Scientists from Montreal Neurological Institute and McGill University have accomplished a new finding: one universal protein in human cells may be a key switch that could activate cancer cell metastasis. This finding is largely ignored so far. The finding of this protein expands our knowledge on epithelioma such as breast cancer and lung cancer. This study was published in JCB.

Rab  GTPases are master regulators of membrane trafficking controlling the formation of vesicles, vesicle transport via the actin and microtubule cytoskeletons, and vesicle tethering and fusion. Rabs are activated by guanine-nucleotide exchange factors(GEFs) that catalyze the exchange of GDP for GTP. The DENN(differentially expressed in normal and neoplastic cells) domain is an evolutionarily ancient and structurally conserved protein module.

Currently, there are 26 identified DENN domain proteins, the majority of which are poorly characterized. One such protein, DENND2B, is a member of the DENND2A-D subfamily that contains a C-terminal DENN domain but few other distinguishing features. DENND2B was originally identified by screening a cDNA expression library for gene products that suppress the tumorigenicity of HeLa cells in nude mice and was named ST5.

In this study, researchers demonstrate that DENND2B localizes to the cell surface in association with the actin regulatory protein MICAL-L2, a Rab13 effector that induces membrane ruffles when bound to active Rab13. They develop and optimize a novel Forster resonance energy transfer(FRET)-based Rab13 biosensor that reveals selective activation of Rab13 on membrane ruffles at the dynamic leading edge of migrating cells, and they demonstrate that Rab13 activation by DENND2B at the cell surface is required for cell migration and invasion.

Finally, they find that disruption of the Rab13-DENND2B trafficking pathway dramatically reduces the migration of highly aggressive breast cancer cells in vivo. These findings provide evidence for a DENND2B-centered module that appears critical for the metastasis of cancer cells.

Reference:

Ioannou M S, Bell E S, Girard M, et al. DENND2B activates Rab13 at the leading edge of migrating cells and promotes metastatic behavior[J]. The Journal of cell biology, 2015, 208(5): 629-648.