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Related Experiment Videos

Signaling pathways in Ras-mediated tumorigenicity and metastasis

C P Webb1, L Van Aelst, M H Wigler

  • 1Advanced BioScience Laboratories, Basic Research Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, MD 21072-1201, USA.

Proceedings of the National Academy of Sciences of the United States of America
|July 22, 1998
PubMed
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Ras effector domain mutants cause tumors, but only V12S35 Ras promotes metastasis by activating the Raf-mitogen-activated protein kinase kinase (MEK)-extracellular regulated kinase (ERK) 1/2 pathway. This pathway is crucial for experimental metastasis, not just tumor formation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Oncogenic Ras proteins are key regulators of cell signaling pathways.
  • Ras effector domain mutations can alter downstream signaling and cellular phenotypes.
  • The Raf-mitogen-activated protein kinase kinase (MEK)-extracellular regulated kinase (ERK) 1/2 pathway is a critical signaling cascade.

Purpose of the Study:

  • To investigate the role of Ras effector domain mutations in tumorigenicity and metastasis.
  • To determine the specific signaling pathways involved in Ras-mediated metastasis.
  • To understand the relationship between ERK1/2 pathway activation and metastatic potential.

Main Methods:

  • Expression of Ras effector domain mutants (V12S35, V12G37, V12C40) in NIH 3T3 fibroblasts.

Related Experiment Videos

  • Tumorigenicity and metastasis assays in athymic nude mice.
  • Direct activation of the MEK-ERK1/2 pathway using mos or constitutively active MEK.
  • Analysis of ERK1/2 activation levels in tumor and metastasis samples.

    • Main Results:

    • All Ras mutants were tumorigenic, but only V12S35 Ras induced experimental metastasis.
    • Direct MEK-ERK1/2 activation induced metastasis, while R-Ras (non-ERK activator) was tumorigenic but nonmetastatic.
    • V12S35 Ras-derived tumors and metastases showed higher activated ERK1/2 levels, indicating selection for pathway activation.
    • Passaging in vivo confirmed that only V12S35 Ras-derived cells formed numerous lung metastases.

    Conclusions:

    • Ras-mediated tumorigenicity can occur independently of ERK1/2 activation.
    • Constitutive activation of the ERK1/2 pathway is required for experimental metastasis.
    • The metastatic potential of Ras mutants is dependent on their ability to activate the MEK-ERK1/2 pathway.