

  • To identify the specific phosphatase for p38gamma MAPK.
  • To elucidate the functional relationship between p38gamma and its phosphatase in Ras-driven oncogenesis.
  • To investigate the potential of the p38gamma/phosphatase complex as a therapeutic target.

Main Methods:

  • Yeast two-hybrid screening to identify binding partners.
  • In vitro and in vivo biochemical and cellular assays.
  • Analysis of primary colon cancer tissues for protein expression correlation.

Main Results:

  • Protein tyrosine phosphatase H1 (PTPH1) was identified as the specific phosphatase for p38gamma MAPK via PDZ-mediated binding.
  • PTPH1 binding and phosphatase activity are crucial for p38gamma's role in Ras-dependent malignant growth.
  • Ras signaling upregulates both p38gamma and PTPH1 expression, which are coupled in colon cancer tissues.

Conclusions:

  • A novel cooperative oncogenic signaling axis between p38gamma MAPK and its specific phosphatase PTPH1 has been uncovered.
  • The PDZ-mediated interaction between p38gamma and PTPH1 is critical for Ras-dependent malignancies.
  • The p38gamma/PTPH1 complex represents a potential therapeutic target for Ras-driven cancers.

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