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Rab5 is required in metastatic cancer cells for Caveolin-1-enhanced Rac1 activation, migration and invasion

Jorge Díaz1, Pablo Mendoza2, Rina Ortiz3

  • 1Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Calle Sergio Livingstone 943, Santiago, Chile Center for Molecular Studies of the Cell, Faculty of Medicine, Universidad de Chile, Avenida Independencia 1027, Santiago, Chile Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Avenida Independencia 1027, Santiago, Chile.

Journal of Cell Science
|March 25, 2014
PubMed

Insights

Caveolin-1 (CAV1) activates Rab5, a protein involved in cell migration. This CAV1-Rab5 pathway enhances Rac1 activity, promoting cancer cell migration and invasion by preventing Rab5 inactivation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Rab5 GTPase regulates early endosome trafficking and is implicated in cell migration.
  • Caveolin-1 (CAV1) is a scaffolding protein known to promote Rac1 activation and cancer cell migration.
  • Upstream regulators of Rab5 activity, particularly in the context of cancer cell migration, remain largely uncharacterized.

Purpose of the Study:

  • To investigate the hypothesis that Caveolin-1 (CAV1) stimulates Rab5 activation, consequently increasing Rac1 activity and promoting cancer cell migration.
  • To elucidate the molecular mechanisms by which CAV1 influences Rab5 activity and downstream signaling pathways involved in tumor cell motility.

Main Methods:

  • Assessed Rab5 GTP loading in response to CAV1 expression or knockdown in melanoma, colon, and breast cancer cell lines.
  • Utilized shRNA to downregulate Rab5 and evaluated its impact on CAV1-mediated Rac1 activation, cell migration, and invasion.
  • Investigated the recruitment of Tiam1 (Rac1 GEF) to Rab5-positive endosomes and assessed the role of Tiam1 in CAV1- and Rab5-induced cell migration using NSC23766 inhibitor.
  • Examined the involvement of p85α (PIK3R1), a Rab5 GAP, in CAV1-dependent signaling by assessing its recruitment and its effect on Rab5 inactivation and cell migration.

Main Results:

  • CAV1 expression increased Rab5 GTP loading in B16-F10 and HT-29(US) cells, while CAV1 knockdown decreased Rab5-GTP levels in MDA-MB-231 cells.
  • Rab5 downregulation abrogated CAV1-induced Rac1 activation, cell migration, and invasion in B16-F10 and HT-29(US) cells.
  • CAV1 expression enhanced Tiam1 recruitment to Rab5-positive endosomes, and Tiam1 was essential for CAV1- and Rab5-mediated Rac1 activation and migration.
  • CAV1 was found to recruit p85α, inhibiting its GAP activity towards Rab5, thereby preventing Rab5 inactivation and promoting cell migration.

Conclusions:

  • A novel signaling axis involving CAV1, Rab5, and Rac1 has been identified, which is critical for regulating tumor cell migration and invasion.
  • CAV1 promotes cancer cell migration by preventing Rab5 inactivation, leading to sustained Rac1 activation.
  • This pathway represents a potential therapeutic target for inhibiting cancer metastasis.
Keywords:
Caveolin-1Metastatic cell migrationRab5Rac1Small GTPasesp85α

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