YAP1

File:Modular Structure of YAP1 Isoforms.jpg

Cloning of the YAP1 gene facilitated the identification of a modular protein domain, known as the WW domain. Two splice isoforms of the YAP1 gene product were initially identified, named YAP1-1 and YAP1-2, which differed by the presence of an extra 38 amino acids that encoded the WW domain. Apart from the WW domain, the modular structure of YAP1 contains a proline-rich region at the very amino terminus, which is followed by a TID (TEAD transcription factor interacting domain). Next, following a single WW domain, which is present in the YAP1-1 isoform, and two WW domains, which are present in the YAP1-2 isoform, there is the SH3-BM (Src Homology 3 binding motif). Following the SH3-BM is a TAD (transactivation domain) and a PDZ domain-binding motif (PDZ-BM) (Figure 1).

YAP1 is a transcriptional co-activator and its proliferative and oncogenic activity is driven by its association with the TEAD family of transcription factors, which up-regulate genes that promote cell growth and inhibit apoptosis. Several other functional partners of YAP1 were identified, including RUNX, SMADs, p73, ErbB4, TP53BP2, LATS1/2, PTPN14, AMOTs, and ZO1/2. YAP1 and its close paralog, TAZ (WWTR1), are the main effectors of the Hippo tumor suppressor pathway. When the pathway is activated, YAP1 and TAZ are phosphorylated on a serine residue and sequestered in the cytoplasm by 14-3-3 proteins. When the Hippo pathway is not activated, YAP1/TAZ enter the nucleus and regulate gene expression.

It is reported that several genes are regulated by YAP1, including Birc2, Birc5, connective tissue growth factor (CTGF), amphiregulin (AREG), Cyr61, Hoxa1 and Hoxc13.

YAP/TAZ have also been shown to act as stiffness sensors, regulating mechanotransduction independently of the Hippo signalling cascade.{{cite journal | vauthors = McMurray RJ, Dalby MJ, Tsimbouri PM | title = Using biomaterials to study stem cell mechanotransduction, growth and differentiation | journal = Journal of Tissue Engineering and Regenerative Medicine | volume = 9 | issue = 5 | pages = 528–39 | date = May 2015 | pmid = 25370612 | doi = 10.1002/term.1957 | s2cid = 39642567 | url = http://eprints.gla.ac.uk/97094/1/97094.pdf | doi-access = free }}

As YAP and TAZ are transcriptional co-activators, they do not have DNA-binding domains. Instead, when inside the nucleus, they regulate gene expression through TEAD1-4 which are sequence-specific transcription factors that mediate the main transcriptional output of the Hippo pathway.{{cite journal | vauthors = Zhao B, Ye X, Yu J, Li L, Li W, Li S, Yu J, Lin JD, Wang CY, Chinnaiyan AM, Lai ZC, Guan KL | display-authors = 6 | title = TEAD mediates YAP-dependent gene induction and growth control | journal = Genes & Development | volume = 22 | issue = 14 | pages = 1962–71 | date = July 2008 | pmid = 18579750 | pmc = 2492741 | doi = 10.1101/gad.1664408 }} The YAP/TAZ and TEAD interaction competitively inhibits and actively dissociates the TEAD/VGLL4 interaction which functions as a transcriptional repressor.{{cite journal | vauthors = Koontz LM, Liu-Chittenden Y, Yin F, Zheng Y, Yu J, Huang B, Chen Q, Wu S, Pan D | display-authors = 6 | title = The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression | journal = Developmental Cell | volume = 25 | issue = 4 | pages = 388–401 | date = May 2013 | pmid = 23725764 | pmc = 3705890 | doi = 10.1016/j.devcel.2013.04.021 }} Mouse models with YAP over-expression have been shown to exhibit up-regulation of the TEAD target gene expression which results in increased expansion of progenitor cells and tissue overgrowth.{{cite journal | vauthors = Chen Q, Zhang N, Xie R, Wang W, Cai J, Choi KS, David KK, Huang B, Yabuta N, Nojima H, Anders RA, Pan D | display-authors = 6 | title = Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP | journal = Genes & Development | volume = 29 | issue = 12 | pages = 1285–97 | date = June 2015 | pmid = 26109051 | pmc = 4495399 | doi = 10.1101/gad.264234.115 }}

File:YAP and TAZ - Biochemical Regulation Diagram.png

At the biochemical level, YAP is part of and regulated by the Hippo signaling pathway where a kinase cascade results in its “inactivation”, along with that of TAZ.{{cite journal | vauthors = Meng Z, Moroishi T, Guan KL | title = Mechanisms of Hippo pathway regulation | journal = Genes & Development | volume = 30 | issue = 1 | pages = 1–17 | date = January 2016 | pmid = 26728553 | pmc = 4701972 | doi = 10.1101/gad.274027.115 }} In this signaling cascade, TAO kinases phosphorylate Ste20-like kinases, MST1/2, at their activation loops (Thr183 for MST1 and Thr180 for MST2).{{cite journal | vauthors = Boggiano JC, Vanderzalm PJ, Fehon RG | title = Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway | journal = Developmental Cell | volume = 21 | issue = 5 | pages = 888–95 | date = November 2011 | pmid = 22075147 | pmc = 3217187 | doi = 10.1016/j.devcel.2011.08.028 }}{{cite journal | vauthors = Poon CL, Lin JI, Zhang X, Harvey KF | title = The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Salvador-Warts-Hippo pathway | journal = Developmental Cell | volume = 21 | issue = 5 | pages = 896–906 | date = November 2011 | pmid = 22075148 | doi = 10.1016/j.devcel.2011.09.012 | doi-access = free }} Active MST1/2 then phosphorylate SAV1 and MOB1A/B which are scaffold proteins that assist in the recruitment and phosphorylation of LATS1/2.{{cite journal | vauthors = Callus BA, Verhagen AM, Vaux DL | title = Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation | journal = The FEBS Journal | volume = 273 | issue = 18 | pages = 4264–76 | date = September 2006 | pmid = 16930133 | doi = 10.1111/j.1742-4658.2006.05427.x | s2cid = 8261982 | doi-access = free }}{{cite journal | vauthors = Praskova M, Xia F, Avruch J | title = MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation | journal = Current Biology | volume = 18 | issue = 5 | pages = 311–21 | date = March 2008 | pmid = 18328708 | pmc = 4682548 | doi = 10.1016/j.cub.2008.02.006 | bibcode = 2008CBio...18..311P }} LATS1/2 can also be phosphorylated by two groups of MAP4Ks.{{cite journal | vauthors = Meng Z, Moroishi T, Mottier-Pavie V, Plouffe SW, Hansen CG, Hong AW, Park HW, Mo JS, Lu W, Lu S, Flores F, Yu FX, Halder G, Guan KL | display-authors = 6 | title = MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway | journal = Nature Communications | volume = 6 | pages = 8357 | date = October 2015 | pmid = 26437443 | pmc = 4600732 | doi = 10.1038/ncomms9357 | bibcode = 2015NatCo...6.8357M }}{{cite journal | vauthors = Zheng Y, Wang W, Liu B, Deng H, Uster E, Pan D | title = Identification of Happyhour/MAP4K as Alternative Hpo/Mst-like Kinases in the Hippo Kinase Cascade | journal = Developmental Cell | volume = 34 | issue = 6 | pages = 642–55 | date = September 2015 | pmid = 26364751 | pmc = 4589524 | doi = 10.1016/j.devcel.2015.08.014 }} LATS1/2 then phosphorylate YAP and TAZ which causes them to bind with 14-3-3, resulting in cytoplasmic sequestration of YAP and TAZ.{{cite journal | vauthors = Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu J, Li L, Zheng P, Ye K, Chinnaiyan A, Halder G, Lai ZC, Guan KL | display-authors = 6 | title = Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control | journal = Genes & Development | volume = 21 | issue = 21 | pages = 2747–61 | date = November 2007 | pmid = 17974916 | pmc = 2045129 | doi = 10.1101/gad.1602907 }} The result of the activation of this pathway is the restriction of YAP/TAZ from entering the cell nucleus.

Additionally, YAP is regulated by mechanical cues such as extracellular matrix (ECM) rigidity, strain, shear stress, or adhesive area, processes that are reliant on cytoskeletal integrity.{{cite journal | vauthors = Elosegui-Artola A, Andreu I, Beedle AE, Lezamiz A, Uroz M, Kosmalska AJ, Oria R, Kechagia JZ, Rico-Lastres P, Le Roux AL, Shanahan CM, Trepat X, Navajas D, Garcia-Manyes S, Roca-Cusachs P | display-authors = 6 | title = Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores | journal = Cell | volume = 171 | issue = 6 | pages = 1397–1410.e14 | date = November 2017 | pmid = 29107331 | doi = 10.1016/j.cell.2017.10.008 | doi-access = free }} These mechanically induced localization phenomena are thought to be the result of nuclear flattening induced pore size change, mechanosensitive nuclear membrane ion channels, mechanical protein stability, or a variety of other factors. These mechanical factors have also been linked to certain cancer cells via nuclear softening and higher ECM stiffnesses.{{cite journal | vauthors = Cross SE, Jin YS, Rao J, Gimzewski JK | title = Nanomechanical analysis of cells from cancer patients | journal = Nature Nanotechnology | volume = 2 | issue = 12 | pages = 780–3 | date = December 2007 | pmid = 18654431 | doi = 10.1038/nnano.2007.388 | bibcode = 2007NatNa...2..780C }}{{cite journal | vauthors = Guck J, Schinkinger S, Lincoln B, Wottawah F, Ebert S, Romeyke M, Lenz D, Erickson HM, Ananthakrishnan R, Mitchell D, Käs J, Ulvick S, Bilby C | display-authors = 6 | title = Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence | language = English | journal = Biophysical Journal | volume = 88 | issue = 5 | pages = 3689–98 | date = May 2005 | pmid = 15722433 | pmc = 1305515 | doi = 10.1529/biophysj.104.045476 | url = | bibcode = 2005BpJ....88.3689G }}{{cite journal | vauthors = Friedl P, Alexander S | title = Cancer invasion and the microenvironment: plasticity and reciprocity | journal = Cell | volume = 147 | issue = 5 | pages = 992–1009 | date = November 2011 | pmid = 22118458 | doi = 10.1016/j.cell.2011.11.016 | doi-access = free }} Under this framework, the nuclear softening phenotype of cancer cells would promote nuclear flattening in response to a force, causing YAP localization, which could explain its over-expression and promoted proliferation in oncogenic cells.{{cite journal | vauthors = Shimomura T, Miyamura N, Hata S, Miura R, Hirayama J, Nishina H | title = The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity | journal = Biochemical and Biophysical Research Communications | volume = 443 | issue = 3 | pages = 917–23 | date = January 2014 | pmid = 24380865 | doi = 10.1016/j.bbrc.2013.12.100 }} Additionally, the higher ECM stiffness phenotype commonly seen in tumors due to enhanced integrin signaling could flatten the cell and nucleus, once again causing higher YAP nuclear localization. Likewise, the opposite effect of nuclear stiffening as a result of a variety of stimuli such as an over-expression of lamin A, has been shown to decrease nuclear YAP localization.{{cite journal | vauthors = Swift J, Ivanovska IL, Buxboim A, Harada T, Dingal PC, Pinter J, Pajerowski JD, Spinler KR, Shin JW, Tewari M, Rehfeldt F, Speicher DW, Discher DE | display-authors = 6 | title = Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation | journal = Science | volume = 341 | issue = 6149 | pages = 1240104 | date = August 2013 | pmid = 23990565 | pmc = 3976548 | doi = 10.1126/science.1240104 }}{{cite journal | vauthors = Gjorevski N, Sachs N, Manfrin A, Giger S, Bragina ME, Ordóñez-Morán P, Clevers H, Lutolf MP | display-authors = 6 | title = Designer matrices for intestinal stem cell and organoid culture | journal = Nature | volume = 539 | issue = 7630 | pages = 560–564 | date = November 2016 | pmid = 27851739 | doi = 10.1038/nature20168 | s2cid = 4470849 }}

Dysregulation of YAP/TAZ-mediated transcriptional activity is implicated in the development of abnormal cell growth and hyperactivation of YAP and TAZ has been observed amongst many cancers.{{cite journal | vauthors = Harvey KF, Zhang X, Thomas DM | title = The Hippo pathway and human cancer | journal = Nature Reviews. Cancer | volume = 13 | issue = 4 | pages = 246–57 | date = April 2013 | pmid = 23467301 | doi = 10.1038/nrc3458 | s2cid = 2008641 }}{{cite journal | vauthors = Johnson R, Halder G | title = The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment | journal = Nature Reviews. Drug Discovery | volume = 13 | issue = 1 | pages = 63–79 | date = January 2014 | pmid = 24336504 | pmc = 4167640 | doi = 10.1038/nrd4161 }} Hence YAP1 represents a potential target for the treatment of cancer.{{cite journal | vauthors = Moroishi T, Hansen CG, Guan KL | title = The emerging roles of YAP and TAZ in cancer | journal = Nature Reviews. Cancer | volume = 15 | issue = 2 | pages = 73–79 | date = February 2015 | pmid = 25592648 | pmc = 4562315 | doi = 10.1038/nrc3876 }}

While YAP has been identified as a proto-oncogene, it can also act as a tumor suppressor depending on cellular context.{{cite journal | vauthors = Jho E | title = Dual role of YAP: oncoprotein and tumor suppressor | journal = Journal of Thoracic Disease | volume = 10 | issue = Suppl 33 | pages = S3895–S3898 | date = November 2018 | pmid = 30631509 | pmc = 6297531 | doi = 10.21037/jtd.2018.10.70 | doi-access = free }}

The YAP1 oncogene serves as a target for the development of new cancer drugs. Small compounds have been identified that disrupt the YAP1-TEAD complex or block the binding function of WW domains. These small molecules represent lead compounds for the development of therapies for cancer patients, who harbor amplified or overexpressed YAP oncogene.

The Hippo/YAP signaling pathway may exert neuroprotective effects through mitigating blood-brain barrier disruption after cerebral ischemia/reperfusion injury.{{cite journal | vauthors = Gong P, Zhang Z, Zou C, Tian Q, Chen X, Hong M, Liu X, Chen Q, Xu Z, Li M, Wang J | display-authors = 6 | title = Hippo/YAP signaling pathway mitigates blood–brain barrier disruption after cerebral ischemia/reperfusion injury | journal = Behavioural Brain Research | volume = 356 | pages = 8–17 | date = January 2019 | pmid = 30092249 | pmc = 6193462 | doi = 10.1016/j.bbr.2018.08.003 }}

Heterozygous loss-of-function mutations in the YAP1 gene have been identified in two families with major eye malformations with or without extra-ocular features such as hearing loss, cleft lip, intellectual disability and renal disease.{{cite journal | vauthors = Williamson KA, Rainger J, Floyd JA, Ansari M, Meynert A, Aldridge KV, Rainger JK, Anderson CA, Moore AT, Hurles ME, Clarke A, van Heyningen V, Verloes A, Taylor MS, Wilkie AO, Fitzpatrick DR | display-authors = 6 | title = Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects | journal = American Journal of Human Genetics | volume = 94 | issue = 2 | pages = 295–302 | date = February 2014 | pmid = 24462371 | pmc = 3928658 | doi = 10.1016/j.ajhg.2014.01.001 }}

• {{PDBe-KB2|P46937|Human Transcriptional coactivator YAP1}}
• {{PDBe-KB2|P46938|Mouse Transcriptional coactivator YAP1}}

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{{reflist|33em|refs=

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{{cite journal | vauthors = Vassilev A, Kaneko KJ, Shu H, Zhao Y, DePamphilis ML | title = TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm | journal = Genes & Development | volume = 15 | issue = 10 | pages = 1229–41 | date = May 2001 | pmid = 11358867 | pmc = 313800 | doi = 10.1101/gad.888601 }}

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.{{cite journal | vauthors = Zhao B, Kim J, Ye X, Lai ZC, Guan KL | title = Both TEAD-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein | journal = Cancer Research | volume = 69 | issue = 3 | pages = 1089–98 | date = February 2009 | pmid = 19141641 | doi = 10.1158/0008-5472.CAN-08-2997 | doi-access = free }}

.{{cite journal | vauthors = Ferrigno O, Lallemand F, Verrecchia F, L'Hoste S, Camonis J, Atfi A, Mauviel A | title = Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling | journal = Oncogene | volume = 21 | issue = 32 | pages = 4879–84 | date = July 2002 | pmid = 12118366 | doi = 10.1038/sj.onc.1205623 | url = http://www.hal.inserm.fr/inserm-00147464 | doi-access = free }}

.{{cite journal | vauthors = Aragón E, Goerner N, Xi Q, Gomes T, Gao S, Massagué J, Macias MJ | title = Structural basis for the versatile interactions of Smad7 with regulator WW domains in TGF-β Pathways | journal = Structure | volume = 20 | issue = 10 | pages = 1726–36 | date = October 2012 | pmid = 22921829 | pmc = 3472128 | doi = 10.1016/j.str.2012.07.014 }}

{{cite journal | vauthors = Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A, Oren M, Sudol M, Cesareni G, Blandino G | display-authors = 6 | title = Physical interaction with Yes-associated protein enhances p73 transcriptional activity | journal = The Journal of Biological Chemistry | volume = 276 | issue = 18 | pages = 15164–73 | date = May 2001 | pmid = 11278685 | doi = 10.1074/jbc.M010484200 | doi-access = free }}

{{cite journal | vauthors = Komuro A, Nagai M, Navin NE, Sudol M | title = WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus | journal = The Journal of Biological Chemistry | volume = 278 | issue = 35 | pages = 33334–41 | date = August 2003 | pmid = 12807903 | doi = 10.1074/jbc.M305597200 | doi-access = free }}

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.{{cite journal | vauthors = Espanel X, Sudol M | title = Yes-associated protein and p53-binding protein-2 interact through their WW and SH3 domains | journal = The Journal of Biological Chemistry | volume = 276 | issue = 17 | pages = 14514–23 | date = April 2001 | pmid = 11278422 | doi = 10.1074/jbc.M008568200 | doi-access = free }}

{{cite journal | vauthors = Oka T, Mazack V, Sudol M | title = Mst2 and Lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP) | journal = The Journal of Biological Chemistry | volume = 283 | issue = 41 | pages = 27534–46 | date = October 2008 | pmid = 18640976 | doi = 10.1074/jbc.M804380200 | doi-access = free }}

{{cite journal | vauthors = Liu X, Yang N, Figel SA, Wilson KE, Morrison CD, Gelman IH, Zhang J | title = PTPN14 interacts with and negatively regulates the oncogenic function of YAP | journal = Oncogene | volume = 32 | issue = 10 | pages = 1266–73 | date = March 2013 | pmid = 22525271 | pmc = 4402938 | doi = 10.1038/onc.2012.147 }}

{{cite journal | vauthors = Wang W, Huang J, Chen J | title = Angiomotin-like proteins associate with and negatively regulate YAP1 | journal = The Journal of Biological Chemistry | volume = 286 | issue = 6 | pages = 4364–70 | date = February 2011 | pmid = 21187284 | pmc = 3039387 | doi = 10.1074/jbc.C110.205401 | doi-access = free }}

{{cite journal | vauthors = Chan SW, Lim CJ, Chong YF, Pobbati AV, Huang C, Hong W | title = Hippo pathway-independent restriction of TAZ and YAP by angiomotin | journal = The Journal of Biological Chemistry | volume = 286 | issue = 9 | pages = 7018–26 | date = March 2011 | pmid = 21224387 | pmc = 3044958 | doi = 10.1074/jbc.C110.212621 | doi-access = free }}

{{cite journal | vauthors = Zhao B, Li L, Lu Q, Wang LH, Liu CY, Lei Q, Guan KL | title = Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein | journal = Genes & Development | volume = 25 | issue = 1 | pages = 51–63 | date = January 2011 | pmid = 21205866 | pmc = 3012936 | doi = 10.1101/gad.2000111 }}

.{{cite journal | vauthors = Oka T, Schmitt AP, Sudol M | title = Opposing roles of angiomotin-like-1 and zona occludens-2 on pro-apoptotic function of YAP | journal = Oncogene | volume = 31 | issue = 1 | pages = 128–34 | date = January 2012 | pmid = 21685940 | doi = 10.1038/onc.2011.216 | doi-access = free }}

{{cite journal | vauthors = Oka T, Remue E, Meerschaert K, Vanloo B, Boucherie C, Gfeller D, Bader GD, Sidhu SS, Vandekerckhove J, Gettemans J, Sudol M | display-authors = 6 | title = Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling | journal = The Biochemical Journal | volume = 432 | issue = 3 | pages = 461–72 | date = December 2010 | pmid = 20868367 | doi = 10.1042/BJ20100870 | url = https://biblio.ugent.be/publication/1256657 | type = Submitted manuscript | hdl = 1854/LU-1256657 | hdl-access = free }}

{{cite journal | vauthors = Pan D | title = The hippo signaling pathway in development and cancer | journal = Developmental Cell | volume = 19 | issue = 4 | pages = 491–505 | date = October 2010 | pmid = 20951342 | pmc = 3124840 | doi = 10.1016/j.devcel.2010.09.011 }}

.{{cite journal | vauthors = Sudol M, Shields DC, Farooq A | title = Structures of YAP protein domains reveal promising targets for development of new cancer drugs | journal = Seminars in Cell & Developmental Biology | volume = 23 | issue = 7 | pages = 827–33 | date = September 2012 | pmid = 22609812 | pmc = 3427467 | doi = 10.1016/j.semcdb.2012.05.002 }}

{{cite journal | vauthors = Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee SJ, Anders RA, Liu JO, Pan D | display-authors = 6 | title = Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP | journal = Genes & Development | volume = 26 | issue = 12 | pages = 1300–5 | date = June 2012 | pmid = 22677547 | pmc = 3387657 | doi = 10.1101/gad.192856.112 }}

{{cite journal | vauthors = Kang SG, Huynh T, Zhou R | title = Non-destructive inhibition of metallofullerenol Gd@C(82)(OH)(22) on WW domain: implication on signal transduction pathway | journal = Scientific Reports | volume = 2 | pages = 957 | year = 2012 | pmid = 23233876 | pmc = 3518810 | doi = 10.1038/srep00957 | bibcode = 2012NatSR...2..957K }}

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{{Hippo signaling pathway}}

Category:Genes on human chromosome 11

Category:Transcription factors