Abstract
Neuropilins (NRPs) are cell surface glycoproteins that often act as co-receptors for plexins and VEGF family receptors. Neuropilin-2 (NRP2), a family member of NRPs, was shown to regulate autophagy and endocytic trafficking in cancer cells, a function distinctly different from its role as a co-receptor. WD Repeat and FYVE domain containing 1 (WDFY1)–protein acts downstream of NRP2 for this function. Our results indicated that NRP2 maintains an optimum concentration of WDFY1 by negatively regulating its expression. Since increased expression of WDFY1 reduces the endocytic activity, maintenance of WDFY1 level is crucial in metastatic cancer cells to sustain high endocytic activity, essential for promotion of oncogenic activation and cancer cell survival. Here, we have delineated the underlying molecular mechanism of WDFY1 synthesis by NRP2. Our results indicated that NRP2 inhibits WDFY1 transcription by preventing the nuclear localization of a transcription factor, Fetal ALZ50-reactive clone 1 (FAC1). Our finding is novel as transcriptional regulation of a gene by NRP2 axis has not been reported previously. Regulation of WDFY1 transcription by NRP2 axis is a critical event in maintaining metastatic phenotype in cancer cells. Thus, inhibiting NRP2 or hyper-activating WDFY1 can be an effective strategy to induce cell death in metastatic cancer.
Highlights
Neuropilins (NRPs) are the cell surface glycoprotein receptors for class-3 semaphorins and vascular endothelial growth factors (VEGFs)[1,2,3]
Our results indicated that depletion of NRP2 though increased both the mRNA and protein level of WDFY1, had no effect on WDFY2 expression
Our recent reports showed a novel function of NRP2 in the maturation of early to late endosomes, necessary for the maintenance of cell surface receptor activation during metastatic progression and autophagic activity during therapeutic stress[16,24]
Summary
Neuropilins (NRPs) are the cell surface glycoprotein receptors for class-3 semaphorins and vascular endothelial growth factors (VEGFs)[1,2,3]. NRP1 with its PDZ domain at the C-terminal end of cytosolic tail binds GIPC molecules and thereby regulates the cellular cytoskeleton structure[13]. We have previously reported a survival promoting function of NRP2 in cancer cells by enhancing autophagy during therapeutic stress[14,15,16]. WD40 repeats and single FYVE domain containing protein 1 (WDFY1) functions downstream of NRP2. It co-localizes with EEA1 positive early endosomes[18,19] and acts as an adaptor molecule for protein-protein or protein-DNA interaction[18,20,21] due to the presence of propeller-like structures made by several antiparallel beta-sheets. As cancer cells depend on their endocytic activities to maintain the metastatic phenotype[25], targeting NRP2/WDFY1 axis can be an effective therapeutic strategy for metastatic cancer
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