YAP1

Last updated
YAP1
Protein YAP1 PDB 1jmq.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases YAP1 , COB1, YAP, YAP2, YAP65, YKI, Yes associated protein 1, Yap, Yes1 associated transcriptional regulator, YAP-1
External IDs OMIM: 606608; MGI: 103262; HomoloGene: 4452; GeneCards: YAP1; OMA:YAP1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001171147
NM_009534

RefSeq (protein)

NP_001164618
NP_033560

Location (UCSC) Chr 11: 102.11 – 102.23 Mb Chr 9: 7.93 – 8 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

YAP1 (yes-associated protein 1), also known as YAP or YAP65, is a protein that acts as a transcription coregulator that promotes transcription of genes involved in cellular proliferation and suppressing apoptotic genes. YAP1 is a component in the hippo signaling pathway which regulates organ size, regeneration, and tumorigenesis. YAP1 was first identified by virtue of its ability to associate with the SH3 domain of Yes and Src protein tyrosine kinases. [5] YAP1 is a potent oncogene, which is amplified in various human cancers. [6] [7]

Structure

Modular Structure of YAP1 Isoforms Modular Structure of YAP1 Isoforms.jpg
Modular Structure of YAP1 Isoforms

Cloning of the YAP1 gene facilitated the identification of a modular protein domain, known as the WW domain. [8] [9] [10] 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. [11] [12] 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). [13] 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). [5] [14] Following the SH3-BM is a TAD (transactivation domain) and a PDZ domain-binding motif (PDZ-BM) (Figure 1). [15] [16]

Function

YAP1 is a transcriptional co-activator [17] and its proliferative and oncogenic activity is driven by its association with the TEAD family of transcription factors, [13] which up-regulate genes that promote cell growth and inhibit apoptosis. [18] Several other functional partners of YAP1 were identified, including RUNX, [17] SMADs, [19] [20] p73, [21] ErbB4, [22] [23] TP53BP2, [24] LATS1/2, [25] PTPN14, [26] AMOTs, [27] [28] [29] [30] and ZO1/2. [31] YAP1 and its close paralog, TAZ (WWTR1), are the main effectors of the Hippo tumor suppressor pathway. [32] When the pathway is activated, YAP1 and TAZ are phosphorylated on a serine residue and sequestered in the cytoplasm by 14-3-3 proteins. [32] When the Hippo pathway is not activated, YAP1/TAZ enter the nucleus and regulate gene expression. [32]

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. [33]

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. [34] The YAP/TAZ and TEAD interaction competitively inhibits and actively dissociates the TEAD/VGLL4 interaction which functions as a transcriptional repressor. [35] 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. [36]

Regulation

Biochemical

On the left, the signaling cascade is inactivated so YAP readily localizes to the nucleus for transcription. On the right, the signal cascade causes YAP to localize to the cytoplasm, preventing transcription. YAP and TAZ - Biochemical Regulation Diagram.png
On the left, the signaling cascade is inactivated so YAP readily localizes to the nucleus for transcription. On the right, the signal cascade causes YAP to localize to the cytoplasm, preventing transcription.

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. [37] In this signaling cascade, TAO kinases phosphorylate Ste20-like kinases, MST1/2, at their activation loops (Thr183 for MST1 and Thr180 for MST2). [38] [39] Active MST1/2 then phosphorylate SAV1 and MOB1A/B which are scaffold proteins that assist in the recruitment and phosphorylation of LATS1/2. [40] [41] LATS1/2 can also be phosphorylated by two groups of MAP4Ks. [42] [43] LATS1/2 then phosphorylate YAP and TAZ which causes them to bind with 14-3-3, resulting in cytoplasmic sequestration of YAP and TAZ. [44] The result of the activation of this pathway is the restriction of YAP/TAZ from entering the cell nucleus.

Mechanotransductive

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. [45] 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. [45] These mechanical factors have also been linked to certain cancer cells via nuclear softening and higher ECM stiffnesses. [46] [47] [48] 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. [49] Additionally, the higher ECM stiffness phenotype commonly seen in tumors due to enhanced integrin signaling [48] 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. [50] [51]

Clinical significance

Cancer

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. [49] [52] [53] Hence YAP1 represents a potential target for the treatment of cancer. [54]

While YAP has been identified as a proto-oncogene, it can also act as a tumor suppressor depending on cellular context. [55]

As a drug target

The YAP1 oncogene serves as a target for the development of new cancer drugs. [56] Small compounds have been identified that disrupt the YAP1-TEAD complex or block the binding function of WW domains. [57] [58] These small molecules represent lead compounds for the development of therapies for cancer patients, who harbor amplified or overexpressed YAP oncogene.

Neuroprotection

The Hippo/YAP signaling pathway may exert neuroprotective effects through mitigating blood-brain barrier disruption after cerebral ischemia/reperfusion injury. [59]

Mutations

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. [60]

Related Research Articles

<span class="mw-page-title-main">Oncogene</span> Gene that has the potential to cause cancer

An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

<span class="mw-page-title-main">Angiomotin</span> Protein-coding gene in the species Homo sapiens

Angiomotin (AMOT) is a protein that in humans is encoded by the AMOT gene. It belongs to the motin family of angiostatin binding proteins, which includes angiomotin, angiomotin-like 1 (AMOTL1) and angiomotin-like 2 (AMOTL2) characterized by coiled-coil domains at N-terminus and consensus PDZ-binding domain at the C-terminus. Angiomotin is expressed predominantly in endothelial cells of capillaries as well as angiogenic tissues such as placenta and solid tumor.

<span class="mw-page-title-main">Transcription factor Jun</span> Mammalian protein found in Homo sapiens

Transcription factor Jun is a protein that in humans is encoded by the JUN gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the JUN gene. c-jun was the first oncogenic transcription factor discovered. The proto-oncogene c-Jun is the cellular homolog of the viral oncoprotein v-jun. The viral homolog v-jun was discovered in avian sarcoma virus 17 and was named for ju-nana, the Japanese word for 17. The human JUN encodes a protein that is highly similar to the viral protein, which interacts directly with specific target DNA sequences to regulate gene expression. This gene is intronless and is mapped to 1p32-p31, a chromosomal region involved in both translocations and deletions in human malignancies.

<span class="mw-page-title-main">AP-1 transcription factor</span> Instance of defined set in Homo sapiens with Reactome ID (R-HSA-6806560)

Activator protein 1 (AP-1) is a transcription factor that regulates gene expression in response to a variety of stimuli, including cytokines, growth factors, stress, and bacterial and viral infections. AP-1 controls a number of cellular processes including differentiation, proliferation, and apoptosis. The structure of AP-1 is a heterodimer composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families.

α-Catenin Primary protein link between cadherins and the actin cytoskeleton

α-Catenin (alpha-catenin) functions as the primary protein link between cadherins and the actin cytoskeleton. It has been reported that the actin binding proteins vinculin and α-actinin can bind to alpha-catenin. It has been suggested that alpha-catenin does not bind with high affinity to both actin filaments and the E-cadherin-beta-catenin complex at the same time. It has been observed that when α-catenin is not in a molecular complex with β-catenin, it dimerizes and functions to regulate actin filament assembly, possibly by competing with Arp2/3 protein. α-Catenin exhibits significant protein dynamics. However, a protein complex including a cadherin, actin, β-catenin and α-catenin has not been isolated.

<span class="mw-page-title-main">FYN</span> Mammalian protein found in Homo sapiens

Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.

<span class="mw-page-title-main">TEAD2</span> Protein-coding gene in the species Homo sapiens

TEAD2, together with TEAD1, defines a novel family of transcription factors, the TEAD family, highly conserved through evolution. TEAD proteins were notably found in Drosophila (Scalloped), C. elegans, S. cerevisiae and A. nidulans. TEAD2 has been less studied than TEAD1 but a few studies revealed its role during development.

<span class="mw-page-title-main">Proto-oncogene tyrosine-protein kinase Src</span> Mammalian protein found in humans

Proto-oncogene tyrosine-protein kinase Src, also known as proto-oncogene c-Src, or simply c-Src, is a non-receptor tyrosine kinase protein that in humans is encoded by the SRC gene. It belongs to a family of Src family kinases and is similar to the v-Src gene of Rous sarcoma virus. It includes an SH2 domain, an SH3 domain and a tyrosine kinase domain. Two transcript variants encoding the same protein have been found for this gene.

<span class="mw-page-title-main">Tyrosine-protein kinase Yes</span> Protein-coding gene in the species Homo sapiens

Tyrosine-protein kinase Yes is a non-receptor tyrosine kinase that in humans is encoded by the YES1 gene.

<span class="mw-page-title-main">TEAD1</span> Protein-coding gene in the species Homo sapiens

Transcriptional enhancer factor TEF-1 also known as TEA domain family member 1 (TEAD1) and transcription factor 13 (TCF-13) is a protein that in humans is encoded by the TEAD1 gene. TEAD1 was the first member of the TEAD family of transcription factors to be identified.

<span class="mw-page-title-main">MAP3K4</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 4 is an enzyme that in humans is encoded by the MAP3K4 gene.

<span class="mw-page-title-main">LATS1</span> Protein-coding gene in the species Homo sapiens

Large tumor suppressor kinase 1 (LATS1) is an enzyme that in humans is encoded by the LATS1 gene.

<span class="mw-page-title-main">STK3</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase 3 is an enzyme that in humans is encoded by the STK3 gene.

<span class="mw-page-title-main">LATS2</span> Protein-coding gene in the species Homo sapiens

Large tumor suppressor kinase 2 (LATS2) is an enzyme that in humans is encoded by the LATS2 gene.

<span class="mw-page-title-main">WWTR1</span> Protein-coding gene in the species Homo sapiens

WW domain-containing transcription regulator protein 1 (WWTR1), also known as Transcriptional coactivator with PDZ-binding motif (TAZ), is a protein that in humans is encoded by the WWTR1 gene. WWTR1 acts as a transcriptional coregulator and has no effect on transcription alone. When in complex with transcription factor binding partners, WWTR1 helps promote gene expression in pathways associated with development, cell growth and survival, and inhibiting apoptosis. Aberrant WWTR1 function has been implicated for its role in driving cancers. WWTR1 is often referred to as TAZ due to its initial characterization with the name TAZ. However, WWTR1 (TAZ) is not to be confused with the protein tafazzin, which originally held the official gene symbol TAZ, and is now TAFAZZIN.

The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.

<span class="mw-page-title-main">Hippo signaling pathway</span> Signaling pathway that controls organ size

The Hippo signaling pathway, also known as the Salvador-Warts-Hippo (SWH) pathway, is a signaling pathway that controls organ size in animals through the regulation of cell proliferation and apoptosis. The pathway takes its name from one of its key signaling components—the protein kinase Hippo (Hpo). Mutations in this gene lead to tissue overgrowth, or a "hippopotamus"-like phenotype.

<span class="mw-page-title-main">WW domain</span>

The WW domain is a modular protein domain that mediates specific interactions with protein ligands. This domain is found in a number of unrelated signaling and structural proteins and may be repeated up to four times in some proteins. Apart from binding preferentially to proteins that are proline-rich, with particular proline-motifs, [AP]-P-P-[AP]-Y, some WW domains bind to phosphoserine- and phosphothreonine-containing motifs.

<span class="mw-page-title-main">Marius Sudol</span> American cellular biologist (born 1954)

Marius Sudol is an American molecular and cellular biologist. He was born in 1954 in Tarnow, Poland. In 1978, he immigrated to the United States to study at The Rockefeller University in New York City, where he received his Ph.D. in 1983. He is currently an Adjunct Faulty at the Icahn School of Medicine at Mount Sinai in NYC.

Barry James Thompson is an Australian and British developmental biologist and cancer biologist. Thompson is known for identifying genes, proteins and mechanisms involved in epithelial polarity, morphogenesis and cell signaling via the Wnt and Hippo signaling pathways, which have key roles in human cancer.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000137693 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000053110 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Sudol M (August 1994). "Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product". Oncogene. 9 (8): 2145–52. PMID   8035999.
  6. Huang J, Wu S, Barrera J, Matthews K, Pan D (August 2005). "The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP". Cell. 122 (3): 421–34. doi: 10.1016/j.cell.2005.06.007 . PMID   16096061. S2CID   14139806.
  7. Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, et al. (August 2006). "Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon". Proceedings of the National Academy of Sciences of the United States of America. 103 (33): 12405–10. Bibcode:2006PNAS..10312405O. doi: 10.1073/pnas.0605579103 . PMC   1533802 . PMID   16894141.
  8. Bork P, Sudol M (December 1994). "The WW domain: a signalling site in dystrophin?". Trends in Biochemical Sciences. 19 (12): 531–3. doi:10.1016/0968-0004(94)90053-1. PMID   7846762.
  9. André B, Springael JY (December 1994). "WWP, a new amino acid motif present in single or multiple copies in various proteins including dystrophin and the SH3-binding Yes-associated protein YAP65". Biochemical and Biophysical Research Communications. 205 (2): 1201–5. doi:10.1006/bbrc.1994.2793. PMID   7802651.
  10. Hofmann K, Bucher P (January 1995). "The rsp5-domain is shared by proteins of diverse functions". FEBS Letters. 358 (2): 153–7. Bibcode:1995FEBSL.358..153H. doi: 10.1016/0014-5793(94)01415-W . PMID   7828727. S2CID   23110605.
  11. Sudol M, Bork P, Einbond A, Kastury K, Druck T, Negrini M, et al. (June 1995). "Characterization of the mammalian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain". The Journal of Biological Chemistry. 270 (24): 14733–41. doi: 10.1074/jbc.270.24.14733 . PMID   7782338.
  12. Gaffney CJ, Oka T, Mazack V, Hilman D, Gat U, Muramatsu T, et al. (November 2012). "Identification, basic characterization and evolutionary analysis of differentially spliced mRNA isoforms of human YAP1 gene". Gene. 509 (2): 215–22. doi:10.1016/j.gene.2012.08.025. PMC   3455135 . PMID   22939869.
  13. 1 2 Vassilev A, Kaneko KJ, Shu H, Zhao Y, DePamphilis ML (May 2001). "TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm". Genes & Development. 15 (10): 1229–41. doi:10.1101/gad.888601. PMC   313800 . PMID   11358867.
  14. Ren R, Mayer BJ, Cicchetti P, Baltimore D (February 1993). "Identification of a ten-amino acid proline-rich SH3 binding site". Science. 259 (5098): 1157–61. Bibcode:1993Sci...259.1157R. doi:10.1126/science.8438166. PMID   8438166.
  15. Wang S, Raab RW, Schatz PJ, Guggino WB, Li M (May 1998). "Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR)". FEBS Letters. 427 (1): 103–8. Bibcode:1998FEBSL.427..103W. doi: 10.1016/S0014-5793(98)00402-5 . PMID   9613608. S2CID   20803242.
  16. Mohler PJ, Kreda SM, Boucher RC, Sudol M, Stutts MJ, Milgram SL (November 1999). "Yes-associated protein 65 localizes p62(c-Yes) to the apical compartment of airway epithelia by association with EBP50". The Journal of Cell Biology. 147 (4): 879–90. doi:10.1083/jcb.147.4.879. PMC   2156157 . PMID   10562288.
  17. 1 2 Yagi R, Chen LF, Shigesada K, Murakami Y, Ito Y (May 1999). "A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator". The EMBO Journal. 18 (9): 2551–62. doi:10.1093/emboj/18.9.2551. PMC   1171336 . PMID   10228168.
  18. Zhao B, Kim J, Ye X, Lai ZC, Guan KL (February 2009). "Both TEAD-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein". Cancer Research. 69 (3): 1089–98. doi: 10.1158/0008-5472.CAN-08-2997 . PMID   19141641.
  19. Ferrigno O, Lallemand F, Verrecchia F, L'Hoste S, Camonis J, Atfi A, Mauviel A (July 2002). "Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling". Oncogene. 21 (32): 4879–84. doi: 10.1038/sj.onc.1205623 . PMID   12118366.
  20. Aragón E, Goerner N, Xi Q, Gomes T, Gao S, Massagué J, Macias MJ (October 2012). "Structural basis for the versatile interactions of Smad7 with regulator WW domains in TGF-β Pathways". Structure. 20 (10): 1726–36. doi:10.1016/j.str.2012.07.014. PMC   3472128 . PMID   22921829.
  21. Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A, et al. (May 2001). "Physical interaction with Yes-associated protein enhances p73 transcriptional activity". The Journal of Biological Chemistry. 276 (18): 15164–73. doi: 10.1074/jbc.M010484200 . PMID   11278685.
  22. Komuro A, Nagai M, Navin NE, Sudol M (August 2003). "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". The Journal of Biological Chemistry. 278 (35): 33334–41. doi: 10.1074/jbc.M305597200 . PMID   12807903.
  23. Omerovic J, Puggioni EM, Napoletano S, Visco V, Fraioli R, Frati L, et al. (April 2004). "Ligand-regulated association of ErbB-4 to the transcriptional co-activator YAP65 controls transcription at the nuclear level". Experimental Cell Research. 294 (2): 469–79. doi:10.1016/j.yexcr.2003.12.002. PMID   15023535.
  24. Espanel X, Sudol M (April 2001). "Yes-associated protein and p53-binding protein-2 interact through their WW and SH3 domains". The Journal of Biological Chemistry. 276 (17): 14514–23. doi: 10.1074/jbc.M008568200 . PMID   11278422.
  25. Oka T, Mazack V, Sudol M (October 2008). "Mst2 and Lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP)". The Journal of Biological Chemistry. 283 (41): 27534–46. doi: 10.1074/jbc.M804380200 . PMID   18640976.
  26. Liu X, Yang N, Figel SA, Wilson KE, Morrison CD, Gelman IH, Zhang J (March 2013). "PTPN14 interacts with and negatively regulates the oncogenic function of YAP". Oncogene. 32 (10): 1266–73. doi:10.1038/onc.2012.147. PMC   4402938 . PMID   22525271.
  27. Wang W, Huang J, Chen J (February 2011). "Angiomotin-like proteins associate with and negatively regulate YAP1". The Journal of Biological Chemistry. 286 (6): 4364–70. doi: 10.1074/jbc.C110.205401 . PMC   3039387 . PMID   21187284.
  28. Chan SW, Lim CJ, Chong YF, Pobbati AV, Huang C, Hong W (March 2011). "Hippo pathway-independent restriction of TAZ and YAP by angiomotin". The Journal of Biological Chemistry. 286 (9): 7018–26. doi: 10.1074/jbc.C110.212621 . PMC   3044958 . PMID   21224387.
  29. Zhao B, Li L, Lu Q, Wang LH, Liu CY, Lei Q, Guan KL (January 2011). "Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein". Genes & Development. 25 (1): 51–63. doi:10.1101/gad.2000111. PMC   3012936 . PMID   21205866.
  30. Oka T, Schmitt AP, Sudol M (January 2012). "Opposing roles of angiomotin-like-1 and zona occludens-2 on pro-apoptotic function of YAP". Oncogene. 31 (1): 128–34. doi: 10.1038/onc.2011.216 . PMID   21685940.
  31. Oka T, Remue E, Meerschaert K, Vanloo B, Boucherie C, Gfeller D, et al. (December 2010). "Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling". The Biochemical Journal (Submitted manuscript). 432 (3): 461–72. doi:10.1042/BJ20100870. hdl: 1854/LU-1256657 . PMID   20868367.
  32. 1 2 3 Pan D (October 2010). "The hippo signaling pathway in development and cancer". Developmental Cell. 19 (4): 491–505. doi:10.1016/j.devcel.2010.09.011. PMC   3124840 . PMID   20951342.
  33. McMurray RJ, Dalby MJ, Tsimbouri PM (May 2015). "Using biomaterials to study stem cell mechanotransduction, growth and differentiation" (PDF). Journal of Tissue Engineering and Regenerative Medicine. 9 (5): 528–39. doi: 10.1002/term.1957 . PMID   25370612. S2CID   39642567.
  34. Zhao B, Ye X, Yu J, Li L, Li W, Li S, et al. (July 2008). "TEAD mediates YAP-dependent gene induction and growth control". Genes & Development. 22 (14): 1962–71. doi:10.1101/gad.1664408. PMC   2492741 . PMID   18579750.
  35. Koontz LM, Liu-Chittenden Y, Yin F, Zheng Y, Yu J, Huang B, et al. (May 2013). "The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression". Developmental Cell. 25 (4): 388–401. doi:10.1016/j.devcel.2013.04.021. PMC   3705890 . PMID   23725764.
  36. Chen Q, Zhang N, Xie R, Wang W, Cai J, Choi KS, et al. (June 2015). "Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP". Genes & Development. 29 (12): 1285–97. doi:10.1101/gad.264234.115. PMC   4495399 . PMID   26109051.
  37. Meng Z, Moroishi T, Guan KL (January 2016). "Mechanisms of Hippo pathway regulation". Genes & Development. 30 (1): 1–17. doi:10.1101/gad.274027.115. PMC   4701972 . PMID   26728553.
  38. Boggiano JC, Vanderzalm PJ, Fehon RG (November 2011). "Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway". Developmental Cell. 21 (5): 888–95. doi:10.1016/j.devcel.2011.08.028. PMC   3217187 . PMID   22075147.
  39. Poon CL, Lin JI, Zhang X, Harvey KF (November 2011). "The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Salvador-Warts-Hippo pathway". Developmental Cell. 21 (5): 896–906. doi: 10.1016/j.devcel.2011.09.012 . PMID   22075148.
  40. Callus BA, Verhagen AM, Vaux DL (September 2006). "Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation". The FEBS Journal. 273 (18): 4264–76. doi: 10.1111/j.1742-4658.2006.05427.x . PMID   16930133. S2CID   8261982.
  41. Praskova M, Xia F, Avruch J (March 2008). "MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation". Current Biology. 18 (5): 311–21. Bibcode:2008CBio...18..311P. doi:10.1016/j.cub.2008.02.006. PMC   4682548 . PMID   18328708.
  42. Meng Z, Moroishi T, Mottier-Pavie V, Plouffe SW, Hansen CG, Hong AW, et al. (October 2015). "MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway". Nature Communications. 6: 8357. Bibcode:2015NatCo...6.8357M. doi:10.1038/ncomms9357. PMC   4600732 . PMID   26437443.
  43. Zheng Y, Wang W, Liu B, Deng H, Uster E, Pan D (September 2015). "Identification of Happyhour/MAP4K as Alternative Hpo/Mst-like Kinases in the Hippo Kinase Cascade". Developmental Cell. 34 (6): 642–55. doi:10.1016/j.devcel.2015.08.014. PMC   4589524 . PMID   26364751.
  44. Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, et al. (November 2007). "Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control". Genes & Development. 21 (21): 2747–61. doi:10.1101/gad.1602907. PMC   2045129 . PMID   17974916.
  45. 1 2 Elosegui-Artola A, Andreu I, Beedle AE, Lezamiz A, Uroz M, Kosmalska AJ, et al. (November 2017). "Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores". Cell. 171 (6): 1397–1410.e14. doi: 10.1016/j.cell.2017.10.008 . PMID   29107331.
  46. Cross SE, Jin YS, Rao J, Gimzewski JK (December 2007). "Nanomechanical analysis of cells from cancer patients". Nature Nanotechnology. 2 (12): 780–3. Bibcode:2007NatNa...2..780C. doi:10.1038/nnano.2007.388. PMID   18654431.
  47. Guck J, Schinkinger S, Lincoln B, Wottawah F, Ebert S, Romeyke M, et al. (May 2005). "Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence". Biophysical Journal. 88 (5): 3689–98. Bibcode:2005BpJ....88.3689G. doi:10.1529/biophysj.104.045476. PMC   1305515 . PMID   15722433.
  48. 1 2 Friedl P, Alexander S (November 2011). "Cancer invasion and the microenvironment: plasticity and reciprocity". Cell. 147 (5): 992–1009. doi: 10.1016/j.cell.2011.11.016 . PMID   22118458.
  49. 1 2 Shimomura T, Miyamura N, Hata S, Miura R, Hirayama J, Nishina H (January 2014). "The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity". Biochemical and Biophysical Research Communications. 443 (3): 917–23. doi:10.1016/j.bbrc.2013.12.100. PMID   24380865.
  50. Swift J, Ivanovska IL, Buxboim A, Harada T, Dingal PC, Pinter J, et al. (August 2013). "Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation". Science. 341 (6149): 1240104. doi:10.1126/science.1240104. PMC   3976548 . PMID   23990565.
  51. Gjorevski N, Sachs N, Manfrin A, Giger S, Bragina ME, Ordóñez-Morán P, et al. (November 2016). "Designer matrices for intestinal stem cell and organoid culture". Nature. 539 (7630): 560–564. doi:10.1038/nature20168. PMID   27851739. S2CID   4470849.
  52. Harvey KF, Zhang X, Thomas DM (April 2013). "The Hippo pathway and human cancer". Nature Reviews. Cancer. 13 (4): 246–57. doi:10.1038/nrc3458. PMID   23467301. S2CID   2008641.
  53. Johnson R, Halder G (January 2014). "The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment". Nature Reviews. Drug Discovery. 13 (1): 63–79. doi:10.1038/nrd4161. PMC   4167640 . PMID   24336504.
  54. Moroishi T, Hansen CG, Guan KL (February 2015). "The emerging roles of YAP and TAZ in cancer". Nature Reviews. Cancer. 15 (2): 73–79. doi:10.1038/nrc3876. PMC   4562315 . PMID   25592648.
  55. Jho E (November 2018). "Dual role of YAP: oncoprotein and tumor suppressor". Journal of Thoracic Disease. 10 (Suppl 33): S3895–S3898. doi: 10.21037/jtd.2018.10.70 . PMC   6297531 . PMID   30631509.
  56. Sudol M, Shields DC, Farooq A (September 2012). "Structures of YAP protein domains reveal promising targets for development of new cancer drugs". Seminars in Cell & Developmental Biology. 23 (7): 827–33. doi:10.1016/j.semcdb.2012.05.002. PMC   3427467 . PMID   22609812.
  57. Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee SJ, Anders RA, et al. (June 2012). "Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP". Genes & Development. 26 (12): 1300–5. doi:10.1101/gad.192856.112. PMC   3387657 . PMID   22677547.
  58. Kang SG, Huynh T, Zhou R (2012). "Non-destructive inhibition of metallofullerenol Gd@C(82)(OH)(22) on WW domain: implication on signal transduction pathway". Scientific Reports. 2: 957. Bibcode:2012NatSR...2E.957K. doi:10.1038/srep00957. PMC   3518810 . PMID   23233876.
  59. Gong P, Zhang Z, Zou C, Tian Q, Chen X, Hong M, et al. (January 2019). "Hippo/YAP signaling pathway mitigates blood–brain barrier disruption after cerebral ischemia/reperfusion injury". Behavioural Brain Research. 356: 8–17. doi:10.1016/j.bbr.2018.08.003. PMC   6193462 . PMID   30092249.
  60. Williamson KA, Rainger J, Floyd JA, Ansari M, Meynert A, Aldridge KV, et al. (February 2014). "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects". American Journal of Human Genetics. 94 (2): 295–302. doi:10.1016/j.ajhg.2014.01.001. PMC   3928658 . PMID   24462371.