Biology:YAP1

From HandWiki
Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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.[1] YAP1 is a potent oncogene, which is amplified in various human cancers.[2][3]

Structure

Modular Structure of YAP1 Isoforms

Cloning of the YAP1 gene facilitated the identification of a modular protein domain, known as the WW domain.[4][5][6] 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.[7][8] 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).[9] 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).[1][10] Following the SH3-BM is a TAD (transactivation domain) and a PDZ domain-binding motif (PDZ-BM) (Figure 1).[11][12]

Function

YAP1 is a transcriptional co-activator[13] and its proliferative and oncogenic activity is driven by its association with the TEAD family of transcription factors,[9] which up-regulate genes that promote cell growth and inhibit apoptosis.[14] Several other functional partners of YAP1 were identified, including RUNX,[13] SMADs,[15][16] p73,[17] ErbB4,[18][19] TP53BP2,[20] LATS1/2,[21] PTPN14,[22] AMOTs,[23][24][25][26] and ZO1/2.[27] YAP1 and its close paralog, TAZ (WWTR1), are the main effectors of the Hippo tumor suppressor pathway.[28] When the pathway is activated, YAP1 and TAZ are phosphorylated on a serine residue and sequestered in the cytoplasm by 14-3-3 proteins.[28] When the Hippo pathway is not activated, YAP1/TAZ enter the nucleus and regulate gene expression.[28]

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.[29]

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.[30] The YAP/TAZ and TEAD interaction competitively inhibits and actively dissociates the TEAD/VGLL4 interaction which functions as a transcriptional repressor.[31] 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.[32]

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.

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.[33] In this signaling cascade, TAO kinases phosphorylate Ste20-like kinases, MST1/2, at their activation loops (Thr183 for MST1 and Thr180 for MST2).[34][35] Active MST1/2 then phosphorylate SAV1 and MOB1A/B which are scaffold proteins that assist in the recruitment and phosphorylation of LATS1/2.[36][37] LATS1/2 can also be phosphorylated by two groups of MAP4Ks.[38][39] LATS1/2 then phosphorylate YAP and TAZ which causes them to bind with 14-3-3, resulting in cytoplasmic sequestration of YAP and TAZ.[40] 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.[41] 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.[41] These mechanical factors have also been linked to certain cancer cells via nuclear softening and higher ECM stiffnesses.[42][43][44] 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.[45] Additionally, the higher ECM stiffness phenotype commonly seen in tumors due to enhanced integrin signaling[44] 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.[46][47]

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.[45][48][49] Hence YAP1 represents a potential target for the treatment of cancer.[50]

While YAP has been identified as a proto-oncogene, it can also act as a tumor suppressor depending on cellular context.[51]

As a drug target

The YAP1 oncogene serves as a target for the development of new cancer drugs.[52] Small compounds have been identified that disrupt the YAP1-TEAD complex or block the binding function of WW domains.[53][54] 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.[55]

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.[56]

External links

  • Overview of all the structural information available in the PDB for UniProt: P46937 (Human Transcriptional coactivator YAP1) at the PDBe-KB.
  • Overview of all the structural information available in the PDB for UniProt: P46938 (Mouse Transcriptional coactivator YAP1) at the PDBe-KB.

References

  1. ↑ 1.0 1.1 "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. August 1994. PMID 8035999. 
  2. ↑ "The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP". Cell 122 (3): 421–34. August 2005. doi:10.1016/j.cell.2005.06.007. PMID 16096061. 
  3. ↑ "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. August 2006. doi:10.1073/pnas.0605579103. PMID 16894141. Bibcode: 2006PNAS..10312405O. 
  4. ↑ "The WW domain: a signalling site in dystrophin?". Trends in Biochemical Sciences 19 (12): 531–3. December 1994. doi:10.1016/0968-0004(94)90053-1. PMID 7846762. 
  5. ↑ "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. December 1994. doi:10.1006/bbrc.1994.2793. PMID 7802651. 
  6. ↑ "The rsp5-domain is shared by proteins of diverse functions". FEBS Letters 358 (2): 153–7. January 1995. doi:10.1016/0014-5793(94)01415-W. PMID 7828727. 
  7. ↑ "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. June 1995. doi:10.1074/jbc.270.24.14733. PMID 7782338. 
  8. ↑ "Identification, basic characterization and evolutionary analysis of differentially spliced mRNA isoforms of human YAP1 gene". Gene 509 (2): 215–22. November 2012. doi:10.1016/j.gene.2012.08.025. PMID 22939869. 
  9. ↑ 9.0 9.1 "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. May 2001. doi:10.1101/gad.888601. PMID 11358867. 
  10. ↑ "Identification of a ten-amino acid proline-rich SH3 binding site". Science 259 (5098): 1157–61. February 1993. doi:10.1126/science.8438166. PMID 8438166. Bibcode: 1993Sci...259.1157R. 
  11. ↑ "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. May 1998. doi:10.1016/S0014-5793(98)00402-5. PMID 9613608. 
  12. ↑ "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. November 1999. doi:10.1083/jcb.147.4.879. PMID 10562288. 
  13. ↑ 13.0 13.1 "A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator". The EMBO Journal 18 (9): 2551–62. May 1999. doi:10.1093/emboj/18.9.2551. PMID 10228168. 
  14. ↑ "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. February 2009. doi:10.1158/0008-5472.CAN-08-2997. PMID 19141641. 
  15. ↑ "Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling". Oncogene 21 (32): 4879–84. July 2002. doi:10.1038/sj.onc.1205623. PMID 12118366. http://www.hal.inserm.fr/inserm-00147464. 
  16. ↑ "Structural basis for the versatile interactions of Smad7 with regulator WW domains in TGF-β Pathways". Structure 20 (10): 1726–36. October 2012. doi:10.1016/j.str.2012.07.014. PMID 22921829. 
  17. ↑ "Physical interaction with Yes-associated protein enhances p73 transcriptional activity". The Journal of Biological Chemistry 276 (18): 15164–73. May 2001. doi:10.1074/jbc.M010484200. PMID 11278685. 
  18. ↑ "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. August 2003. doi:10.1074/jbc.M305597200. PMID 12807903. 
  19. ↑ "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. April 2004. doi:10.1016/j.yexcr.2003.12.002. PMID 15023535. 
  20. ↑ "Yes-associated protein and p53-binding protein-2 interact through their WW and SH3 domains". The Journal of Biological Chemistry 276 (17): 14514–23. April 2001. doi:10.1074/jbc.M008568200. PMID 11278422. 
  21. ↑ "Mst2 and Lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP)". The Journal of Biological Chemistry 283 (41): 27534–46. October 2008. doi:10.1074/jbc.M804380200. PMID 18640976. 
  22. ↑ "PTPN14 interacts with and negatively regulates the oncogenic function of YAP". Oncogene 32 (10): 1266–73. March 2013. doi:10.1038/onc.2012.147. PMID 22525271. 
  23. ↑ "Angiomotin-like proteins associate with and negatively regulate YAP1". The Journal of Biological Chemistry 286 (6): 4364–70. February 2011. doi:10.1074/jbc.C110.205401. PMID 21187284. 
  24. ↑ "Hippo pathway-independent restriction of TAZ and YAP by angiomotin". The Journal of Biological Chemistry 286 (9): 7018–26. March 2011. doi:10.1074/jbc.C110.212621. PMID 21224387. 
  25. ↑ "Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein". Genes & Development 25 (1): 51–63. January 2011. doi:10.1101/gad.2000111. PMID 21205866. 
  26. ↑ "Opposing roles of angiomotin-like-1 and zona occludens-2 on pro-apoptotic function of YAP". Oncogene 31 (1): 128–34. January 2012. doi:10.1038/onc.2011.216. PMID 21685940. 
  27. ↑ "Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling". The Biochemical Journal 432 (3): 461–72. December 2010. doi:10.1042/BJ20100870. PMID 20868367. https://biblio.ugent.be/publication/1256657. 
  28. ↑ 28.0 28.1 28.2 "The hippo signaling pathway in development and cancer". Developmental Cell 19 (4): 491–505. October 2010. doi:10.1016/j.devcel.2010.09.011. PMID 20951342. 
  29. ↑ "Using biomaterials to study stem cell mechanotransduction, growth and differentiation". Journal of Tissue Engineering and Regenerative Medicine 9 (5): 528–39. May 2015. doi:10.1002/term.1957. PMID 25370612. http://eprints.gla.ac.uk/97094/1/97094.pdf. 
  30. ↑ "TEAD mediates YAP-dependent gene induction and growth control". Genes & Development 22 (14): 1962–71. July 2008. doi:10.1101/gad.1664408. PMID 18579750. 
  31. ↑ "The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression". Developmental Cell 25 (4): 388–401. May 2013. doi:10.1016/j.devcel.2013.04.021. PMID 23725764. 
  32. ↑ "Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP". Genes & Development 29 (12): 1285–97. June 2015. doi:10.1101/gad.264234.115. PMID 26109051. 
  33. ↑ "Mechanisms of Hippo pathway regulation". Genes & Development 30 (1): 1–17. January 2016. doi:10.1101/gad.274027.115. PMID 26728553. 
  34. ↑ "Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway". Developmental Cell 21 (5): 888–95. November 2011. doi:10.1016/j.devcel.2011.08.028. PMID 22075147. 
  35. ↑ "The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Salvador-Warts-Hippo pathway". Developmental Cell 21 (5): 896–906. November 2011. doi:10.1016/j.devcel.2011.09.012. PMID 22075148. 
  36. ↑ "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. September 2006. doi:10.1111/j.1742-4658.2006.05427.x. PMID 16930133. 
  37. ↑ "MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation". Current Biology 18 (5): 311–21. March 2008. doi:10.1016/j.cub.2008.02.006. PMID 18328708. 
  38. ↑ "MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway". Nature Communications 6: 8357. October 2015. doi:10.1038/ncomms9357. PMID 26437443. Bibcode: 2015NatCo...6.8357M. 
  39. ↑ "Identification of Happyhour/MAP4K as Alternative Hpo/Mst-like Kinases in the Hippo Kinase Cascade". Developmental Cell 34 (6): 642–55. September 2015. doi:10.1016/j.devcel.2015.08.014. PMID 26364751. 
  40. ↑ "Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control". Genes & Development 21 (21): 2747–61. November 2007. doi:10.1101/gad.1602907. PMID 17974916. 
  41. ↑ 41.0 41.1 "Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores". Cell 171 (6): 1397–1410.e14. November 2017. doi:10.1016/j.cell.2017.10.008. PMID 29107331. 
  42. ↑ "Nanomechanical analysis of cells from cancer patients". Nature Nanotechnology 2 (12): 780–3. December 2007. doi:10.1038/nnano.2007.388. PMID 18654431. Bibcode: 2007NatNa...2..780C. 
  43. ↑ "Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence" (in English). Biophysical Journal 88 (5): 3689–98. May 2005. doi:10.1529/biophysj.104.045476. PMID 15722433. Bibcode: 2005BpJ....88.3689G. 
  44. ↑ 44.0 44.1 "Cancer invasion and the microenvironment: plasticity and reciprocity". Cell 147 (5): 992–1009. November 2011. doi:10.1016/j.cell.2011.11.016. PMID 22118458. 
  45. ↑ 45.0 45.1 "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. January 2014. doi:10.1016/j.bbrc.2013.12.100. PMID 24380865. 
  46. ↑ "Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation". Science 341 (6149): 1240104. August 2013. doi:10.1126/science.1240104. PMID 23990565. 
  47. ↑ "Designer matrices for intestinal stem cell and organoid culture". Nature 539 (7630): 560–564. November 2016. doi:10.1038/nature20168. PMID 27851739. 
  48. ↑ "The Hippo pathway and human cancer". Nature Reviews. Cancer 13 (4): 246–57. April 2013. doi:10.1038/nrc3458. PMID 23467301. 
  49. ↑ "The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment". Nature Reviews. Drug Discovery 13 (1): 63–79. January 2014. doi:10.1038/nrd4161. PMID 24336504. 
  50. ↑ "The emerging roles of YAP and TAZ in cancer". Nature Reviews. Cancer 15 (2): 73–79. February 2015. doi:10.1038/nrc3876. PMID 25592648. 
  51. ↑ "Dual role of YAP: oncoprotein and tumor suppressor". Journal of Thoracic Disease 10 (Suppl 33): S3895–S3898. November 2018. doi:10.21037/jtd.2018.10.70. PMID 30631509. 
  52. ↑ "Structures of YAP protein domains reveal promising targets for development of new cancer drugs". Seminars in Cell & Developmental Biology 23 (7): 827–33. September 2012. doi:10.1016/j.semcdb.2012.05.002. PMID 22609812. 
  53. ↑ "Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP". Genes & Development 26 (12): 1300–5. June 2012. doi:10.1101/gad.192856.112. PMID 22677547. 
  54. ↑ "Non-destructive inhibition of metallofullerenol Gd@C(82)(OH)(22) on WW domain: implication on signal transduction pathway". Scientific Reports 2: 957. 2012. doi:10.1038/srep00957. PMID 23233876. Bibcode: 2012NatSR...2E.957K. 
  55. ↑ "Hippo/YAP signaling pathway mitigates blood–brain barrier disruption after cerebral ischemia/reperfusion injury". Behavioural Brain Research 356: 8–17. January 2019. doi:10.1016/j.bbr.2018.08.003. PMID 30092249. 
  56. ↑ "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. February 2014. doi:10.1016/j.ajhg.2014.01.001. PMID 24462371. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:YAP1&oldid=3554721"