4.4 Article

Regulation of Early Endosomal Entry by the Drosophila Tumor Suppressors Rabenosyn and Vps45

Journal

MOLECULAR BIOLOGY OF THE CELL
Volume 19, Issue 10, Pages 4167-4176

Publisher

AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E08-07-0716

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Funding

  1. National Institutes of Health [R01 GM-068675]
  2. American Cancer Society [RSG-07-040-01]
  3. The Norwegian Research Council
  4. Funksjonell Genomforskning, Norway
  5. The Norwegian Cancer Society
  6. Novo Nordisk Foundation
  7. U.S. Department of Energy [DE-AC-02-05CH11231.]
  8. NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM090150, R01GM068675] Funding Source: NIH RePORTER

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The small GTPase Rab5 has emerged as an important regulator of animal development, and it is essential for endocytic trafficking. However, the mechanisms that link Rab5 activation to cargo entry into early endosomes remain unclear. We show here that Drosophila Rabenosyn (Rbsn) is a Rab5 effector that bridges an interaction between Rab5 and the Sec1/Munc18-family protein Vps45, and we further identify the syntaxin Avalanche (Avl) as a target for Vps45 activity. Rbsn and Vps45, like Avl and Rab5, are specifically localized to early endosomes and are required for endocytosis. Ultrastructural analysis of rbsn, Vps45, avl, and Rab5 null mutant cells, which show identical defects, demonstrates that all four proteins are required for vesicle fusion to form early endosomes. These defects lead to loss of epithelial polarity in mutant tissues, which overproliferate to form neoplastic tumors. This work represents the first characterization of a Rab5 effector as a tumor suppressor, and it provides in vivo evidence for a Rbsn-Vps45 complex on early endosomes that links Rab5 to the SNARE fusion machinery.

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