Hippo信号通路转录效应因子TAZ/YAP对间充质干细胞分化的调控

doi:10.3724/SP.J.1005.2013.01283

遗传 ›› 2013, Vol. 35 ›› Issue (11): 1283-1290.doi: 10.3724/SP.J.1005.2013.01283

Hippo信号通路转录效应因子TAZ/YAP对间充质干细胞分化的调控

门通, 朴善花, 滕春波

东北林业大学生命科学学院动物发育生物学研究室, 哈尔滨 150040

收稿日期:2013-05-06 修回日期:2013-07-14 出版日期:2013-11-20 发布日期:2013-10-25
通讯作者: 滕春波, 博士, 教授, 研究方向：发育生物学。 E-mail:chunboteng@nefu.edu.cn
作者简介:门通, 硕士研究生, 专业方向：发育生物学。Tel: 0451-82191784; E-mail: tongmen1987@126.com
基金资助:
国家自然科学基金项目(编号：31272520)和黑龙江省自然科学基金项目(编号：C201215)资助

Regulation of differentiation of mesenchymal stem cells by the Hippo pathway effectors TAZ/YAP

MEN Tong, PIAO Shan-Hua, TENG Chun-Bo

Laboratory of Animal DevelopmentalＢiology, College of Life Sciences, Northeast Forestry University, Harbin 150040, China

Received:2013-05-06 Revised:2013-07-14 Online:2013-11-20 Published:2013-10-25

摘要/Abstract

摘要：

间充质干细胞(Mesenchymal stem cells, MSCs)是一种多能性细胞, 可分化为软骨细胞、脂肪细胞、肌细胞等不同世系细胞。一些世系特异性转录因子, 如Runt相关转录因子2 (Runt related transcription factor 2, RUNX2)、过氧化物增殖子激活型受体γ (Peroxisome proliferator-activator receptor gamma, PPARγ)、肌发生分化因子1(Myogenic differentiation 1, MyoD)等在MSCs分别向成骨、脂肪和生肌细胞分化过程中具有关键的调控作用。近几年研究发现, Hippo信号通路可通过其转录效应因子TAZ (Tafazzin)/YAP(Yes-associated protein)对上述世系特异性转录因子进行调控, 从而影响MSCs的分化方向。TAZ与RUNX2结合可增强骨发生程序的执行并促进MSCs向成骨分化, 而与PPAR-γ结合则会抑制MSCs向脂肪细胞方向分化。在MSC样细胞中, TAZ异位表达会以一种MyoD依赖方式增加生肌基因表达并加速肌纤维生成。此外, BMP-2、TNF-α、Eph-Ephrin等信号通路, 小分子药物(KR62980、TM-25659等)以及机械刺激都可通过调控Hippo信号通路转录效应因子TAZ/YAP活性影响MSCs的命运决定。文章综述了哺乳动物Hippo信号通路的转导途径, 转录效应因子TAZ/YAP与间充质世系特异性转录因子的作用机理, 及与其他信号通路相互作用对MSCs分化的影响。

关键词: Hippo信号通路, TAZ/YAP, 间充质干细胞, 分化, 组织再生

Abstract:

Mesenchymal stem cells (MSCs) are pluripotent cells which can differentiate into several distinct lineages, such as chondrocytes, adipocytes and myofibers. It has been reported that the lineage-specific transcriptional factors including Runt related transcription factor 2 (RUNX2), Peroxisome proliferator-activator receptor gamma (PPARγ) and Myogenic differentiation 1 (MyoD) may play key regulatory roles among the differentiation of MSCs. Recently, researches have confirmed that the Hippo pathway impacts the differentiation fates of MSCs through regulating the activity of line-age-specific transcription factors by the Hippo pathway effectors Tafazzin (TAZ) and/or Yes-associated protein (YAP). The interaction between TAZ and RUNX2 boosts the osteogenic processes and promotes MSCs differentiating into osteoblast lineage. However, PPARγ binding to TAZ may inhibit the adipocytes differentiation, and thus overexpression of TAZ in mesenchymal stem cell-like cells increases the expression of myogenic genes and hastens myofiber formation through a MyoD-dependent manner. Moreover, other signaling pathways (such as BMP-2, TNF-α, Eph-Ephrin, etc.), small molecules (KR62980, TM-25659, etc.), and mechanistic stimuli can also affect the fate by regulating the activity of TAZ/YAP. In this review, we summarized the signaling pattern of Hippo pathway and the function mechanism of TAZ and/or YAP by enu-merating their interaction to several lineage-specific transcriptional factors and relationship with other signal pathways dur-ing MSCs differentiation.

Key words: Hippo signaling pathway, TAZ/YAP, mesenchymal stem cells, differentiation, tissue regeneration

门通朴善花滕春波. Hippo信号通路转录效应因子TAZ/YAP对间充质干细胞分化的调控[J]. 遗传, 2013, 35(11): 1283-1290.

参考文献

[1] Owen M, Friedenstein AJ. Stromal stem cells: marrow- derived osteogenic precursors. Ciba Found Symp, 1988, 136(1): 42–60.<\p>

[2] Caplan A, Bruder SP. Mesenchymal stem cells: building blocks for molecular medicine in the 21st century. Trends Mol Med, 2001, 7(6): 259–264.<\p>

[3] Chen Y, Shao JZ, Xiang LX, Dong XJ, Zhang GR. Mes-enchymal stem cells: a promising candidate in regenera-tive medicine. Int J Biochem Cell Biol, 2008, 40(5): 815– 820.<\p>

[4] Caplan AI. Mesenchymal stem cells. J Orthop Res, 1991, 9(5): 641–650.<\p>

[5] Baksh D, Boland GM, Tuan RS. Cross-talk between Wnt signaling pathways in human mesenchymal stem cells leads to functional antagonism during osteogenic differen-tiation. J Cell Biochem, 2007, 101(5): 1109–1124.<\p>

[6] McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell, 2004, 6(4): 483–495.<\p>

[7] Wu R, Liu G, Bharadwaj S, Zhang Y. Isolation and myogenic differentiation of mesenchymal stem cells for urologic tis- sue engineering. Methods Mol Biol, 2013, 1001(1): 65–80.<\p>

[8] Beier JP, Bitto FF, Lange C, Klumpp D, Arkudas A, Ble-iziffer O, Boos AM, Horch RE, Kneser U. Myogenic dif-ferentiation of mesenchymal stem cells co-cultured with primary myoblasts. Cell Biol Int, 2011, 35(4): 397– 406.<\p>

[9] Lee KD. Applications of mesenchymal stem cells: an up-dated review. Chang Gung Med J, 2008, 31(3): 228–236.<\p>

[10] Ramos A and Camargo FD. The Hippo signaling pathway and stem cell biology. Trends Cell Biol, 2012, 22(7): 339– 346.<\p>

[11] Zhao B, Tumaneng K, Guan KL. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol, 2011, 13(8): 877–883.<\p>

[12] Byun MR, Jeong H, Bae SJ, Kim AR, Hwang ES, Hong JH. TAZ is required for the osteogenic and anti-adipogenic ac-tivities of kaempferol. Bone, 2012, 50(1): 364–372.<\p>

[13] Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, Mueller E, Benjamin T, Spiegelman BM, Sharp PA, Hopkins N, Yaffe MB. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Sci-ence, 2005, 309(5737): 1074–1078.<\p>

[14] Zhao B, Lei QY, Guan KL. The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr Opin Cell Biol, 2008, 20(6): 638–646.<\p>

[15] Mao YP, Mulvaney J, Zakaria S, Yu T, Morgan KM, Allen S, Basson MA, Francis-West P, Irvine KD. Characteriza-tion of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development. Development, 2011, 138(5): 947–957.<\p>

[16] Zhao B, Li L, Lei QY, Guan KL. The Hippo-YAP pathway in organ size control and tumorigenesis. Genes Dev, 2010, 24(9): 862–874.<\p>

[17] 许传铭, 万福生. 哺乳动物Hippo信号通路: 肿瘤治疗的新标靶. 遗传, 2012, 34(3): 269–280.<\p>

[18] Kanai F, Marignani PA, Sarbassova D, Yagi R, Hall RA, Donowitz M, Hisaminato A, Fujiwara T, Ito Y, Cantley LC, Yaffe MB. TAZ: a novel transcriptional co-activator regu-lated by interactions with 14-3-3 and PDZ domain proteins. EMBO J, 2000, 19(24): 6778–6791.<\p>

[19] Zhao B, Wei XM, Li WQ, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu JD, Li L, Zheng P, Ye KQ, Chinnaiyan A, Halder G, Lai ZC, Guan KL. Inactivation of YAP onco-protein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev, 2007, 21(21): 2747–2761.<\p>

[20] Hong WJ, Guan KL. The YAP and TAZ transcription co-activators: Key downstream effectors of the mammal-ian Hippo pathway. Seminars Cell Dev Biol, 2012, 23(7): 785–793.<\p>

[21] Bork P, Sudol M. The WW domain: a signalling site in dystrophin. Trends Biochem Sci, 1994, 19(12): 531–533.<\p>

[22] Sudol M, Bork P, Einbond A, Kastury K, Druck T, Negrini M, Huebner K, Lehman D. Characterization of the mam-malian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain. J Biol Chem, 1995, 270(24): 14733–14741.<\p>

[23] Pobbati AV, Hong W. Emerging roles of TEAD transcrip-tion factors and its coactivators in cancers. Cancer Biol Ther, 2013, 14(5): 390–398.<\p>

[24] Cui CB, Cooper LF, Yang XL, Karsenty G, Aukhil I. Transcriptional coactivation of bone-specific transcription factor Cbfa1 by TAZ. Mol Cell Biol, 2003, 23(3): 1004– 1013.<\p>

[25] Sudol M. Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product. Oncogene, 1994, 9(8): 2145–2152.<\p>

[26] Id Boufker H, Lagneaux L, Najar M, Piccart M, Ghanem G, Body JJ, Journé F. The Src inhibitor dasatinib accelerates the differentiation of human bone marrow-derived mes-enchymal stromal cells into osteoblasts. BMC Cancer, 2010, 10(1): 298.<\p>

[27] Yagi R, Chen LF, Shigesada K, Murakami Y, Ito Y. A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J, 1999, 18(9): 2551–2562.<\p>

[28] He Q, Huang HY, Zhang YY, Li X, Qian SW, Tang QQ. TAZ is downregulated by dexamethasone during the dif-ferentiation of 3T3-L1 preadipocytes. Biochem Biophys Res Commun, 2012, 419(3): 573–577.<\p>

[29] Park BH, Kim DS, Won GW, Jeon HJ, Oh BC, Lee Y, Kim EG, Lee YH. Mammalian ste20-like kinase and SAV1 promote 3T3-L1 adipocyte differentiation by activation of PPARγ. PLoS ONE, 2012, 7(1): e30983.<\p>

[30] Genini D, Catapano CV. Control of peroxisome prolifera-tor-activated receptor fate by the ubiquitinproteasome system. J Recept Signal Transduct Res, 2006, 26(5-6): 679–692.<\p>

[31] Tedesco FS, Dellavalle A, Diaz-Manera J, Messina G, Cossu G. Repairing skeletal muscle: regenerative potential of skeletal muscle stem cells. J Clin Invest, 2010, 120(1): 11–19.<\p>

[32] Grabowska I, Streminska W, Janczyk-Ilach K, Machaj EK, Pojda Z, Hoser G, Kawiak J, Moraczewski J, Ciemerych MA, Brzoska E. Myogenic potential of mesenchymal stem cells - the case of adhesive fraction of human umbilical cord blood cells. Curr Stem Cell Res Ther, 2013, 8(1): 82– 90.<\p>

[33] Jeong H, Bae SJ, An SY, Byun MR, Hwang JH, Yaffe MB, Hong JH, Hwang ES. TAZ as a novel enhancer of MyoD-mediated myogenic differentiation. FASEB J, 2010, 24(9): 3310–3320.<\p>

[34] Nejigane S, Haramoto Y, Okuno M, Takahashi S, Asashima M. The transcriptional coactivators Yap and TAZ are expressed during early Xenopus development. Int J Dev Biol, 2011, 55(1): 121–126.<\p>

[35] Watt KI, Judson R, Medlow P, Reid K, Kurth TB, Burniston JG, Ratkevicius A, De Bari C, Wackerhage H. Yap is a novel regulator of C2C12 myogenesis. Biochem Biophys Res Commun, 2010, 393(4): 619–624.<\p>

[36] Boland GM, Perkins G, Hall DJ, Tuan RS. Wnt 3a pro-motes proliferation and suppresses osteogenic differentia-tion of adult human mesenchymal stem cells. J Cell Bio-chem, 2004, 93(6): 1210–1230.<\p>

[37] Moldes M, Zuo Y, Morrison RF, Silva D, Park BH, Liu J, Farmer SR. Peroxisome-proliferator-activated receptor gamma suppresses Wnt/beta-catenin signalling during adi-pogenesis. Biochem J, 2003, 376(Pt 3): 607–613.<\p>

[38] Hartmann C, Tabin CJ. Dual roles of Wnt signaling during chondrogenesis in the chicken limb. Development, 2000, 127(14): 3141–3159.<\p>

[39] Varelas X, Miller BW, Sopko R, Song SY, Gregorieff A, Fellouse FA, Sakuma R, Pawson T, Hunziker W, McNeill H, Wrana JL, Attisano L. The Hippo pathway regulates Wnt/β-catenin signaling. Dev Cell, 2010, 18(4): 579–591.<\p>

[40] Zhao LM, Jiang S, Hantash BM. Transforming growth factor β1 induces osteogenic differentiation of murine bone marrow stromal cells. Tissue Eng Part A, 2010, 16(2): 725–733.<\p>

[41] Varelas X, Sakuma R, Samavarchi-Tehrani P, Peerani R, Rao BM, Dembowy J, Yaffe MB, Zandstra PW, Wrana JL. TAZ controls Smad nucleocytoplasmic shuttling and regu-lates human embryonic stem-cell self-renewal. Nat Cell Biol, 2008, 10(7): 837–848.<\p>

[42] Zimmermann G, Henle P, Küsswetter M, Moghaddam A, Wentzensen A, Richter W, Weiss S. TGF-β1 as a marker of delayed fracture healing. Bone, 2005, 36(5): 779–785.<\p>

[43] Cho HH, Shin KK, Kim YJ, Song JS, Kim JM, Bae YC, Kim CD, Jung JS. NF-kappaB activation stimulates os-teogenic differentiation of mesenchymal stem cells de-rived from human adipose tissue by increasing TAZ ex-pression. J Cell Physiol, 2010, 223(1): 168–177.<\p>

[44] Gilbert L, He XF, Farmer P, Boden S, Kozlowski M, Rubin J, Nanes MS. Inhibition of osteoblast differentiation by tumor necrosis factor-α. Endocrinology, 2000, 141(11): 3956–3964.<\p>

[45] Li BZ, Shi MX, Li J, Zhang HB, Chen B, Chen L, Gao WB, Giuliani N, Zhao RC. Elevated tumor necrosis factor-αsuppresses TAZ expression and impairs osteogenic po-tential of Flk-1+ mesenchymal stem cells in patients with multiple myeloma. Stem Cells Dev, 2007, 16(6): 921–930.<\p>

[46] Xing WR, Kim J, Wergedal J, Chen ST, Mohan S. Ephrin B1 regulates bone marrow stromal cell differentiation and bone formation by influencing TAZ transactivation via complex formation with NHERF1. Mol Cell Biol, 2010, 30(3): 711–721.<\p>

[47] Jang EJ, Jeong H, Kang JO, Kim NJ, Kim MS, Choi SH, Yoo SE, Hong JH, Bae MA, Hwang ES. TM-25659 en-hances osteogenic differentiation and suppresses adipo-genic differentiation by modulating the transcriptional co-activator TAZ. Br J Pharmacol, 2012, 165(5): 1584–1594.<\p>

[48] Jung H, Lee MS, Jang EJ, Ahn JH, Kang NS, Yoo SE, Bae MA, Hong JH, Hwang ES. Augmentation of PPARγ-TAZ interaction contributes to the anti-adipogenic activity of KR62980. Biochem Pharmacol, 2009, 78(10): 1323–1329.<\p>

[49] Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N, Piccolo S. Role of YAP/TAZ in mechanotransduction. Nature, 2011, 474(7350): 179–183.<\p>

[50] Wada K I, Itoga K, Okano T, Yonemura S, Sasaki H. Hippo pathway regulation by cell morphology and stress fibers. Development, 2011, 138(18): 3907–3914.<\p>

[51] Mauviel A, Nallet-Staub F, Varelas X. Integrating devel-opmental signals: a Hippo in the (path)way. Oncogene, 2012, 31(14): 1743–1756.<\p>

[52] Regué L, Mou F, Avruch J. G protein-coupled receptors engage the mammalian Hippo pathway through F-actin: F-Actin, assembled in response to Galpha12/13 induced RhoA-GTP, promotes dephosphorylation and activation of the YAP oncogene. BioEssays, 2013, 35(5): 430–435.<\p>

编辑推荐

Metrics

www.chinagene.cn
备案号：京ICP备09063187号
总访问:,今日访问:,当前在线:

Hippo信号通路转录效应因子TAZ/YAP对间充质干细胞分化的调控

Regulation of differentiation of mesenchymal stem cells by the Hippo pathway effectors TAZ/YAP

PDF (PC)

可视化

被引次数

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

[1]	李欢, 冯晋川, 李贵林, 王讯, 李明洲, 刘海峰. Lnc-RAP3对小鼠3T3-L1前脂肪细胞分化的影响[J]. 遗传, 2018, 40(9): 758-766.
[2]	李夏, 滑慧娟, 郝捷, 王柳, 刘忠华. 利用微载体悬浮培养人脐带间充质干细胞[J]. 遗传, 2018, 40(12): 1120-1128.
[3]	任岚,肖茹丹,张倩,娄晓敏,张昭军,方向东. KLF1和KLF9对K562细胞红系分化的协同调控作用[J]. 遗传, 2018, 40(11): 998-1006.
[4]	杨熳,卢冰婕,段媛媛,陈晓峰,马建岗,郭燕. 骨质疏松症易感基因BDNF的遗传学关联分析及功能研究[J]. 遗传, 2017, 39(8): 726-736.
[5]	孙书国, 吴世安, 张雷. Hippo信号通路在果蝇遗传学研究中的发现与扩展[J]. 遗传, 2017, 39(7): 537-545.
[6]	吉新彦, 钟国轩, 赵斌. 哺乳动物Hippo信号通路分子机制研究进展[J]. 遗传, 2017, 39(7): 546-567.
[7]	张平平,佟鑫,张天乐,黎子琛,龚清秋. 植物Hippo信号通路研究进展[J]. 遗传, 2017, 39(7): 568-575.
[8]	顾远, 张雷, 余发星. Hippo信号通路在肠道稳态、再生及癌变过程中的作用及机制[J]. 遗传, 2017, 39(7): 588-596.
[9]	付思玲,赵婉滢,张雯婧,宋海,季红斌,汤楠. Hippo信号通路在肺发育、再生和疾病中的功能[J]. 遗传, 2017, 39(7): 597-606.
[10]	姚传波, 周鑫, 陈策实, 雷群英. Hippo信号通路在乳腺癌中的调控机制及作用[J]. 遗传, 2017, 39(7): 617-629.
[11]	包笑妹, 何晴, 王莹, 黄智慧, 袁增强. Hippo/YAP信号通路在神经系统中的作用及机制研究进展[J]. 遗传, 2017, 39(7): 630-641.
[12]	周欣,李伟芸,王红艳. MST1/2调控先天免疫的功能和机制[J]. 遗传, 2017, 39(7): 642-649.
[13]	余淑娟,耿晶,陈兰芬. Hippo信号通路调控免疫细胞的功能[J]. 遗传, 2017, 39(7): 650-658.
[14]	胡立桥,周兆才,田伟. Hippo信号通路结构生物学研究进展[J]. 遗传, 2017, 39(7): 659-674.
[15]	亢逸,关桂君,洪云汉. 用模式生物青鳉概观硬骨鱼性别决定及性分化研究进展[J]. 遗传, 2017, 39(6): 441-454.