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The epsin family of endocytic adaptors promotes fibrosarcoma migration and invasion.

Abstract
Abnormalities in the process of endocytosis are classically linked to malignant transformation through the deficient down-regulation of signaling receptors. The present study describes a non-classical mechanism that does not require internalization by which endocytic proteins affect cell migration and basement membrane invasion. Specifically, we found that the endocytic adaptor epsin binds and regulates the biological properties of the signaling molecule RalBP1 (Ral-binding protein 1). Epsin interacted with the N terminus of RalBP1 via its characteristic epsin N-terminal homology (ENTH) domain. A combination of siRNA-mediated knock-down and transfection of siRNA-resistant constructs in fibrosarcoma cells demonstrated that impairment of the epsin-RalBP1 interaction led to cell migration and basement membrane invasion defects. We found the ENTH domain was necessary and sufficient to sustain normal cell migration and invasion. Because all the epsin endocytic motifs reside in the C-terminal part of the molecule, these results suggest that this novel regulatory circuit does not require endocytosis. In addition, cells depleted of epsin-RalBP1 complex displayed deficient activation of Rac1 and Arf6 suggesting a signaling function for this novel interaction. Further, overexpression of either epsin or RalBP1 enhanced migration and invasion of fibrosarcoma cells. Collectively, our results indicate that epsin regulates RalBP1 function in Rac1- and Arf6-dependent pathways to ultimately affect cell migration and invasion. We propose that the observed up-regulation of both epsin and RalBP1 in certain cancers contributes to their invasive characteristics.
AuthorsBrian G Coon, John Burgner, Jacques H Camonis, R Claudio Aguilar
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 43 Pg. 33073-33081 (Oct 22 2010) ISSN: 1083-351X [Electronic] United States
PMID20709745 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • ADP-Ribosylation Factor 6
  • ATP-Binding Cassette Transporters
  • Adaptor Proteins, Vesicular Transport
  • GTPase-Activating Proteins
  • Neuropeptides
  • RAC1 protein, human
  • RALBP1 protein, human
  • Rac1 protein, mouse
  • Ralbp1 protein, mouse
  • epsin
  • ADP-Ribosylation Factors
  • ARF6 protein, human
  • Arf6 protein, mouse
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein
Topics
  • ADP-Ribosylation Factor 6
  • ADP-Ribosylation Factors (genetics, metabolism)
  • ATP-Binding Cassette Transporters (genetics, metabolism)
  • Adaptor Proteins, Vesicular Transport (genetics, metabolism)
  • Amino Acid Motifs
  • Animals
  • Basement Membrane (metabolism, pathology)
  • Cell Line, Tumor
  • Cell Movement
  • Endocytosis (genetics)
  • Fibrosarcoma (genetics, metabolism, pathology)
  • GTPase-Activating Proteins (genetics, metabolism)
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Neoplasm Invasiveness (genetics)
  • Neuropeptides (genetics, metabolism)
  • Protein Structure, Tertiary
  • rac GTP-Binding Proteins (genetics, metabolism)
  • rac1 GTP-Binding Protein (genetics, metabolism)

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