神经毡蛋白Neuropilin-2相关信号通路研究进展
Research Progress of Neuropeptin-2 Related Signaling Pathway
DOI: 10.12677/ACM.2023.131074, PDF,   
作者: 杨晓帆, 潘 浩, 杨光路*:内蒙古医科大学,内蒙古 呼和浩特
关键词: Neuropilin-2Sema3FVEGF信号通路神经系统肿瘤Neuropilin-2 Sema3F VEGF Signal Pathways Nervous System Tumor
摘要: 神经毡蛋白2 (Neuropilin-2, Npn-2)是Npn家族中重要成员之一,在神经系统中,Npn-2最初被认为是脑信号蛋白(Semaphorins, Sema)家族的受体,参与诱导轴突生长锥的塌陷,但随后研究发现,Npn-2也是血管内皮生长因子(VEGF)的受体,而血管内皮生长因子(VEGF)对神经元有营养作用,促进轴突的生长和迁移。此外,Npn-2还在其他疾病的发生发展中有突出作用,成为靶向治疗的热点。这篇综述着重于对近年Npn-2介导的信号通路进行一个系统的总结,其中一些神经系统外的信号通路可能给Npn-2在癫痫等神经系统疾病研究中提供思路和借鉴。
Abstract: Neuropilin-2 (Npn-2) is one of the important members of the Npn family. In the nervous system, Npn-2 was initially considered to be the receptor of the brain signal proteins (Semaphorins, Sema) family and involved in inducing the collapse of the axon growth cone. However, later studies found that Npn-2 is also the receptor of vascular endothelial growth factor (VEGF), which has a nutritional effect on neurons and promotes the growth and migration of axons. In addition, Npn-2 also plays a prominent role in the occurrence and development of other diseases, becoming a hot spot of tar-geted therapy. This review focuses on a systematic summary of the signal pathways mediated by Npn-2 in recent years. Some signal pathways outside the nervous system may provide ideas and references for Npn-2 in the study of epilepsy and other nervous system diseases.
文章引用:杨晓帆, 潘浩, 杨光路. 神经毡蛋白Neuropilin-2相关信号通路研究进展[J]. 临床医学进展, 2023, 13(1): 501-508. https://doi.org/10.12677/ACM.2023.131074

参考文献

[1] Nakamura, F. and Goshima, Y. (2002) Structural and Functional Relation of Neuropilins. In: Bagnard, D., Ed., Neuro-pilin: From Nervous System to Vascular and Tumor Biology, Springer, Berlin, 55-69. [Google Scholar] [CrossRef] [PubMed]
[2] Dhupar, R., Jones, K.E., Powers, A.A., et al. (2022) Isoforms of Neuropilin-2 Denote Unique Tumor-Associated Macrophages in Breast Cancer. Frontiers in Immunology, 13, Article ID: 830169. [Google Scholar] [CrossRef] [PubMed]
[3] Ni, Q., Sun, J.L., Ma C., et al. (2018) The Neuropilins and Their Ligands in Hematogenous Metastasis of Salivary Adenoid Cystic Carcinoma—An Immunohistochemical Study. Journal of Oral and Maxillofacial Surgery, 76, 569-579. [Google Scholar] [CrossRef] [PubMed]
[4] Dimou, A., Nasarre, C., Peterson, Y.K., et al. (2021) Neuro-pilin-2b Facilitates Resistance to Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. The Journal of Thoracic and Cardiovascular Surgery, 162, 463-473. [Google Scholar] [CrossRef] [PubMed]
[5] Wittmann, P., Grubinger, M., Gröger, C., et al. (2015) Neuro-pilin-2 Induced by Transforming Growth Factor-β Augments Migration of Hepatocellular Carcinoma Cells. BMC Cancer, 15, 909. [Google Scholar] [CrossRef] [PubMed]
[6] Takahashi, T., Nakamura, F., Jin, Z., et al. (1998) Semaphorins A and E Act as Antagonists of Neuropilin-1 and Agonists of Neuropilin-2 Receptors. Nature Neuroscience, 1, 487-493. [Google Scholar] [CrossRef] [PubMed]
[7] Siemerink, M.J., Klaassen, I., Vogels, I.M.C., et al. (2012) CD34 Marks Angio-genic Tip Cells in Human Vascular Endothelial Cell Cultures. Angiogenesis, 15, 151-163. [Google Scholar] [CrossRef] [PubMed]
[8] Alto, L.T. and Terman, J.R. (2017) Semaphorins and Their Sig-naling Mechanisms. Methods in Molecular Biology, 1493, 1-25. [Google Scholar] [CrossRef] [PubMed]
[9] Toledano, S., Nir-Zvi, I., Engelman, R., et al. (2019) Class-3 Semaphorins and Their Receptors: Potent Multifunctional Modulators of Tumor Progression. International Journal of Molecular Sciences, 20, 556. [Google Scholar] [CrossRef] [PubMed]
[10] Parker, M.W., Linkugel, A.D., Goel, H.L., et al. (2015) Structural Basis for VEGF-C Binding to Neuropilin-2 and Sequestration by a Soluble Splice Form. Structure, 23, 677-687. [Google Scholar] [CrossRef] [PubMed]
[11] Roy, S., Bag, A.K., Dutta, S., et al. (2018) Macrophage-Derived Neuropilin-2 Exhibits Novel Tumor-Promoting Functions. Cancer Research, 78, 5600-5617. [Google Scholar] [CrossRef
[12] Rizzolio, S., Battistini, C., Cagnoni, G., et al. (2018) Downregulating Neuropilin-2 Triggers a Novel Mechanism Enabling EGFR-Dependent Resistance to Onco-gene-Targeted Therapies. Cancer Research, 78, 1058-1068. [Google Scholar] [CrossRef
[13] Duncan, B.W., Mohan, V., Wade, S.D., et al. (2021) Sem-aphorin3F Drives Dendritic Spine Pruning through Rho- GTPase Signaling. Molecular Neurobiology, 58, 3817-3834. [Google Scholar] [CrossRef] [PubMed]
[14] Li, Y., Tong, F.C., Zhang, Y.Y., et al. (2022) Neuropilin-2 Sig-naling Modulates Mossy Fiber Sprouting by Regulating Axon Collateral Formation Through CRMP2 in a Rat Model of Epilepsy. Molecular Neurobiology, 59, 6817-6833. [Google Scholar] [CrossRef] [PubMed]
[15] Gao, X., Mao, Y.-H., Xiao, C.T., et al. (2018) Calpain-2 Trig-gers Prostate Cancer Metastasis via Enhancing CRMP4 Promoter Methylation through NF-κB/DNMT1 Signaling Path-way. Prostate, 78, 682-690. [Google Scholar] [CrossRef] [PubMed]
[16] Watterston, C., Halabi, R., McFarlane, S. and Childs, S.J. (2021) Endothe-lial Semaphorin 3fb Regulates Vegf Pathway-Mediated Angiogenic Sprouting. PLOS Genetics, 17, e1009769. [Google Scholar] [CrossRef] [PubMed]
[17] Karolak, J.A., Gambin, T., Szafranski, P., et al. (2021) Pertur-bation of Semaphorin and VEGF Signaling in ACDMPV Lungs Due to FOXF1 Deficiency. Respiratory Research, 22, 212. [Google Scholar] [CrossRef] [PubMed]
[18] Yang, Y., Zhang, B., Yang, Y.F., et al. (2022) FOXM1 Accelerates Wound Healing in Diabetic Foot Ulcer by Inducing M2 Macrophage Polarization through a Mechanism In-volving SEMA3C/NRP2/Hedgehog Signaling. Diabetes Research and Clinical Practice, 184, Article ID: 109121. [Google Scholar] [CrossRef] [PubMed]
[19] Kong, D., Zhou, H.B., Neelakantan, D., et al. (2021) VEGF-C Mediates Tumor Growth and Metastasis through Promoting EMT-Epithelial Breast Cancer Cell Crosstalk. Oncogene, 40, 964-979. [Google Scholar] [CrossRef] [PubMed]
[20] Goel, H.L., Pursell, B., Chang, C., et al. (2013) GLI1 Regulates a Novel Neuropilin-2/α6β1 Integrin Based Autocrine Pathway That Contributes to Breast Cancer Initiation. EMBO Mo-lecular Medicine, 5, 488-508. [Google Scholar] [CrossRef] [PubMed]
[21] Elaimy, A.L., Amante, J.J., Zhu, L., et al. (2019) The VEGF Re-ceptor Neuropilin 2 Promotes Homologous Recombination by Stimulating YAP/TAZ-Mediated Rad51 Expression. Pro-ceedings of the National Academy of Sciences of the United States of America, 116, 14174-14180. [Google Scholar] [CrossRef] [PubMed]
[22] Po, A., Silvano, M., Miele, E., et al. (2017) Noncanonical GLI1 Signaling Promotes Stemness Features and in Vivo Growth in Lung Adenocarcinoma. Oncogene, 36, 4641-4652. [Google Scholar] [CrossRef] [PubMed]
[23] Luo, X., He, J.-Y., Xu, J., et al. (2020) Vascular NRP2 Triggers PNET Angiogenesis by Activating the SSH1-Cofilin Axis. Cell & Bioscience, 10, 113. [Google Scholar] [CrossRef] [PubMed]
[24] Wang, J., Li, J.J., Yin, L.J., et al. (2022) Neuropilin-2 Promotes Lineage Plasticity and Progression to Neuroendocrine Prostate Cancer. Oncogene, 41, 4307-4317. [Google Scholar] [CrossRef] [PubMed]
[25] Marimuthu, S., Lakshmanan, I., Muniyan, S., et al. (2022) MUC16 Promotes Liver Metastasis of Pancreatic Ductal Adenocarcinoma by Upregulating NRP2-Associated Cell Ad-hesion. Molecular Cancer Research, 20, 1208-1221. [Google Scholar] [CrossRef
[26] Lee, G., Kang, Y.E., Oh, C., et al. (2020) Neuropilin-2 Promotes Growth and Progression of Papillary Thyroid Cancer Cells. Auris Nasus Larynx, 47, 870-880. [Google Scholar] [CrossRef] [PubMed]
[27] Chang, X., Yang, Q., Zhang, C.H., et al. (2019) Roles for VEGF-C/NRP-2 Axis in Regulating Renal Tubular Epithelial Cell Survival and Autophagy during Serum Deprivation. Cell Biochemistry and Function, 37, 290-300. [Google Scholar] [CrossRef] [PubMed]
[28] Chi, J., Wang, L., Zhang, X.H., et al. (2018) Cyclosporin A Induces Au-tophagy in Cardiac Fibroblasts through the NRP-2/WDFY-1 Axis. Biochimie, 148, 55-62. [Google Scholar] [CrossRef] [PubMed]
[29] Schulz, A., Gorodetska, I., Behrendt, R., et al. (2019) Linking NRP2 with EMT and Chemoradioresistance in Bladder Cancer. Frontiers in Oncology, 9, 1461. [Google Scholar] [CrossRef] [PubMed]
[30] Gemmill, R.M., Nasarre, P., Nair-Menon, J., et al. (2017) The Neu-ropilin 2 Isoform NRP2b Uniquely Supports TGFβ- Mediated Progression in Lung Cancer. Science Signaling, 10, eaag0528. [Google Scholar] [CrossRef] [PubMed]
[31] Poghosyan, S., Frenkel, N., Lentzas, A., et al. (2022) Loss of Neuropilin-2 in Murine Mesenchymal-Like Colon Cancer Organoids Causes Mesenchymal-to-Epithelial Transi-tion and an Acquired Dependency on Insulin-Receptor Signaling and Autophagy. Cancers (Basel), 14, 671. [Google Scholar] [CrossRef] [PubMed]
[32] Yang, E., Tacchelly-Benites, O., Wang, Z.H., et al. (2016) WNT Pathway Activation by ADP-Ribosylation. Nature Communications, 7, Article No. 11430. [Google Scholar] [CrossRef] [PubMed]
[33] Kang, Y., Zhang, Y.Y., Zhang, Y. and Sun, Y. (2021) NRP2, a Poten-tial Biomarker for Oral Squamous Cell Carcinoma. American Journal of Translational Research, 13, 8938.
[34] Goel, H.L., Pursell, B., Standley, C., et al. (2012) Neuropilin-2 Regulates α6β1 Integrin in the Formation of Focal Adhesions and Signaling. Journal of Cell Science, 125, 497-506. [Google Scholar] [CrossRef] [PubMed]
[35] Guo, Y., Zhang, Q., Chen, H.L., et al. (2019) Overexpression of Calcitonin Gene-Related Peptide Protects Mouse Cerebral Microvascular Endothelial Cells from High-Glucose-Induced Damage via ERK/HIF-1/VEGF Signaling. Journal of Physiological Sci-ences, 69, 939-952. [Google Scholar] [CrossRef] [PubMed]
[36] Wang, L., Wang, L.L., Wang, S.Y., et al. (2021) N2E4, a Monoclonal Antibody Targeting Neuropilin-2, Inhibits Tumor Growth and Metastasis in Pancreatic Ductal Adenocarcinoma via Suppressing FAK/Erk/HIF-1alpha Signaling. Frontiers in Oncology, 11, Article ID: 657008. [Google Scholar] [CrossRef] [PubMed]
[37] Wang, M., Li, C.L., Cai, T.Z., et al. (2022) Circ_CHFR Promotes Platelet-Derived Growth Factor-BB-Induced Proliferation, Invasion, and Migration in Vascular Smooth Muscle Cells via the miR-149-5p/NRP2 Axis. Journal of Cardiovascular Pharmacology, 79, e94-e102. [Google Scholar] [CrossRef
[38] Peng, H., Liu, S.F., Li, Y., et al. (2022) A Novel cir-cUBR4/miR-491-5p/NRP2 ceRNA Network Regulates Oxidized Low-Density Lipoprotein-induced Proliferation and Migration in Vascular Smooth Muscle Cells. Journal of Cardiovascular Pharmacology, 79, 512-522. [Google Scholar] [CrossRef
[39] Xie, Z., Liu, S., Chu, S.C., Liu, Y.Q., et al. (2021) lncRNA RMRP Predicts Poor Prognosis and Mediates Tumor Progression of Esophageal Squamous Cell Carcinoma by Regulat-ing miR-613/Neuropilin 2 (NRP2) Axis. Bioengineered, 12, 6913-6922. [Google Scholar] [CrossRef] [PubMed]
[40] Wang, Y., Yin, H. and Chen, X. (2021) Circ-LDLRAD3 Enhances Cell Growth, Migration, and Invasion and Inhibits Apoptosis by Regulating MiR-224-5p/NRP2 Axis in Gas-tric Cancer. Digestive Diseases and Sciences, 66, 3862-3871. [Google Scholar] [CrossRef] [PubMed]
[41] Liu, A., Liu, L. and Lu, H. (2019) LncRNA XIST Facilitates Proliferation and Epithelial-Mesenchymal Transition of Colorectal Cancer Cells through Targeting miR-486-5p and Pro-moting Neuropilin-2. Journal of Cellular Physiology, 234, 13747-13761. [Google Scholar] [CrossRef] [PubMed]
[42] Zhao, M., Zhang, M.M., Tao, Z.H., et al. (2020) miR-331-3p Suppresses Cell Proliferation in TNBC Cells by Downregulating NRP2. Technology in Cancer Research and Treatment, 19. [Google Scholar] [CrossRef] [PubMed]
[43] Li, P., Zeng, Y., Chen, Y.D., et al. (2022) LRP11-AS1 Promotes the Proliferation and Migration of Triple Negative Breast Cancer Cells via the miR-149-3p/NRP2 Axis. Cancer Cell In-ternational, 22, 116. [Google Scholar] [CrossRef] [PubMed]