NRP2 transcriptionally regulates its downstream effector WDFY1.
NRP2 transcriptionally regulates its downstream effector WDFY1.
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DOI：
10.1038/srep23588
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发表时间：
2016-03-30
影响因子：
4.6
通讯作者：
Datta K
中科院分区：
文献类型：
--
作者：
Dutta S;Roy S;Polavaram NS;Baretton GB;Muders MH;Batra S;Datta K
神经纤毛蛋白（NRP）是细胞表面糖蛋白，通常充当丛蛋白和VEGF家族受体的共受体。神经纤毛蛋白-2（NRP 2）是NRPs家族成员，被证明可调节癌细胞中的自噬和内吞运输，这一功能与其作为辅助受体的作用明显不同。WD Repeat and FYVE domain containing 1（WDFY 1）-蛋白质在NRP 2下游发挥此功能。我们的研究结果表明，NRP 2通过负调控其表达来维持WDFY 1的最佳浓度。由于WDFY 1的表达增加降低了内吞活性，因此在转移性癌细胞中维持WDFY 1水平对于维持高内吞活性至关重要，这对于促进致癌活化和癌细胞存活至关重要。在这里，我们描绘了NRP 2合成WDFY 1的潜在分子机制。我们的研究结果表明，NRP 2通过阻止转录因子Fetal ALZ 50-reactive clone 1（FAC 1）的核定位来抑制WDFY 1的转录。我们的发现是新颖的，因为以前没有报道过NRP 2轴对基因的转录调控。通过NRP 2轴调节WDFY 1转录是维持癌细胞转移表型的关键事件。因此，抑制NRP 2或过度激活WDFY 1可以是诱导转移性癌症中细胞死亡的有效策略。
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.