Hippo信号通路
日期：2018-06-13 15:10:30
一、Hippo信号通路概述
Hippo 信号通路，也称为Salvador / Warts / Hippo（SWH）通路，命名主要源于果蝇中的蛋白激酶Hippo（Hpo），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YAP和TAZ。而细胞骨架蛋白会与磷酸化后的YAP和TAZ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——YAP和TAZ，同时抑制了YAP和TAZ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RASSF2，NF2，MST1/2，SAV1，LATS1/2，Ajuba，MOB1，YAP和TAZ。其中，RASSF2，NF2和MST1/2主要参与破骨细胞增殖前期调控，而SAV1，LATS1/2，YAP和TAZ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RASSF，MST和TAZ，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-κB，MAPK和钙信号通路相互作用在这些过程中发挥作用。在Hippo-和NF-κB信号通路中，RASSF2和MST2可以分别通过抑制IKK和I-κBα活性来阻断NF-κB信号通路。在Hippo-和MAPK信号传导途径中，Ajuba可以激活TRAF6，YAP / TAZ / TEAD可以激活ERK、JNK、p38和AP1。此外，在Hippo和钙信号传导途径中，YAP激活CREB和TEADs依赖于降低神经钙蛋白活性，从而抑制NFATc1[7]。
四.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ROCK1和ROCK2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MST1/2和LATS2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]。
Hippo信号通路相关抗体推荐:
| 名称 | 货号 | uniprot | 种属反应性 | 应用范围 |
| ACTB Antibody | CSB-PA01629A0Rb | P60709 | Human, Mouse | ELISA, WB, IHC, IF |
| ACTG1 Antibody | CSB-PA02619A0Rb | P63261 | Human | ELISA, WB, IHC, IF |
| AFP Antibody | CSB-PA09989A0Rb | P02771 | Human | ELISA, WB |
| AMH Antibody | CSB-PA12639A0Rb | P03971 | Human, Mouse | ELISA, WB, IHC, IF |
| AMOT Antibody | CSB-PA001677ESR2HU | Q4VCS5 | Human | ELISA, WB, IHC |
| ANAPC2 Antibody | CSB-PA892446DSR1HU | Q9UJX6 | Human | ELISA, IHC, IF |
| AREG Antibody | CSB-PA11339A0Rb | P15514 | Human | ELISA, IHC, IF |
| AXIN1 Antibody | CSB-PA517675LA01HU | O15169 | Human | ELISA, IHC |
| BIRC5 Antibody | CSB-PA07249A0Rb | O15392 | Human | ELISA, IF |
| BMP2 Antibody | CSB-PA09419A0Rb | P12643 | Human | ELISA, WB, IHC, IF |
| BMP4 Antibody | CSB-PA05799A0Rb | P12644 | Human, Mouse, Rat, Zebrafish | ELISA, WB, IHC |
| BMP6 Antibody | CSB-PA10709A0Rb | P22004 | Human | ELISA, IHC |
| BMP7 Antibody | CSB-PA05805A0Rb | P18075 | Human, Mouse | ELISA, WB, IHC, IF |
| BMPR1A Antibody | CSB-PA002748LA01HU | P36894 | Human | ELISA, WB, IHC, IF |
| BMPR1B Antibody | CSB-PA002751LA01HU | O00238 | Human, Rat | ELISA, WB, IHC, IF |
| BTRC Antibody | CSB-PA897464LA01HU | Q9Y297 | Human | ELISA, WB, IHC, IF |
| 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 |
| CDH1 Antibody | CSB-PA005034MA01HU | P12830 | Human | ELISA, WB, IHC, IF, IP |
| 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 |
| CTNNA2 Antibody | CSB-PA006165LA01HU | P26232 | Human | ELISA, IF |
| 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 |
| PARD3 Antibody | CSB-PA819481LA01HU | Q8TEW0 | Human | ELISA, WB, IHC |
| PARD6A Antibody | CSB-PA878839LA01HU | Q9NPB6 | Human, Mouse | ELISA, WB, IF |
| PARD6B Antibody | CSB-PA861174DSR1HU | Q9BYG5 | Human | ELISA, IHC, IF |
| PARD6G Antibody | CSB-PA863155LA01HU | Q9BYG4 | Human, Mouse | ELISA, WB, IF |
| PPP1CA Antibody | CSB-PA018503LA01HU | P62136 | Human | ELISA, IHC, IF |
| PPP1CB Antibody | CSB-PA018504LA01HU | P62140 | Human | ELISA, WB, IHC |
| PPP1CC Antibody | CSB-PA018505LA01HU | P36873 | Human, Mouse | ELISA, WB, IHC |
| PPP2CA Antibody | CSB-PA018559LA01HU | P67775 | Human, Mouse | ELISA, WB, IHC, IF |
| PPP2CB Antibody | CSB-PA00985A0Rb | P62714 | Human | ELISA, WB, IHC, IF |
| PPP2R1B Antibody | CSB-PA830420ESR1HU | P30154 | Human | ELISA, WB, IHC |
| PPP2R2A Antibody | CSB-PA018564LA01HU | P63151 | Human, Mouse, Rat | ELISA, WB, IHC, IF |
| PPP2R2B Antibody | CSB-PA018565LA01HU | Q00005 | Human | ELISA, IHC, IF |
| PPP2R2D Antibody | CSB-PA727750LA01HU | Q66LE6 | Human | ELISA, WB, IHC, IF |
| PRKCZ Antibody | CSB-PA15889A0Rb | Q05513 | Human | ELISA, IF |
| RAC1 Antibody | CSB-PA04329A0Rb | P63000 | Human | ELISA, IHC, IF |
| RASSF1 Antibody | CSB-PA885715LA01HU | Q9NS23 | Human | ELISA, IHC |
| RASSF6 Antibody | CSB-PA754570ESR2HU | Q6ZTQ3 | Human | ELISA, IHC |
| SAV1 Antibody | CSB-PA875672ESR2HU | Q9H4B6 | Human | ELISA, WB, IHC, IF, IP |
| SDCBP Antibody | CSB-PA020893LA01HU | O00560 | Human, Mouse, Rat | ELISA, WB, IHC, IF |
| SERPINE1 Antibody | CSB-PA11239A0Rb | P05121 | Human | ELISA, WB, IHC, IF |
| SMAD1 Antibody | CSB-PA618998LA01HU | Q15797 | Human, Mouse | ELISA, WB, IHC, IF |
| SMAD2 Antibody | CSB-PA15557A0Rb | Q15796 | Human, Mouse | ELISA, WB, IHC, IF |
| SMAD3 Antibody | CSB-PA021788ESR2HU | P84022 | Human | ELISA, WB, IHC, IF, IP |
| SMAD4 Antibody | CSB-PA619768LA01HU | Q13485 | Human | ELISA, WB, IHC, IP |
| SNAI2 Antibody | CSB-PA021869LA01HU | O43623 | Human | ELISA, IHC, IF |
| SOX11 Antibody | CSB-PA022419LA01HU | P35716 | Human, Rat, Mouse | ELISA, WB, IHC |
| SOX2 Antibody | CSB-PA16539A0Rb | P48431 | Human, Mouse | ELISA, WB, IHC, IF |
| 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 |
| TGFB1 Antibody | CSB-PA07309A0Rb | P01137 | Human | ELISA, IHC |
| TGFB2 Antibody | CSB-PA07315A0Rb | P61812 | Human | ELISA, WB, IHC |
| TGFB3 Antibody | CSB-PA023449LA01HU | P10600 | Human | ELISA, IHC |
| TGFBR1 Antibody | CSB-PA023451LA01HU | P36897 | Human | ELISA, WB, IHC, IF |
| TGFBR2 Antibody | CSB-PA023452LA01HU | P37173 | Human | ELISA, IHC, IF |
| TP53 Antibody | CSB-PA07889A0Rb | P04637 | Human, Mouse | ELISA, WB, IHC, ChIP |
| TP53BP2 Antibody | CSB-PA622676ESR2HU | Q13625 | Human, Mouse | ELISA, WB |
| WNT1 Antibody | CSB-PA026128LA01HU | P04628 | Human | ELISA, IHC |
| WNT10A Antibody | CSB-PA884424LA01HU | Q9GZT5 | Human | ELISA, IHC |
| WNT2 Antibody | CSB-PA026133ESR1HU | P09544 | Human | ELISA, WB, IHC |
| WNT3A Antibody | CSB-PA15549A0Rb | P56704 | Human, Mouse | ELISA, WB, IHC |
| WNT4 Antibody | CSB-PA026137LA01HU | P56705 | Human | ELISA, WB, IHC |
| WNT5A Antibody | CSB-PA026138LA01HU | P41221 | Human, Mouse | ELISA, WB, IHC, IF |
| WNT5B Antibody | CSB-PA872432ESR1HU | Q9H1J7 | Human | ELISA, IHC |
| WNT7A Antibody | CSB-PA026141LA01HU | O00755 | Human | ELISA, IF |
| WNT7B Antibody | CSB-PA026142ESR1HU | P56706 | Human, Mouse | ELISA, WB, IHC |
| WNT8A Antibody | CSB-PA863951LA01HU | Q9H1J5 | Human | ELISA, IHC |
| WNT9A Antibody | CSB-PA026145ESR1HU | O14904 | Human | ELISA, IHC |
| WNT9B Antibody | CSB-PA026146LA01HU | O14905 | Human | ELISA, IHC |
| WWC2 Antibody | CSB-PA734879LA01HU | Q6AWC2 | Human | ELISA, IHC |
| YWHAB Antibody | CSB-PA01544A0Rb | P31946 | Human, Mouse, Rat, Zebrafish | ELISA, WB, IHC, IF |
| YWHAE Antibody | CSB-PA026287DA01HU | P62258 | Human, Mouse | ELISA, WB, IHC, IF |
| YWHAG Antibody | CSB-PA026288LA01HU | P61981 | Human, Mouse | ELISA, WB, IHC, IP |
| YWHAH Antibody | CSB-PA02174A0Rb | Q04917 | Human, Mouse | ELISA, WB, IHC, IF |
| YWHAQ Antibody | CSB-PA026290ESR1HU | P27348 | Human, Mouse | ELISA, WB, IHC, IF |
| YWHAZ Antibody | CSB-PA01459A0Rb | P63104 | Human, Mouse | ELISA, WB, IHC, IF |
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