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Hippo信号通路

浏览次数:76      日期:2018年06月13日 15:10

一、Hippo信号通路概述

Hippo 信号通路,也称为Salvador / Warts / HippoSWH)通路,命名主要源于果蝇中的蛋白激酶HippoHpo),是通路中的关键调控因子。该通路由一系列保守激酶组成,主要是通过调控细胞增殖和凋亡来控制器官大小。

Hippo信号通路是一条抑制细胞生长的通路。哺乳动物中,Hippo信号通路上游膜蛋白受体作为胞外生长抑制信号的感受器,一旦感受到胞外生长抑制信号,就会激活一系列激酶级联磷酸化反应,最终磷酸化下游效应因子YAPTAZ。而细胞骨架蛋白会与磷酸化后的YAPTAZ结合,使它滞留在细胞质内,降低其细胞核活性,从而实现对器官大小和体积的调控。

二、Hippo信号通路家族成员

虽然Hippo信号通路在各个物种中保守性很高,但是相同功能的调控因子或效应因子在不同物种间还是存在着差异,下表中我们对比了果蝇与哺乳动物中Hippo信号通路相同功能的关键因子[1]

分子名称对照表
果蝇中的名称 人体内的同源物 蛋白功能
Dachsous(Ds) DCHS1,DCHS2 非典型cadherin,可能是Fat受体的配体
Fat(Ft) FAT1,FAT2,FAT3,
FAT4(FATJ)
非典型cadherin,可能是Hippo信号通路的受体
Expanded(Ex) FRMD6/Willin 含有FERM结构域的蛋白,能与Kibra及Mer结合,调控Hippo信号通路的上游信号
Dachs(Dachs)   肌浆球蛋白myosin的一种,能结合Wts并促进其降解
Kibra(Kibra) WWC1 含有WW结构域的蛋白,能与Ex及Mer结合,调控Hippo信号通路的上游信号
Merlin(Mer) NF2 含有FERM结构域的蛋白,能与Kibra及Ex结合,调控Hippo信号通路的上游信号
Hippo(Hpo) MST1,MST2 Sterile-20-样激酶,磷酸化并激活Wts
Salvador(Sav) WW45(SAV1) 含有WW结构域的蛋白,能起到一个脚手架蛋白的作用,易化Hippo对Warts的磷酸化
Warts(Wts) LATS1,LATS2 核内DBF-2相关激酶,能磷酸化Yki并使之失活
Mob as tumor suppressor(Mats) MOBKL1A,MOBKL1B 能与Wts结合的激酶,与Wts结合后能促进Wts的催化活性
Yorkie(YKi) YAP,TAZ 转录共激活因子,能在非磷酸化的激活状态下与转录因子Sd结合,并激活下游靶基因的转录。这些受调控的下游靶基因主要参与了细胞的增殖、生长并抑制凋亡的发生
Scalloped(Sd) TEAD1,TEAD2,TEAD3,
TEAD4
能与Yki结合的转录因子,与Yki共同作用,调控靶基因的转录

 

三、Hippo信号通路的功能

近十年相关研究结果表明,无论是果蝇还是哺乳动物,Hippo信号通路都可以通过调节细胞增殖、凋亡和干细胞自我更新能力实现对器官大小的调控。Hippo信号通路异常会导致大量组织过度生长。此外,大量研究证实,Hippo信号通路在癌症发生、组织再生以及干细胞功能调控上发挥着重要功能[2][3][4]

a.Hippo信号通路在器官大小控制中的作用

起初,关于Hippo信号通路的研究主要集中在器官大小的调控。大量研究表明,Hippo途径主要通过抑制细胞增殖并促进细胞凋亡,继而实现对器官大小的调控。激酶级联反应是该信号传导的关键。Mst1/2激酶与SAV1形成复合物,然后磷酸化LATS1/2;活化后的LATS1/2激酶随即磷酸化Hippo信号通路下游关键效应分子——YAPTAZ,同时抑制了YAPTAZ的转录活性。反之,未磷酸化的YAP/TAZ会进入细胞核与TEAD1-4或其他转录因子结合,继而诱导促增值和抑凋亡的基因表达上调。Hippo通路在器官大小中的调控作用已在小鼠模型中得到证实。比如肝脏中的YAP特异性过表达会导致肝脏增大,但一旦停止YAP过表达,肝脏大小可以恢复正常[5][6]

b.Hippo信号通路在破骨细胞形成中的作用

成骨细胞骨形成与破骨细胞骨吸收间的平衡在保持骨稳态中起关键作用。相关研究表明,Hippo信号通路是调控该平衡的途径之一,涉及的主要调控因子包括RASSF2NF2MST1/2SAV1LATS1/2AjubaMOB1YAPTAZ。其中,RASSF2NF2MST1/2主要参与破骨细胞增殖前期调控,而SAV1LATS1/2YAPTAZ参与破骨细胞分化调节[7][8][9][10]。此外,参与骨凋亡调节的基因RASSFMSTTAZ,它们同样也是Hippo信号传导途径的下游基因[11][12][13]

一般来说,破骨细胞的细胞过程包括破骨细胞前体增殖,破骨细胞分化及凋亡,其中凋亡又涉及了不同分子级联。大量的证据表明,Hippo通路可能通过与NF-κBMAPK和钙信号通路相互作用在这些过程中发挥作用。在Hippo-NF-κB信号通路中,RASSF2MST2可以分别通过抑制IKKI-κBα活性来阻断NF-κB信号通路。在Hippo-MAPK信号传导途径中,Ajuba可以激活TRAF6YAP / TAZ / TEAD可以激活ERKJNKp38AP1。此外,在Hippo和钙信号传导途径中,YAP激活CREBTEADs依赖于降低神经钙蛋白活性,从而抑制NFATc1[7]

.Hippo信号通路和疾病
a. Hippo信号通路和癌症

癌症是涉及异常细胞生长,可能侵入或蔓延到其他多个身体部位的疾病。虽然第一次发现Hippo通路是因为它可以通过促进细胞凋亡及抑制细胞周期来控制成像椎间盘生长,但是目前在动物模型中的研究已经将该通路的功能扩展到了其他癌症,如乳头状肾癌,结直肠癌,卵巢癌,乳腺癌和胃癌[14][15][16][17][18] Carole Sourbier的研究显示,用达沙替尼靶向抑制YAP激活肿瘤中的Yes可能对失去Hippo信号通路调节的NF2缺陷型PRCC肿瘤患者具有治疗潜力。另一研究表明TFAP2C通过转录激活Hippo信号传导的负调控因子ROCK1ROCK2促进CSCs特征和化疗耐药,导致结肠直肠癌(CRC)细胞中Hippo信号的失活。 YAP / TAZ-TEAD转录因子复合物代表致癌转化的普遍目标。已经证实YAP基因位点在人和小鼠肿瘤如髓母细胞瘤,肺癌,胰腺癌,食管癌,肝癌和乳腺癌中以不同频率上调[19]

b.心血管发展中的Hippo信号通路

无论是发达国家还是发展中国家,心脏病仍然是主要的致死因素。心脏畸形可直接导致胚胎死亡或出生后死亡,而且在强烈刺激如压力超负荷或局部缺血情况下,导致的心脏损伤是不可逆转的。相关研究显示,Hippo信号通路参与了多个生理病理过程的调控,包括心血管发育、肥大、细胞凋亡、自噬、血管生成和再生[20][21][22][23][24]

Heallen等人研究证实,心脏特异性敲除SAV1,会阻断Hippo信号传导途径,明显降低YAP磷酸化水平,从而导致心脏扩大,但细胞大小不变。这一结果在MST1/2LATS2基因敲除小鼠中也得到了验证[20]。而且在经腺病毒处理的RASSF1A转基因小鼠中,磷酸化MST1明显增多,加速了心肌细胞的凋亡。但若是将成纤维细胞和心脏暴露于超负荷压力下,可以减弱他们的增殖能力[21]

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名称 货号 uniprot 种属反应性 应用范围
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AXIN1 Antibody CSB-PA517675LA01HU O15169 Human ELISA, IHC 
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BMP2 Antibody CSB-PA09419A0Rb P12643 Human ELISA, WB, IHC, IF 
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CASP3 Antibody CSB-PA05689A0Rb P42574 Human ELISA, IHC, IF 
CCND1 Antibody CSB-PA004811LA01HU P24385 Human ELISA
CCND2 Antibody CSB-PA004812ESR2HU P30279 Human ELISA, WB, IHC,IF 
CCND3 Antibody CSB-PA004814ESR2HU P30281 Human ELISA, WB, IHC, IF, IP 
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CRB1 Antibody CSB-PA005941DSR1HU P82279 Human ELISA, IHC, IF 
CRB2 Antibody CSB-PA692212LA01HU Q5IJ48 Human ELISA, IHC 
CSNK1D Antibody CSB-PA006067LA01HU P48730 Human ELISA, WB, IHC, IF, IP 
CSNK1E Antibody CSB-PA01319A0Rb P49674 Human ELISA, WB, IHC, IF 
CTGF Antibody CSB-PA09429A0Rb P29279 Human ELISA, IHC, IF 
CTNNA1 Antibody CSB-PA006164EA01HU P35221 Human, Mouse ELISA, WB, IHC, IF 
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CTNNB1 Antibody CSB-PA00174A0Rb P35222 Human ELISA, WB, IHC, IF, IP 
DLG1 Antibody CSB-PA614264LA01HU Q12959 Human ELISA, IHC, IF 
DLG2 Antibody CSB-PA621882LA01HU Q15700 Human, Rat ELISA, WB, IHC, IF 
DVL2 Antibody CSB-PA007286ESR2HU O14641 Human ELISA, WB, IHC, IF 
DVL3 Antibody CSB-PA856442LA01HU Q92997 Human ELISA, IHC, IF 
FAT4 Antibody CSB-PA740927LA01HU Q6V0I7 Human ELISA, IF 
FBXW11 Antibody CSB-PA891721ESR2HU Q9UKB1 Human ELISA, WB, IHC 
FGF1 Antibody CSB-PA008615ESR1HU P05230 Human, Mouse ELISA, WB, IHC, IF 
FRMD6 Antibody CSB-PA822270ESR2HU Q96NE9 Human ELISA, WB, IHC 
FZD1 Antibody CSB-PA891570LA01HU Q9UP38 Human ELISA, IHC, IF 
FZD10 Antibody CSB-PA891782LA01HU Q9ULW2 Human ELISA, WB, IHC, IF 
FZD3 Antibody CSB-PA882067ESR1HU Q9NPG1 Human, Rat ELISA, WB, IHC 
FZD4 Antibody CSB-PA890755LA01HU Q9ULV1 Human ELISA, WB, IHC, IF 
FZD8 Antibody CSB-PA880970LA01HU Q9H461 Human, Mouse ELISA, WB, IHC 
FZD9 Antibody CSB-PA009112LA01HU O00144 Human, Mouse ELISA, WB, IHC 
GDF5 Antibody CSB-PA009349ESR1HU P43026 Human ELISA, WB, IHC, IF 
GDF7 Antibody CSB-PA768769LA01HU Q7Z4P5 Human ELISA, WB, IHC 
GSK3B Antibody CSB-PA009963LA01HU P49841 Human, Mouse ELISA, WB, IF 
ID2 Antibody CSB-PA010967LA01HU Q02363 Human ELISA, IHC, IF 
ITGB2 Antibody CSB-PA011884LA01HU P05107 Human ELISA, IHC, IF 
LATS1 Antibody CSB-PA012769LA01HU O95835 Human ELISA, IHC, IF, IP 
LEF1 Antibody CSB-PA012856LA01HU Q9UJU2 Human, Mouse ELISA, WB, IHC, IF 
LLGL2 Antibody CSB-PA764711LA01HU Q6P1M3 Human ELISA, IF 
MARK3 Antibody CSB-PA013498LA01HU P27448 Human ELISA, IHC, IF 
MOB1A Antibody CSB-PA872519HA01HU Q9H8S9 Human, Mouse ELISA, WB, IHC, IF, IP 
MOB1B Antibody CSB-PA762574HA01HU Q7L9L4 Human, Mouse ELISA, IHC, IF, IP 
MPP5 Antibody CSB-PA847626LA01HU Q8N3R9 Human ELISA, IF 
MYC Antibody CSB-PA02589A0Rb P01106 Human, Mouse ELISA, WB, IHC 
NEK8 Antibody CSB-PA801219ESR1HU Q86SG6 Human ELISA, IHC 
NF2 Antibody CSB-PA015741LA01HU P35240 Human, Mouse ELISA, WB, IHC, IF 
NPHP4 Antibody CSB-PA015987LA01HU O75161 Human ELISA, IHC, IF 
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PPP1CA Antibody CSB-PA018503LA01HU P62136 Human ELISA, IHC, IF 
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RASSF1 Antibody CSB-PA885715LA01HU Q9NS23 Human ELISA, IHC 
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SAV1 Antibody CSB-PA875672ESR2HU Q9H4B6 Human ELISA, WB, IHC, IF, IP 
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STK3 Antibody CSB-PA614396ESR2HU Q13188 Human ELISA, WB, IHC, IF 
TEAD1 Antibody CSB-PA023363DSR2HU P28347 Human ELISA, WB, IHC, IF 
TEAD3 Antibody CSB-PA860344LA01HU Q99594 Human ELISA, IHC 
TEAD4 Antibody CSB-PA618010LA01HU Q15561 Human ELISA, WB, IHC 
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