Abstract
RILP (Rab7-interacting lysosomal protein) is a key regulator for late endosomal/lysosomal trafficking, and probably a tumor suppressor in prostate cancer. However, the role of RILP in other cancers and the underlying mechanism for RILP in regulating the invasion of cancer cells remain to be investigated. In this study, we showed that overexpression of RILP in breast cancer cells inhibits the migration and invasion, whereas the depletion of RILP by RNAi-mediated knockdown promotes the migration and invasion. We identified RalGDS (Ral guanine nucleotide dissociation stimulator) as a novel interacting partner for RILP, and truncation analysis revealed the N-terminal region of RILP is responsible for interacting with the guanine nucleotide exchange factor (GEF) domain of RalGDS. Immunofluorescence microscopy revealed that RalGDS can be recruited to the late endosomal compartments by RILP. Further investigations indicated that the overexpression of RILP inhibits the activity of RalA, a downstream target of RalGDS. Our data suggest that RILP suppresses the invasion of breast cancer cells by interacting with RalGDS to inhibit its GEF activity for RalA.
Highlights
Aberrant activities of Rab proteins are closely related to some cancers.[12,13,14,15] Some Rab proteins mediate the trafficking of cargos, especially membrane proteins on the plasma membrane, such as integrin and E-cadherin
We examined the expression of RILP in different breast cancer cell lines, and found that the expression of RILP is lower in the highly invasive cells, such as BT549, Hs578t and MDAMB-231 compared with less-invasive cell lines such as MCF7, SKBR3 and ZR75.1 (Figure 1a), suggesting downregulation of RILP is potentially associated with the increased invasion of breast cancer cells
RILP interacts with Rab[7], Rab[34] and dynein/ dynactin complex to regulate late endosomal/lysosomal trafficking from peripheral region to peri-Golgi region marked by MTOC,[18,19,36] this event may inhibit the anterograde transport and result in the suppression of invasion of prostate cancer cells.[22,23]
Summary
Aberrant activities of Rab proteins are closely related to some cancers.[12,13,14,15] Some Rab proteins mediate the trafficking of cargos, especially membrane proteins on the plasma membrane, such as integrin and E-cadherin. Their aberrant trafficking is proposed to be the underlying mechanism for the functional regulation of Rab protein in cancer cells.[16,17].
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