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Advances in Clinical Medicine
Vol. 13  No. 01 ( 2023 ), Article ID: 60585 , 8 pages
10.12677/ACM.2023.131074

神经毡蛋白Neuropilin-2相关信号通路 研究进展

杨晓帆，潘浩，杨光路*

内蒙古医科大学，内蒙古 呼和浩特

收稿日期：2022年12月19日；录用日期：2023年1月11日；发布日期：2023年1月28日

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。

关键词

Neuropilin-2，Sema3F，VEGF，信号通路，神经系统，肿瘤

Research Progress of Neuropeptin-2 Related Signaling Pathway

Xiaofan Yang, Hao Pan, Guanglu Yang*

Inner Mongolia Medical University, Hohhot Inner Mongolia

Received: Dec. 19th, 2022; accepted: Jan. 11th, 2023; published: Jan. 28th, 2023

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 targeted 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.

Keywords:Neuropilin-2, Sema3F, VEGF, Signal Pathways, Nervous System, Tumor

Copyright © 2023 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

Figure 1. Structure model diagram of Npn-2

图1. Npn-2结构模型图

Neuropilin-2 (Npn-2)是进化上保守的单次跨膜糖蛋白共受体，在成年脊椎动物中有广泛的组织分布。Npn家族包括Npn-1和Npn-2，Npn-2包括Npn-2a，Npn-2b，以及替代剪接产生的分泌形式(Npn-2a22, Npn-2a17, Npn-2a0, Npn-2b5, Npn-2b0和S9Npn-2) [1]。根据环境刺激和独立信号通路的选择性上调，赋予了Npn-2a和Npn-2b各自独特的功能 [2] [3] [4]。

Npn-2有五个结构域，细胞外的结构包括CUB结构域(a1和a2，补体结合同源性)、FV/FVIII结构域(b1和b2，凝血因子V/VIII同源性)和MAM结构域(c，跨膜肽酶、A-5蛋白和受体蛋白酪氨酸磷酸酶mu)，以及跨膜区结构域和短胞质区结构域 [5]。其中，a1、a2结合Sema3F和PlexinA3参与调节神经元中的轴突引导，b1、b2与各种VEGF结合参与血管和淋巴管的生成 [6] [7]。细胞质尾部包含一个PDZ结构域结合基序，该基序负责结合GIPC1，即Sema家族第7类蛋白——糖基磷脂酰肌醇(Glycosyl Phosphatidylinositol, GPI)连接蛋白 [8] [9]，它连接Npns和肌球蛋白6驱动的细胞转运机制，用于内吞运输并激活小GTPase激活蛋白 [10] [11]。Npn-1和Npn-2a的信号受羧基末端PDZ结合基序的调控，其与PDZ结构域因子如GIPC (RGS-GAIP相互作用蛋白)关联，而Npn-2b的胞质结构域与GS3Kβ相互作用，独立介导通路 [12]。见图1。

Figure 2. Npn-2 related signal path model diagram

图2. Npn-2相关信号通路模型图

2. Sema/Npn-2相关信号通路

Sema/Npn-2有关信号通路主要体现在轴突修剪中，有研究确定了Sema与全受体复合物(免疫球蛋白类粘附分子NrCAM、Npn-2和PlexinA3)结合后诱导树突棘中小GTPases Rac1 (Rac1-PAK1-3-LIMK1/2-Cofilin1)和RhoA (RhoA-ROCK1/2-Myosin II)双重信号级联通路的激活 [13]。在癫痫大鼠模型中，Npn-2信号通过CRMP2调节轴突侧支形成来调节苔藓纤维发芽。Sema3F/Npn-2信号下调CRMP2磷酸化，从而削弱CRMP2促进轴突侧枝形成和伸长的功能 [14]。另外，前列腺癌研究中发现CRMP4通过Sema3B/Npn-2信号抑制VEGF-C的表达而表现出抗转移作用 [15]。

在缺血性视网膜病研究中证明了HIF-2α在缺氧条件下直接调节EC中的Sema3G转录。Sema3G通过Npn-2/PlexinD1受体增加内皮细胞中的β-catenin，从而协调β-catenin和VE-cadherin之间的相互作用。此外，补充Sema3G可增强健康血管网络的形成，并促进血管重塑过程中患病的血管系统消退 [16]。

在过表达FOXF1的小鼠E18.5肺中进行了一项ChIP-seq分析，结果显示具有各种FOXF1异常的肺泡毛细血管发育不良伴肺静脉错位(ACDMPV)患者中Semas、Plxns和Npns水平失调，该分析揭示了FOXF1与其基因座的直接相互作用，意味着SHH/FOXF1和Sema/Npn信号通路之间存在潜在的相互作用 [17]。此外，在糖尿病足的一项研究中发现FOXM1通过涉及Sema3C/Npn-2/Hedgehog信号传导的机制诱导M2巨噬细胞极化，从而加速糖尿病足溃疡的伤口愈合 [18]。

3. VEGF/Npn-2相关信号通路

3.1. VEGF/Npn-2/GLI轴

在乳腺癌研究中发现VEGF/Npn-2与GLI通路相关。研究中表明VEGF-C/Npn-2/GLI轴是一种新的保守的旁分泌方式，VEGF-C通过促进上皮性乳腺癌细胞上皮向间质转化(EMT)来促进肿瘤生长和转移。这里表达Six1的EMT细胞通过增加VEGF-C的产生激活上皮癌细胞中的GLI信号 [19]。在三阴性乳腺癌(Triple Negative Breast Cancer, TNBC)中，也表明了Npn-2与GLI信号通路有关，VEGF-A/Npn-2轴被证明以自分泌方式激活GLI1信号 [20]。Rad51是HR 途径中介导有效的DNA双链断裂修复的必需酶，VEGF/Npn-2促进Rad51的表达和BRCA1野生型TNBC细胞中的同源重组(HR)，提供了VEGF/Npn-2刺激YAP/TAZ依赖性Rad51表达的证据，并且Rad51是直接的YAP/TAZ-TEAD转录靶标 [21]。西尔瓦诺等人在肺腺癌细胞研究中发现，Npn-2通过基质介导的VEGF-A刺激上调HH/GLI信号实现肿瘤的转移 [22]。

3.2. VEGF/Npn-2/SHH轴

胰腺神经内分泌肿瘤(PNETs)研究中发现，血管生成是PNET生长的关键步骤，这里Npn-2与血管密度呈正相关，Npn-2通过独立于VEGF/VEGFR2的途径促进在条件培养基PNET中培养的人脐静脉内皮细胞(HUVECs)的迁移，VEGF结合Npn-2后通过激活SSH1/cofilin/actin轴促进PNET血管生成，是PNET抗血管生成治疗的潜在靶点 [23]。

3.3. VEGF/Npn-2/JAK/STAT轴

在神经内分泌前列腺癌(NEPC)中，Npn-2通过细胞内SEA结构域与VEGFR2物理相互作用，激活STAT3磷酸化，随后激活SOX2，从而驱动NEPC分化和生长 [24]。胰腺导管腺癌(PDAC)研究中发现，MUC16通过介导JAK2/STAT1轴调节Npn-2，在PDAC肝转移中发挥关键作用 [25]。

3.4. VEGF/Npn-2/AKT/ERK轴

GO分析显示，Npn-2与几种已知的甲状腺癌相关信号通路之间存在显著关联，包括VEGF激活受体活性的正调节、ERK的正向调节。Npn-2可以促进乳头状甲状腺癌细胞的生长和进展，敲除Npn-2后，使用蛋白质印迹分析研究了AKT、磷酸化-AKT、ERK 和磷酸化-ERK的表达，结果表明Npn-2可以激活PTC中AKT和ERK的下游信号通路，从而影响PTC的进展 [26]。

3.5. VEGF-C/Npn-2介导细胞自噬有关信号通路

近来研究发现VEGF-C/Npn-2轴还与细胞自噬相关，VEGF-C/Npn-2轴在血清剥夺过程中有调节肾小管上皮细胞存活和自噬的作用，该信号轴可能通过调节细胞中4EBP1和P70S6K的磷酸化来介导自噬 [27]。然而Chi等人发现，环孢菌素A通过Npn-2/WDFY-1轴诱导心脏成纤维细胞自噬，促进心肌纤维化的进展 [28]。

4. Npn-2/TGFβ相关信号通路

一项膀胱癌研究中发现Npn-2与TGFβ1结合后与TGFβ受体结合，增强TGFβ1信号通路，在Npn-2敲除模型中的靶点验证显示，分泌的磷酸蛋白1 (SPP1/OPN/Osteopontin)是受Npn-2正调控的下游靶点 [29]。

最近，在肺癌细胞中证明Npn-2的促肿瘤活性主要存在于Npn-2b亚型中，Npn-2b在TGFβ诱导的上皮间质转化(EMT)过程中上调，通过受体酪氨酸激酶(包括VEGFRs、MET和PDGFR)促进AKT信号的增加。从机制上讲，Npn-2b通过募集RTKs和GSK3β促进向AKT发送的信号。但AKT募集PTEN可以被Npn-2a抑制，迅速熄灭AKT的活性 [4] [30] [31]。

5. Npn-2/Wnt/β-catenin相关通路

在生理状态下Wnt/β-catenin信号通路指导的基本过程是后生动物发育和组织稳态 [32]。

然而口腔鳞癌研究中发现Npn-2通过下调Wnt/β-catenin通路起到肿瘤启动子的作用，从而影响口腔鳞癌细胞的增殖、迁移和侵袭。研究中抑制Npn-2在SCC-25细胞系中的表达后，β-catenin、C-myc、cyclin-D1和MMP-2的表达水平降低 [33]。

6. Npn-2/整合素相关信号通路

在癌细胞转移中细胞骨架决定的细胞刚度变化是决定癌细胞转移能力的一个关键。邹等人发现Npn-2参与肌动蛋白细胞骨架重塑中VEGF对α6β1/FAK/ERK 通路的激活来降低细胞刚度，增强间充质干细胞的迁移。这α6β1整合素与细胞骨架的结合，是层粘连形成的必要条件，而Npn-2是α6β1整合素与细胞骨架结合所必需的，并且还促进整合素α6β1介导的FAK激活。此外，Npn-2调节α6β1整合素与层粘连蛋白相互作用形成局灶性粘连的机制与PKC活化有关 [20] [34]。

在最新胰导管腺癌(PDAC)治疗中，一种针对Npn-2的靶向单克隆抗体N2E4，主要是通过阻断Npn-2与整合素β1的相互作用，从而抑制FAK/ERK/HIF-1a/VEGF信号通路有关，最终抑制胰腺导管腺癌的肿瘤生长和转移。这里ERK级联不仅被认为主要与癌细胞增殖、存活和肌动蛋白重构相关，而且还上调了缺氧诱导因子-1 (HIF-1)和VEGF的表达 [35] [36]。

7. RNA/Npn-2相关信号轴

动脉粥样硬化研究中发现Circ-CHFR通过miR-149-5p/Npn-2轴促进PDGF-BB诱导的血管平滑肌细胞的增殖、侵袭和迁移 [37]。一种新的circUBR4/miR-491-5p/Npn-2 ceRNA网络调节氧化低密度脂蛋白诱导的血管平滑肌细胞增殖和迁移，此外，Npn-2是miR-491-5p调节ox-LDL诱发的VSMC增殖和迁移的功能性下游效应子 [38]。

在消化系统肿瘤研究中发现，lncRNA RMRP通过调节miR-613/Npn-2轴预测食管鳞状细胞癌的不良预后并介导肿瘤进展 [39]。Circ-LDLRAD3通过调节胃癌中的miR-224-5p/Npn-2轴增强细胞生长、迁移和侵袭并抑制细胞凋亡 [40]。长链非编码RNA(lncRNA)XIST/miR-486-5p/Npn-2通路可促进结直肠癌细胞增殖和上皮–间质转化 [41]。

乳腺癌研究中发现了miR-331-3p/Npn-2信号调节三阴性乳腺癌细胞的恶性行为 [42]。近年又发现LRP11-AS1通过miR-149-3p/ Npn-2轴促进了三阴性乳腺癌细胞增殖和迁移 [43]。

8. 总结与展望

综上，我们发现尽管Npn-2缺乏信号转导的激酶结构域，但通过捕获配体、调节生长因子表达、内吞作用以及独立信号传导来调节细胞反应，Npn-2的多功能性使其与多种信号通路相关，如图2。目前Npn-2相关信号通路的研究还是在肿瘤研究中居多，近年更多领域也在尝试有关Npn-2的研究，这些信号通路可以为神经系统或其他系统疾病机制研究、靶向治疗提供一些参考价值。

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
Research Progress of Neuropeptin-2 Related Signaling Pathway[J]. 临床医学进展, 2023, 13(01): 501-508. https://doi.org/10.12677/ACM.2023.131074

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    44. NOTES

    *通讯作者。

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