动物营养学报    2022, Vol. 34 Issue (7): 4200-4212    PDF    
调控Hippo通路的因子及其研究方法
覃怡琅1 , 王佳堃1 , 杨斌2     
1. 浙江大学奶业科学研究所, 杭州 310013;
2. 浙江科技学院生物与化学工程学院, 杭州 310023
摘要: Hippo通路是由核心激酶、效应因子、辅助因子和转录因子共同组成的激酶级联反应链,调控细胞的生长、代谢和信号转导等重要过程。跨膜蛋白、机械信号、G蛋白偶联受体、营养素等均能调控Hippo通路。通过条件性小鼠敲除模型和使用靶向性化学制剂,研究人员发现姜黄素、叶酸、白藜芦醇等通过Hippo通路发挥调控细胞发育的作用,即Hippo信号通路在营养素调控动物生长方面扮演重要角色。为此本文对Hippo通路的组成、作用模式、调控因子和目前的研究方法进行综述,以期为Hippo通路在畜牧生产上的研究提供支持。
关键词: Hippo通路    作用模式    调控因子    小鼠模型    化学制剂    
Factors for Regulating Hippo Pathway and Their Research Methods
QIN Yilang1 , WANG Jiakun1 , YANG Bin2     
1. Institute of Dairy Science, Zhejiang University, Hangzhou 310013, China;
2. School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310023, China
Abstract: The Hippo pathway is a kinase cascade reaction chain composed of core kinases, effectors, cofactors, and transcription factors, which regulates important processes such as cell growth, metabolism, and signal transduction. Factors including transmembrane proteins, mechanical signals, G protein-coupled receptors and nutrients are involved in the regulation of Hippo pathway. Using the conditional mouse knockout models and specific chemical agents, some nutritive substances including curcumin, folic acid and resveratrol are reposted to regulate cell development through the Hippo pathway. Thus, the Hippo signaling pathway can play an important role in nutrient regulation of animal growth. In the present paper, we reviewed the composition, mode of action, regulatory factors and current research methods of the Hippo pathway, in order to provide support for the research on the Hippo pathway in animal husbandry production.
Key words: Hippo pathway    mode of action    regulatory factors    mouse model    chemical agents    

与大多数依赖配体和受体结合发挥作用的通路不同,Hippo通路是由核心激酶、效应因子、辅助因子和转录因子共同组成的激酶级联反应,调控细胞增殖分化、黏附和细胞代谢等生理过程。除跨膜蛋白、机械信号和细胞代谢产物等调控Hippo通路外,姜黄素、胆碱、白藜芦醇等营养素也能调控Hippo通路,提示Hippo通路可能是一些营养素发挥促畜禽生长发育作用的核心通路。因此,本文对Hippo通路的组成及作用模式、调控Hippo通路的各类因子和研究Hippo的试验方法进行综述,以期为利用Hippo通路进行营养干预提供理论依据和技术支持。

1 Hippo通路的组成和作用模式

在哺乳动物体内,Hippo通路高度保守,如表 1所示,它由核心激酶、效应因子、辅助因子和转录因子共同组成。经典的Hippo通路核心激酶由哺乳动物STE-20样激酶1/2(mammalian STE20-like kinases 1/2,MST1/2)、Salvador同系物1(Salvador homolog 1,SAV1)、大肿瘤抑制因子1/2(large tumor suppressor kinase 1/2,LATS1/2)和MOB激酶激活因子1A/B(MOB kinase activator 1A/B,MOB1A/B)共同构成[1]。丝裂原活化蛋白激酶激酶激酶激酶(mitogen-activated protein kinase kinase kinase kinases,MAP4K)和核DBF2相关激酶1/2(nuclear DBF2-related 1/2,NDR1/2)是Hippo通路核心激酶的新增成员[2-3]。Yes相关蛋白(Yes-associated protein,YAP)和具有PDZ结合基序的转录共激活因子(transcriptional co-activator with PDZ-binding motif,TAZ)是Hippo通路的效应因子[1-3],14-3-3接头蛋白是调控YAP/TAZ核质定位的重要辅助因子[1-3]。转录增强缔合域蛋白(transcriptional enhanced associate domain,TEAD)是哺乳动物体内与YAP结合的主要转录因子[1-3]

表 1 Hippo通路的组分及其功能 Table 1 Components and functions of Hippo pathway

Hippo通路是一条激酶级联反应链。当Hippo通路被激活,MAP4K、MST1/2和SAV1共同磷酸化并激活下游的NDR1/2、LATS1/2和MOB1A/B[2-3]。活化的NDR1/2和LATS1/2进一步磷酸化YAP/TAZ[2-3],磷酸化的YAP/TAZ或者与14-3-3接头蛋白结合滞留胞质[1-3],或者在胞质中被泛素化降解[1-3]。反之,当Hippo通路失活,未磷酸化的YAP/TAZ进入细胞核,结合不同的转录因子,驱动下游基因转录,调控细胞的发育。

TEAD是YAP的主要转录伙伴[1-3]。YAP-TEAD转录模块可以激活富半胱氨酸61(cystein rich 61,CYR61)、含杆状病毒IAP重复蛋白5(baculoviral IAP repeat containing 5,BIRC5)、FOS样抗原1(FOS like antigen 1,FOSL1)、双调蛋白(amphiregulin,AREG)、肝素结合性表皮生长因子(heparin-binding EGF-like growth factor,HBEGF)和细胞周期蛋白D1(cyclin D1,CCND1)等调控细胞增殖分化、上皮间质转化、血管生成、细胞代谢、纤维发生和信号转导等[4-8]过程。NKX同源框-1(NK2 homeobox1,NKX2-1)、核小体改构复合体(nucleosome remodeling complex,NURD)、c-Jun氨基端激酶(c-Jun N-terminal kinase,JNK)和钙调蛋白结合转录激活因子1(calmodulin binding transcription activator 1,CAMTA1)是辅助TEAD转录的调节因子。YAP可结合TEAD/NKX2-1转录复合物调控肺的分化[9];结合TEAD/NURD维持细胞的生长和存活[10];结合TEAD/JNK调控细胞代谢[11];结合TEAD/CAMTA1促进血管生成[12]。YAP还可直接结合p73[13]、p63[14]、Myb-MuvB复合物(Myb-MuvB complex,MMB)[15]、配对盒因子3(paired box gene 3,PAX3)[16]、干扰素调节因子3(interferon regulatory factor 3,IRF3)[17]、Runt相关转录因子2(Runt-related transcription factor 2,RUNX2)[18]或T细胞因子/淋巴增强子结合因子(T-cell factor/lymphoid enhancer-binding factor,TCF/LEF)[19]调控细胞的增殖分化。YAP能结合短尾畸形(brachyury)蛋白调控细胞周期和维持细胞干性[20];结合Smad2/3蛋白[21]或T-box转录因子5(T-box transcription factor,TBX5)[22]调控纤维发生;结合磷酸化Jun氨基端激酶(phosphorylated Jun N-terminal kinases,pJNK)调控炎性因子表达[23];结合Krüppel样因子4(krüppel-like factor 4,KLF4)调控细胞黏附[24];结合叉头盒转录因子1(forkhead box O1,FOXO1)调控细胞死亡[25];结合p53转录因子调控细胞存活[26]

2 调控YAP/TAZ转录的因子

YAP/TAZ是Hippo通路的关键因子,必须入核才能驱动下游基因转录,使Hippo通路发挥作用。跨膜蛋白、机械信号和G蛋白偶联受体(G-protein-coupled receptors,GPCR)等通过调控Hippo通路核心激酶活性,影响YAP/TAZ转录;蛋白磷酸酶1(protein phosphatase 1,PP1)、Nemo样激酶(nemo-like kinases,NLK)和血影蛋白(spectrin)等可以直接调控YAP/TAZ转录。

2.1 依赖Hippo通路核心激酶调控YAP/TAZ转录的因子

SCRIB极性蛋白(scribble,SCRIB)、TAO激酶(thousand and one kinases,TAOKs)和棕榈酸(palmitic acid,PA)等通过激活Hippo通路,诱导核心激酶磷酸化,抑制YAP/TAZ入核转录;纹状蛋白相互作用的磷酸酶和激酶复合物(striatin-interacting phosphatases and kinases,STRIPAK)、机械信号和代谢产物等通过抑制核心激酶活性,促进YAP/TAZ入核转录;Ras相关结构域家族蛋白(Ras association domain family,RASSFs)、受体酪氨酸激酶(receptor tyrosine kinase,RTK)和GPCR双向调控Hippo通路核心激酶,影响YAP/TAZ的核质定位。

2.1.1 激活Hippo通路的因子

SCRIB可结合并激活MST1/2和LATS1/2[27]。肾脑蛋白(kidney and brain protein,KIBRA)、神经纤维蛋白2(neurofibromin 2,NF2)和FERM结构域蛋白6(FERM domain containing protein 6,FRMD6)组成复合物,与MST1/2和SAV1结合,促进LATS1/2磷酸化[28];Crumbs跨膜蛋白(CRBs)可结合KIBRA/NF2/FRMD6复合物,协同激活Hippo通路[29]。NF2也可直接诱导MST1/2和LATS1/2磷酸化,独立激活Hippo通路[30]。TAOKs可直接诱导MST1/2磷酸化,也可绕过MST1/2激酶,直接磷酸化LATS1/2[31]。非受体蛋白酪氨酸磷酸酶14(protein tyrosine phosphatase non-receptor type 14,PTPN14)可直接激活LATS1或与KIBRA互作协同激活LATS1[32]。PA可诱导MST1表达和磷酸化[33],激活Hippo通路。

2.1.2 抑制Hippo通路的因子

STRIPAK超蛋白复合物、机械信号、葡萄糖(glucose,Glu)、氨基酸(amino acid,AA)、冠状动脉疾病相关连接蛋白(junctional protein-associated with coro-nary artery diseas,JCAD)、环状RNA PPP1R12A编码的小肽(circPPP1R12A-73aa)、B淋巴瘤Mo-MLV插入蛋白1(B lymphoma Mo-MLV insertion region 1,BMI1)、纤毛相关蛋白4(nephronophthisis 4,NPHP4)和盐诱导激酶2(salt-inducible kinase 2,SIK2)可抑制Hippo通路核心激酶的活性或表达。STRIPAK的成员纹状蛋白3(striatin 3,STRN3)、肌纤维膜结合蛋白(sarcolemmal membrane-associated protein,SLMAP)、蛋白磷酸酶2A(protein phosphatase 2A,PP2A)和丝氨酸/苏氨酸激酶25(serine/threonine kinase 25,STK25)协同抑制MST1/2的磷酸化[34];另一成员纹状蛋白4(striatin 4,STRN4)则会抑制MAP4K的磷酸化[35]。Ras同源基因家族成员A(Ras homolog gene family member A,RhoA)可感知细胞剪切力和胞外基质硬度等复杂的机械信号,重塑肌动蛋白(F-actin),抑制LATS1磷酸化[36]。代谢产物Glu和AA可抑制MST1/2激酶活性[37]。JCAD和BMI1能抑制LATS1/2磷酸化[38-39]。NPHP4可与LAST1共沉淀以下调LAST1表达[40],circPPP1R12A-73aa会下调MST1和LAST1的表达[41]。SAV1通过Ser168位点的磷酸化诱导YAP磷酸化,SIK2可磷酸化SAV1的Ser413位点,拮抗Ser168位点的磷酸化,抑制Hippo通路[42]

2.1.3 双向调控Hippo通路的因子

RASSFs、RTK和GPCR可双向调控Hippo通路。RASSF1A和RASSF5可激活MST1/2,而RASSF6会抑制MST1/2活性[43]。RTK和GPCR靶向LATS1/2激酶。大多数RTK会抑制LATS1/2活性,促进YAP/TAZ核内转录;但其相关配体或受体如酪氨酸激酶受体4(receptor tyrosine protein kinase 4,ERBB4)、Mer酪氨酸激酶(Mer tyrosine kinase,MerTK)、成纤维细胞生长因子2(fibroblast growth factor 2,FGFR2)和血管内皮细胞生长因子受体1(vascular endothelial growth factor receptor 1,VEGFR1)却能同时激活LATS1/2和促进YAP/TAZ核内转录[44]。与G12/13偶联受体(G12/13-coupled receptors,G12/13)或与Gq/11偶联受体(Gq/11-coupled receptors,Gq/11)结合的因子会抑制LATS1/2激酶活性,而与Gs偶联受体(Gs-coupled receptors,Gs)结合的因子会激活LATS1/2激酶活性[45]

2.2 独立于Hippo通路核心激酶调控YAP/TAZ转录的因子

PP1A、NLK和酰基甘油激酶(acylglycerol kinase,AGK)等可不依赖Hippo通路直接促进YAP/TAZ入核转录;血管动蛋白(angiomotin,AMOT)、E-钙黏蛋白(E-cadherin)、β-内酰胺酶(β-lactamase,LACTB)和色素框蛋白7(chromobox7,CBX7)等可不依赖Hippo通路直接抑制YAP/TAZ入核转录。

2.2.1 促进YAP/TAZ转录的因子

YAP通过磷酸化的Ser127位点与14-3-3接头蛋白结合,滞留胞质。PP1A可使YAP的Ser127位点去磷酸化[46];NLK通过磷酸化YAP的Ser128位点,拮抗Ser127位点的磷酸化,解离YAP与14-3-3,促进YAP核易位[37]。AGK不仅能促进YAP核定位,还可与YAP形成正反馈回路,抑制LATS1/2表达[47]。骨形态发生蛋白2(bone morphogenetic protein 2,BMP2)会促进YAP核易位[48],骨形态发生蛋白6(bone morphogenetic protein 6,BMP6)可促进TAZ核定位[49]。Mastermind样蛋白1和2(Mastermind-like 1 and 2,MAML1/2)可同时促进YAP和TAZ的核定位,并形成稳定的MAML/YAP/TAZ核内复合物[50]。由髓锌指蛋白1(myeloid zinc finger 1,MZF1)和GA结合蛋白(GA binding protein,GABP)形成的转录因子复合物以及细胞周期蛋白依赖性激酶7(cyclin-dependent kinase 7,CDK7)都可促进YAP表达,并增强YAP核内表达的稳定性[51-52]

2.2.2 抑制YAP/TAZ转录的因子

AMOT、E-cadherin、闭锁小带蛋白-2(zonula occludens protein-2,ZO-2)和α-连环蛋白(α-catenin)通过把YAP阻滞在紧密连接或黏附连接处[53-54],抑制YAP入核;Spectrin通过调节皮质肌动球蛋白活性影响YAP的核质定位[55-56]。LACTB通过加强自身与PP1A结合来减弱PP1A对YAP的去磷酸化[46]。CBX7和应激诱导蛋白Sestrin2能抑制YAP核定位[57-58]。TEAD是YAP的主要转录因子,一些转录抑制因子,如退变样蛋白4(vestigial-like family member 4,VGLL4)[59]、前mRNA加工因子4激酶(pre-mRNA processing factor 4 kinase,PRP4K)[60]和CCAAT/增强子结合蛋白α基因(CCAAT/enhancer binding protein α gene,C/EBPα)[61]可竞争性结合TEAD,抑制YAP转录。

3 研究Hippo通路的方法

构建条件性小鼠敲除模型和应用化学制剂是目前研究Hippo通路的2种常用试验方法。

3.1 Hippo通路的条件性小鼠敲除模型

近交系小鼠C57BL/6是目前构建Hippo通路基因敲除模型的基础品系。基于C57BL/6小鼠,研究者已成功构建了全身性MST1[62]MST2[62]SAV1[63]MOB1A[64]MOB1B[64]单敲除模型以及MST1/2[62]MOB1A/B[64]双敲除模型。

利用MST1和MST2全身性敲除小鼠与器官靶向性小鼠杂交,研究者成功构建了MST1/2+/-; Hnf1b-Cre[65]MST1/2-/-; Hnf1b-Cre[65]MST1/2-/-; HK[65]MST1/2+/-; HK[65]MST1-/-; MST2fl/fl; NKX2.1Cre/+[4]MST1-/-; MST2fl/fl; NKX2.1Cre/Cre[4]MST1-/-; MST2fl/fl; ShhCre/+[4]7种肺上皮特异性MST1/2双敲除模型;MST1fl/fl; MST2fl/fl; Osx-Cre[66]MST1fl/fl; MST2fl/fl; hOC-Cre[66]MST1fl/fl; MST2fl/fl; Col2a1-Cre[67]3种骨细胞相关模型;MST1fl/fl; MST2fl/fl; KSP-Cre[68]MST1fl/fl; MST2fl/fl; YAPfl/fl; KSP-Cre[68]2种附睾上皮相关模型;MST1fl/fl; MST2fl/fl; Alb-Cre肝脏特异模型[8]以及MST1fl/fl; MST2fl/fl; Lyz-Cre巨噬细胞特异模型[69]

利用SAV1全身性敲除小鼠与器官靶向性小鼠杂交,研究者成功构建了SAV1fl/fl; KSP-Cre[70]SAV1fl/fl; Cdh16-Cre[71]2种肾脏特异性SAV1单缺失模型;FGFR4fl/fl; SAV1fl/fl; Alb-Cre[8]Ptenfl/fl; SAV1fl/fl; Alb-Cre[72]FGFR4fl/fl; SAV1fl/fl; YAPfl/+; Alb-Cre[8]3种靶向肝脏的复合敲除模型;SAV1fl/fl; Lin9fl/fl; NKX2.5-Cre[15]SAV1fl/fl; Lin9fl/fl; αMhc-Cre[15]2种靶向心脏的复合敲除模型;Ptenfl/fl; SAV1fl/fl; Pdx1-Cre胰腺复合敲除模型[73]RASSF1a-/-; SAV1+/-[74]RASSF1a-/-; SAV1+/+[74]2种全身性复合敲除模型。

通过敲除靶向器官的LATA1/2,研究者构建了LATS1fl/fl; LATS2fl/fl; NKX3.2-Cre[75]LATS1fl/fl; LATS2fl/fl; Villin-Cre[76]LATS1/2iΔPβC[77]LATS1fl/fl; LATS2fl/fl; Lgr5-Cre[78]4种肠道相关模型;LATS1fl/fl; LATS2fl/+; Plp1-Cre[79]LATS1fl/fl; LATS2fl/fl; Dhh-Cre[79]LATS1fl/+; LATS2fl/fl; Hoxb7-Cre[80]3种雪旺细胞特异模型;LATS1del/fl; LATS2del/fl; Shh-Cre[81]肺泡上皮特异模型;LATS1fl/fl; LATS2fl/fl; Sox9-Cre[82]胆管上皮特异模型;LATS1fl/fl; LATS2fl/fl; TCF21i-Cre[83]心脏成纤维细胞特异模型和LATS1fl/fl; LATS2fl/fl; Sox9-Cre[82]导管细胞特异模型。

利用MOB1AMOB1B全身性敲除小鼠与器官靶向性小鼠杂交,研究者构建了MOB1Afl/fl; MOB1Bfl/fl; Villin-Cre[84]MOB1Afl/fl; MOB1B-/-; Rosa26-Cre[85]MOB1Afl/flMOB1B-/-; Spc-Cre[86]MOB1Afl/fl; MOB1Btr/tr; Krt14-Cre[64]4种上皮相关缺失模型;MOB1Afl/+; MOB1B-/-; Alb-Cre[6]肝脏特异缺失模型和MOB1Afl/fl; MOB1B-/-; Col2a1-Cre[87]软骨细胞特异模型。

通过条件性敲除,研究者构建了YAPfl/fl; NKX2.5-Cre[88]YAPfl/fl; αMhc-Cre[89]YAP+/fl; αMhc-Cre[90]3种心脏特异性YAP单敲除模型;YAPfl/fl; Spc-Cre[91]YAPfl/fl; Krt14-Cre[5]YAPfl/fl; Tek-Cre[92]3种上皮相关单缺失模型;YAPfl/fl; Alb-Cre[93]Atg7fl/fl; YAPfl/fl; Alb-Cre[94]2种肝脏YAP缺失模型;YAPfl/fl; Has-Cre[95]肌肉细胞单缺失模型;YAPfl/fl; Nestin-Cre[96]YAPfl/fl; Gfap-Cre[96]2种星形胶质细胞YAP缺失模型。研究者还构建了TAZfl/+; αMhc-Cre[89]TAZfl/fl; Spc-Cre[91]TAZfl/+; Cag-Cr[89]3种TAZ单敲除模型。在构建YAP/TAZ双敲除模型方面,研究者已成功构建了YAPfl/+; AZfl/fl; αMhc-Cre[89]YAPfl/fl; AZfl/+; αMhc-Cre[89]YAPfl/fl; AZfl/fl; αMhc-Cre[89]3种心脏特异性YAP/TAZ双敲除模型;YAPfl/fl; TAZfl/fl; NKX3.2-Cre[75]YAP/TAZPβC[77]2种肠道特异性YAP/TAZ双敲除模型;YAPfl/fl; TAZfl/fl; Shh-Cre[75]YAPfl/fl; TAZfl/fl; Spc-Cre[97]2种肺上皮特异性双敲除模型;YAPfl/fl; TAZfl/fl; Col1a2-Cre[98]软骨双敲除模型;YAPfl/fl; TAZfl/fl; Col1a2-Cre[99]成纤维细胞双敲除模型;YAPfl/fl; TAZfl/fl; LysM-Cre[100]骨髓细胞双敲除模型;YAPfl/fl; TAZfl/fl; Emx1-Cre[101]神经胶质细胞双敲除模型;YAPfl/fl; TAZfl/fl; Cdh5-Cre[7]内皮细胞双敲除模型以及Ptenfl/fl; Sav1fl/fl; YAPfl/fl; TAZfl/fl; Alb-Cre[72]肝脏复合敲除模型。

3.2 调控Hippo通路的化学制剂

Hippo通路由于会影响肿瘤细胞的迁移和侵袭,在肿瘤治疗中发挥重要作用。研究者研发出许多靶向Hippo通路的化学制剂,这些化学制剂主要作用于MST1/2-LATS1/2或YAP-TEAD 2个模块。

3.2.1 靶向MST1/2-LATS1/2的化学制剂

XMU-MP-1、二甲双胍(metformin)、西格列汀(Sitagliptin)、C19小分子化合物、SHAP激活肽、F10叔酰胺衍生物、中草药吴茱萸碱(evodiamine)和葫芦素B(cucurbitacin B)、CL-6姜黄素衍生物、恶二唑衍生物(oxadiazole derivative)、麦冬素B(OP-B)、高三尖杉酯碱(HHT)、雷公藤苷(triptonide)、中国蜂胶(Chinese propolis)和酸枣仁活性成分JUA通过影响MST1/2-LATS1/2级联模块进而调控YAP/TAZ转录。XMU-MP-1是公认的MST1/2抑制剂,可直接抑制MST1/2和MOB1的磷酸化[102]。C19[103]、SHAP[104]、F10[105]、西格列汀[106]、吴茱萸碱[107]和CL-6[108]可增强MST1/2或LATS1/2的磷酸化水平。恶二唑衍生物[109]、麦冬素B[110]、葫芦素B[111]、二甲双胍[112]、高三尖杉酯碱[113]、雷公藤苷[114]、中国蜂胶[115]和JUA[116]通过调控MST1/2和LATS1/2的表达或定位,诱导YAP磷酸化。

3.2.2 靶向YAP-TEAD的化学制剂

抗炎药物地塞米松(dexamethasone)是促进YAP转录的化学制剂。维替泊芬(verteporfin)、辛伐他汀(simvastatin)、青蒿素(artemisinin)、雌激素受体巴多昔芬(bazedoxifene)、中草药提取物RA-V和二柱解毒汤(EJD)、褪黑素(melatonin)、小分子MTX和CA3是抑制YAP转录的化学制剂。地塞米松可上调YAP总蛋白和YAP核蛋白的表达[117]。维替泊芬可上调接头蛋白14-3-3表达,促进14-3-3与YAP结合,诱导YAP胞质滞留[118]。青蒿素[119]、巴多昔芬[120]、RA-V[121]、辛伐他汀[122]和MTX[123]可增强YAP的磷酸化水平;二柱解毒汤[124]和CA3[125]可降低YAPTAZ表达;褪黑素既可下调YAP/TAZ表达,又可诱导YAP磷酸化[126]

TEAD是YAP的主要转录伙伴,Super-TDU模拟肽、Fisetin黄酮类化合物、LM98氟芬那酸类似物、MGH-CP1、NSC682769和CPD3.1是抑制YAP与TEAD结合的化学制剂。多肽Super-TDU竞争性结合TEAD[59],NSC682769竞争性结合YAP[127]以阻断YAP与TEAD结合。转录因子TEAD拥有一个保守的疏水口袋,是YAP与其结合的关键位点。Fisetin[128]、LM98[129]和MGH-CP1[19]均通过占据疏水的TEAD口袋,破坏YAP与TEAD结合。CPD3.1则可以直接抑制TEAD活性[130]

4 营养素调控Hippo信号通路的作用机制

通过营养干预促进动物生长发育一直是畜牧业研究的重点,而Hippo通路可能是一些营养素发挥作用的潜在机制。熊果酸(ursolic acid,UA)、岩藻多糖(fucoidan,FUC)和姜黄素(curcumin,CUR)都能够激活Hippo通路。UA通过激活RASSF1,上调MST1/2、LATS1和MOB1的表达,促进YAP磷酸化,下调靶基因CTGF的表达,抑制胃癌细胞存活[131]。FUC通过增强MST1/2、LATS1/2和YAP的磷酸化水平,诱导β-catenin胞质降解,阻断下游的β-catenin通路,进而抑制肿瘤细胞生长[132]。CUR通过促进TAZ磷酸化,驱动TAZ由胞核易位到胞质,抑制下游干性标志物基因CD133、EPCAMOCT4的表达,减弱肺癌细胞干性[133];CUR还可通过抑制YAP/TAZ表达,降解KLF5蛋白,下调CCND1的表达,抑制膀胱癌细胞增殖[134]。叶酸(folic acid,FA)通过抑制LATS和YAP的磷酸化,下调Hippo通路,降低TEAD1和NLRP3炎性因子表达,缓解高葡萄糖对视网膜血管内皮细胞和心肌细胞的损伤[135-136]。胆碱(choline,CHO)供应不足会下调NF2表达,使视网膜细胞缓慢增殖、异常分化,但不会改变YAP/TAZ总蛋白的水平[137]。白藜芦醇(resveratrol,RES)具有双重调控Hippo信号通路的功能:既可通过降低炎性细胞因子表达,抑制Hippo激酶,促进YAP/TAZ入核,上调RUNX2的表达,促进成骨细胞分化[138];又可通过抑制RhoA活性,激活LATS1[139-140],诱导YAP磷酸化和胞质滞留[141],调控下游BAX/BCL-2的表达,诱导肝星状细胞凋亡[142]。目前营养素调控Hippo信号通路的研究主要集中在肿瘤细胞和受损伤细胞,Hippo信号通路对正常细胞的调控作用有待进一步探究。

5 小结

Hippo通路作用广泛且调控网络复杂,它不仅对同一组织在不同状态下的调控存在差异,还与WNT、磷脂酰肌醇-3-羟激酶(PI3K)和哺乳动物雷帕霉素靶蛋白(mTOR)等通路存在复杂的互作效应。Hippo通路在动物营养领域的研究刚刚起步,揭示Hippo通路参与动物生长发育调控的路径和窗口期是利用Hippo通路促进动物生长发育的基础。筛选除熊果酸、姜黄素、白藜芦醇等以外的Hippo通路调控物质是利用Hippo通路促进动物生长发育的路径。WNT、PI3K和mTOR通路已被证实能够调节动物的生长、免疫以及氧化应激等过程,解析动物发育过程中WNT、PI3K和mTOR通路与Hippo通路的互作效应将是未来研究的一个方向,该研究将全面解析动物生长发育的调控网络,推动畜牧业发展。

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