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A novel function of p38-regulated/activated kinase in endothelial cell migration and tumor angiogenesis

Naoto Yoshizuka1, Rebecca M Chen, Zeyu Xu

  • 1Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.

Molecular and Cellular Biology
|November 30, 2011
PubMed

Insights

The p38-regulated/activated kinase (PRAK) pathway initially suppresses tumors but later promotes skin cancer growth and angiogenesis. This dual role depends on cancer stage and tissue context.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • The p38 mitogen-activated protein kinase (MAPK) pathway exhibits dual roles in cancer, potentially suppressing or promoting tumorigenesis.
  • The precise in vivo mechanisms governing these opposing functions of p38 remain incompletely understood.
  • Previous work identified p38-regulated/activated kinase (PRAK) as a tumor suppressor via oncogene-induced senescence.

Purpose of the Study:

  • To elucidate the distinct roles of PRAK in established skin tumors within a murine carcinogenesis model.
  • To investigate PRAK's function in tumor progression and angiogenesis.
  • To identify the signaling pathways mediating PRAK's pro-tumorigenic effects.

Main Methods:

  • Utilized a murine skin carcinogenesis model to study tumor development.
  • Investigated PRAK activation in host endothelial cells in response to tumor factors.
  • Examined PRAK's role in endothelial cell migration and tumor angiogenesis, including downstream signaling via focal adhesion kinase (FAK).

Main Results:

  • PRAK promotes the growth and progression of established skin tumors.
  • PRAK is identified as a critical host factor essential for tumor angiogenesis.
  • PRAK activation in endothelial cells is dependent on p38 and vascular endothelial growth factor receptor 2 (VEGFR2).
  • PRAK regulates endothelial cell migration and vascularization by modulating FAK phosphorylation and cytoskeletal dynamics.

Conclusions:

  • The p38-PRAK pathway exhibits temporally and spatially separated functions in cancer development, acting as a suppressor early on and a promoter later.
  • PRAK is a novel mediator of tumor angiogenesis, crucial for established tumor growth.
  • Understanding the context-dependent roles of the p38-PRAK pathway offers potential therapeutic targets for different cancer stages.

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