Rab GTPase family members control membrane trafficking events that are important for a variety of cellular processes, including those that accompany cancer initiation and progression. Jim Norman's group has previously shown that levels of Rab17 must be suppressed in order for extracellular signal–regulated kinase 2 (ERK2) to be able to drive breast cancer invasiveness, but the endosomal cargoes responsible were unknown. In their study on page 697, Sara Zanivan, Jim Norman and colleagues now develop an unbiased quantitative mass spectrometry-based proteomics assay to elucidate the interactome and protein cargoes of Rab17. They identify the v-SNARE Vamp8 as interacting with Rab17 and observe that Vamp8 associates with Rab17 on late endosomes. The authors then show that reduced levels of either Rab17 or Vamp8 promote the transition of breast cancer cells in 3D culture from a benign to a more invasive phenotype with a disrupted basement membrane. Further proteomics-based analysis combined with compartment-specific protein biotinylation reveals neuropilin2 (NRP2) as a key pro-invasive cargo of the Rab17–Vamp8 complex. Indeed, NRP2 is required for the invasiveness of breast cancer cells that is mediated by knockdown of Rab17 or Vamp8. Taken together, this work highlights a crucial role of Rab17–Vamp8 in sequestering pro-invasive growth factor receptors, such as NRP2, from basolateral membranes in order to maintain their integrity, further underscoring the importance of correct trafficking for cell polarity.
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