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COX2 expression and Erk1/Erk2 activity mediate Cot-induced cell migration.

Cristina Rodríguez1, Pilar López, Maite Pozo

  • 1Instituto de Investigaciones Biomédicas, Dpto. de Bioquímica, UAM, Arturo Duperier 4, 28029 Madrid, Spain.

Cellular Signalling
|June 24, 2008
PubMed
Summary

The proto-oncogene Cot regulates cell migration by affecting adhesion, cytoskeleton dynamics, and metalloproteinase activity. Its oncogenic form (Cot-T) promotes lamellipodia formation and microtubule polarization, essential for cell movement.

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Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • MAPKKK8, also known as Cot/tpl-2, is involved in intracellular signaling pathways activated by Toll-like receptors (TLR) and TNFalpha receptors.
  • Cot has been identified as an oncogene (Cot-T), suggesting a role in cancer development and progression.

Purpose of the Study:

  • To investigate the role of Cot in regulating cell migration processes.
  • To elucidate the molecular mechanisms by which Cot influences cell adhesion, cytoskeleton organization, and metalloproteinase activity.

Main Methods:

  • Overexpression of Cot-T and depletion of endogenous Cot in cellular models.
  • Analysis of cell adhesion, metalloproteinase activity, and cytoskeleton dynamics (microtubules, stress fibers).
  • Assessment of GTP-bound Rac (Rac-GTP) and Rho (Rho-GTP) levels.
  • Evaluation of COX2 expression and Erk1/2 activation.

Main Results:

  • Cot overexpression promotes cell migration by enhancing cell adhesion and metalloproteinase activity.
  • Cot regulates cytoskeleton dynamics, leading to microtubule polarization and loss of stress fibers upon Cot-T overexpression.
  • Cot-T overexpression increases lamellipodia formation, associated with elevated Rac-GTP levels.
  • Depletion of Cot results in increased stress fiber formation and elevated Rho-GTP levels.
  • Cot-mediated induction of cell migration requires increased COX2 expression and Erk1/2 activation.

Conclusions:

  • Cot plays a significant role in regulating multiple steps of cell migration, including adhesion and cytoskeleton remodeling.
  • Both proto-oncogenic and oncogenic forms of Cot exhibit novel functions in cellular processes relevant to migration and potentially cancer.
  • Cot signaling pathways involving Rac, Rho, COX2, and Erk1/2 are critical for its pro-migratory effects.