一、Hippo信號(hào)通路概述

Hippo 信號(hào)通路，也稱為Salvador / Warts / Hippo（SWH）通路，命名主要源于果蠅中的蛋白激酶Hippo（Hpo），是通路中的關(guān)鍵調(diào)控因子。該通路由一系列保守激酶組成，主要是通過(guò)調(diào)控細(xì)胞增殖和凋亡來(lái)控制器官大小。

Hippo信號(hào)通路是一條抑制細(xì)胞生長(zhǎng)的通路。哺乳動(dòng)物中，Hippo信號(hào)通路上游膜蛋白受體作為胞外生長(zhǎng)抑制信號(hào)的感受器，一旦感受到胞外生長(zhǎng)抑制信號(hào)，就會(huì)激活一系列激酶級(jí)聯(lián)磷酸化反應(yīng)，最終磷酸化下游效應(yīng)因子YAP和TAZ。而細(xì)胞骨架蛋白會(huì)與磷酸化后的YAP和TAZ結(jié)合，使它滯留在細(xì)胞質(zhì)內(nèi)，降低其細(xì)胞核活性，從而實(shí)現(xiàn)對(duì)器官大小和體積的調(diào)控。

二、Hippo信號(hào)通路家族成員

雖然Hippo信號(hào)通路在各個(gè)物種中保守性很高，但是相同功能的調(diào)控因子或效應(yīng)因子在不同物種間還是存在著差異，下表中我們對(duì)比了果蠅與哺乳動(dòng)物中Hippo信號(hào)通路相同功能的關(guān)鍵因子^[1]。

分子名稱對(duì)照表
果蠅中的名稱	人體內(nèi)的同源物	蛋白功能
Dachsous(Ds)	DCHS1,DCHS2	非典型cadherin,可能是Fat受體的配體
Fat(Ft)	FAT1,FAT2,FAT3, FAT4(FATJ)	非典型cadherin,可能是Hippo信號(hào)通路的受體
Expanded(Ex)	FRMD6/Willin	含有FERM結(jié)構(gòu)域的蛋白，能與Kibra及Mer結(jié)合，調(diào)控Hippo信號(hào)通路的上游信號(hào)
Dachs(Dachs)		肌漿球蛋白myosin的一種，能結(jié)合Wts并促進(jìn)其降解
Kibra(Kibra)	WWC1	含有WW結(jié)構(gòu)域的蛋白，能與Ex及Mer結(jié)合，調(diào)控Hippo信號(hào)通路的上游信號(hào)
Merlin(Mer)	NF2	含有FERM結(jié)構(gòu)域的蛋白，能與Kibra及Ex結(jié)合，調(diào)控Hippo信號(hào)通路的上游信號(hào)
Hippo(Hpo)	MST1,MST2	Sterile-20-樣激酶，磷酸化并激活Wts
Salvador(Sav)	WW45(SAV1)	含有WW結(jié)構(gòu)域的蛋白，能起到一個(gè)腳手架蛋白的作用，易化Hippo對(duì)Warts的磷酸化
Warts（Wts）	LATS1,LATS2	核內(nèi)DBF-2相關(guān)激酶，能磷酸化Yki并使之失活
Mob as tumor suppressor(Mats)	MOBKL1A,MOBKL1B	能與Wts結(jié)合的激酶，與Wts結(jié)合后能促進(jìn)Wts的催化活性
Yorkie(YKi)	YAP,TAZ	轉(zhuǎn)錄共激活因子，能在非磷酸化的激活狀態(tài)下與轉(zhuǎn)錄因子Sd結(jié)合，并激活下游靶基因的轉(zhuǎn)錄。這些受調(diào)控的下游靶基因主要參與了細(xì)胞的增殖、生長(zhǎng)并抑制凋亡的發(fā)生
Scalloped(Sd)	TEAD1,TEAD2,TEAD3, TEAD4	能與Yki結(jié)合的轉(zhuǎn)錄因子，與Yki共同作用，調(diào)控靶基因的轉(zhuǎn)錄

 

三、Hippo信號(hào)通路的功能

近十年相關(guān)研究結(jié)果表明，無(wú)論是果蠅還是哺乳動(dòng)物，Hippo信號(hào)通路都可以通過(guò)調(diào)節(jié)細(xì)胞增殖、凋亡和干細(xì)胞自我更新能力實(shí)現(xiàn)對(duì)器官大小的調(diào)控。Hippo信號(hào)通路異常會(huì)導(dǎo)致大量組織過(guò)度生長(zhǎng)。此外，大量研究證實(shí)，Hippo信號(hào)通路在癌癥發(fā)生、組織再生以及干細(xì)胞功能調(diào)控上發(fā)揮著重要功能^[2][3][4]。

a.Hippo信號(hào)通路在器官大小控制中的作用

起初，關(guān)于Hippo信號(hào)通路的研究主要集中在器官大小的調(diào)控。大量研究表明，Hippo途徑主要通過(guò)抑制細(xì)胞增殖并促進(jìn)細(xì)胞凋亡，繼而實(shí)現(xiàn)對(duì)器官大小的調(diào)控。激酶級(jí)聯(lián)反應(yīng)是該信號(hào)傳導(dǎo)的關(guān)鍵。Mst1/2激酶與SAV1形成復(fù)合物，然后磷酸化LATS1/2；活化后的LATS1/2激酶隨即磷酸化Hippo信號(hào)通路下游關(guān)鍵效應(yīng)分子——YAP和TAZ，同時(shí)抑制了YAP和TAZ的轉(zhuǎn)錄活性。反之，未磷酸化的YAP/TAZ會(huì)進(jìn)入細(xì)胞核與TEAD1-4或其他轉(zhuǎn)錄因子結(jié)合，繼而誘導(dǎo)促增值和抑凋亡的基因表達(dá)上調(diào)。Hippo通路在器官大小中的調(diào)控作用已在小鼠模型中得到證實(shí)。比如肝臟中的YAP特異性過(guò)表達(dá)會(huì)導(dǎo)致肝臟增大，但一旦停止YAP過(guò)表達(dá)，肝臟大小可以恢復(fù)正常^[5][6]。

b.Hippo信號(hào)通路在破骨細(xì)胞形成中的作用

成骨細(xì)胞骨形成與破骨細(xì)胞骨吸收間的平衡在保持骨穩(wěn)態(tài)中起關(guān)鍵作用。相關(guān)研究表明，Hippo信號(hào)通路是調(diào)控該平衡的途徑之一，涉及的主要調(diào)控因子包括RASSF2，NF2，MST1/2，SAV1，LATS1/2，Ajuba，MOB1，YAP和TAZ。其中，RASSF2，NF2和MST1/2主要參與破骨細(xì)胞增殖前期調(diào)控，而SAV1，LATS1/2，YAP和TAZ參與破骨細(xì)胞分化調(diào)節(jié)^{[7][8][9][10]}。此外，參與骨凋亡調(diào)節(jié)的基因RASSF，MST和TAZ，它們同樣也是Hippo信號(hào)傳導(dǎo)途徑的下游基因^[11][12][13]。

一般來(lái)說(shuō)，破骨細(xì)胞的細(xì)胞過(guò)程包括破骨細(xì)胞前體增殖，破骨細(xì)胞分化及凋亡，其中凋亡又涉及了不同分子級(jí)聯(lián)。大量的證據(jù)表明，Hippo通路可能通過(guò)與NF-κB，MAPK和鈣信號(hào)通路相互作用在這些過(guò)程中發(fā)揮作用。在Hippo-和NF-κB信號(hào)通路中，RASSF2和MST2可以分別通過(guò)抑制IKK和I-κBα活性來(lái)阻斷NF-κB信號(hào)通路。在Hippo-和MAPK信號(hào)傳導(dǎo)途徑中，Ajuba可以激活TRAF6，YAP / TAZ / TEAD可以激活ERK、JNK、p38和AP1。此外，在Hippo和鈣信號(hào)傳導(dǎo)途徑中，YAP激活CREB和TEADs依賴于降低神經(jīng)鈣蛋白活性，從而抑制NFATc1^[7]。

四.Hippo信號(hào)通路和疾病

a. Hippo信號(hào)通路和癌癥

癌癥是涉及異常細(xì)胞生長(zhǎng)，可能侵入或蔓延到其他多個(gè)身體部位的疾病。雖然第一次發(fā)現(xiàn)Hippo通路是因?yàn)樗梢酝ㄟ^(guò)促進(jìn)細(xì)胞凋亡及抑制細(xì)胞周期來(lái)控制成像椎間盤生長(zhǎng)，但是目前在動(dòng)物模型中的研究已經(jīng)將該通路的功能擴(kuò)展到了其他癌癥，如乳頭狀腎癌，結(jié)直腸癌，卵巢癌，乳腺癌和胃癌[^{14][15][16][17][18]}。 Carole Sourbier的研究顯示，用達(dá)沙替尼靶向抑制YAP激活腫瘤中的Yes可能對(duì)失去Hippo信號(hào)通路調(diào)節(jié)的NF2缺陷型PRCC腫瘤患者具有治療潛力。另一研究表明TFAP2C通過(guò)轉(zhuǎn)錄激活Hippo信號(hào)傳導(dǎo)的負(fù)調(diào)控因子ROCK1和ROCK2促進(jìn)CSCs特征和化療耐藥，導(dǎo)致結(jié)腸直腸癌（CRC）細(xì)胞中Hippo信號(hào)的失活。 YAP / TAZ-TEAD轉(zhuǎn)錄因子復(fù)合物代表致癌轉(zhuǎn)化的普遍目標(biāo)。已經(jīng)證實(shí)YAP基因位點(diǎn)在人和小鼠腫瘤如髓母細(xì)胞瘤，肺癌，胰腺癌，食管癌，肝癌和乳腺癌中以不同頻率上調(diào)^[19]。

b.心血管發(fā)展中的Hippo信號(hào)通路

無(wú)論是發(fā)達(dá)國(guó)家還是發(fā)展中國(guó)家，心臟病仍然是主要的致死因素。心臟畸形可直接導(dǎo)致胚胎死亡或出生后死亡，而且在強(qiáng)烈刺激如壓力超負(fù)荷或局部缺血情況下，導(dǎo)致的心臟損傷是不可逆轉(zhuǎn)的。相關(guān)研究顯示，Hippo信號(hào)通路參與了多個(gè)生理病理過(guò)程的調(diào)控，包括心血管發(fā)育、肥大、細(xì)胞凋亡、自噬、血管生成和再生^{[20][21][22][23][24]}。

Heallen等人研究證實(shí)，心臟特異性敲除SAV1，會(huì)阻斷Hippo信號(hào)傳導(dǎo)途徑，明顯降低YAP磷酸化水平，從而導(dǎo)致心臟擴(kuò)大，但細(xì)胞大小不變。這一結(jié)果在MST1/2和LATS2基因敲除小鼠中也得到了驗(yàn)證^[20]。而且在經(jīng)腺病毒處理的RASSF1A轉(zhuǎn)基因小鼠中，磷酸化MST1明顯增多，加速了心肌細(xì)胞的凋亡。但若是將成纖維細(xì)胞和心臟暴露于超負(fù)荷壓力下，可以減弱他們的增殖能力^[21]。

Hippo信號(hào)通路相關(guān)抗體推薦:

名稱	貨號(hào)	uniprot	種屬反應(yīng)性	應(yīng)用范圍
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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