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Hippo signaling pathway

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Title: Hippo signaling pathway  
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Hippo signaling pathway

The Hippo 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.

A fundamental question in cell division and programmed cell death (or apoptosis). The Hippo signaling pathway is involved in restraining cell proliferation and promoting apoptosis. As many cancers are marked by unchecked cell division, this signaling pathway has become increasingly significant in the study of human cancer.[1]

The Hippo signaling pathway appears to be highly conserved. While most of the Hippo pathway components were identified in the fruit fly (Drosophila melanogaster) using mosaic genetic screens, orthologs to these components (genes that function analogously in different species) have subsequently been found in mammals. Thus, the delineation of the pathway in Drosophila has helped to identify many genes that function as oncogenes or tumor suppressors in mammals.

Contents

  • Mechanism 1
  • The Hippo Signaling Pathway in Cancer 2
  • Summary Table 3
  • References 4

Mechanism

The Hippo pathway consists of a core kinase cascade in which Hpo phosphorylates the protein kinase Warts (Wts). Hpo (MST1/2 in mammals) is a member of the Ste-20 family of protein kinases. This highly conserved group of serine/threonine kinases regulates several cellular processes, including cell proliferation, apoptosis, and various stress responses.[2] Once phosphorylated, Wts (LATS1/2 in mammals) becomes active. Wts is a nuclear DBF-2-related kinase. These kinases are known regulators of cell cycle progression, growth, and development.[3] Two proteins are known to facilitate the activation of Wts: Salvador (Sav) and Mob as tumor suppressor (Mats). Sav (WW45 in mammals) is a WW domain-containing protein, meaning that this protein contains a sequence of amino acids in which a tryptophan and an invariant proline are highly conserved.[4] Hpo can bind to and phosphorylate Sav, which may function as a scaffold protein because this Hpo-Sav interaction promotes phosphorylation of Wts.[5] Hpo can also phosphorylate and activate Mats (MOBKL1A/B in mammals), which allows Mats to associate with and strengthen the kinase activity of Wts.[6]

Activated Wts can then go on to phosphorylate and inactivate the cyclin E, which promotes cell cycle progression, and diap1 (Drosophila inhibitor of apopotosis protein-1), which, as its name suggests, prevents apoptosis.[7] Yki also activates expression of the bantam microRNA, a positive growth regulator that specifically affects cell number.[8][9] Thus, the inactivation of Yki by Wts inhibits growth through the transcriptional repression of these pro-growth regulators. By phosphorylating Yki at serine 168, Wts promotes the association of Yki with 14-3-3 proteins, which help to anchor Yki in the cytoplasm and prevent its transport to the nucleus. In mammals, the two Yki orthologs are Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ).[10] When activated, YAP and TAZ can bind to several transcription factors including p73, Runx2 and several TEADs.[11]

The upstream regulators of the core Hpo/Wts kinase cascade include the transmembrane protein Fat and several membrane-associated proteins. As an atypical cadherin, Fat (FAT1-4 in mammals) may function as a receptor, though an extracellular ligand has not been positively identified. While Fat is known to bind to another atypical cadherin, Dachsous (Ds), during tissue patterning,[12] it is unclear what role Ds has in regulating tissue growth. Nevertheless, Fat is recognized as an upstream regulator of the Hpo pathway. Fat activates Hpo through the apical protein Expanded (Ex; FRMD6/Willin in mammals). Ex interacts with two other apically-localized proteins, Kibra (KIBRA in mammals) and Merlin (Mer; NF2 in mammals), to form the Kibra-Ex-Mer (KEM) complex. Both Ex and Mer are FERM domain-containing proteins, while Kibra, like Sav, is a WW domain-containing protein.[13] The KEM complex physically interacts with the Hpo kinase cascade, thereby localizing the core kinase cacade to the plasma membrane for activation.[14] Fat may also regulate Wts independently of Ex/Hpo, through the inhibition of the unconventional myosin Dachs. Normally, Dachs can bind to and promote the degradation of Wts.[15]

The Hippo Signaling Pathway in Cancer

In fruitfly, the Hippo signaling pathway involves a kinase cascade involving the Salvador (Sav), Warts (Wts) and Hippo (Hpo) protein kinases.[16] Many of the genes involved in the Hippo signaling pathway are recognized as tumor suppressors, while Yki/YAP/TAZ is identified as an oncogene. In fact, YAP has been found to be elevated in some human cancers, including breast cancer, colorectal cancer, and liver cancer.[17][18][19] This may be explained by YAP’s recently defined role in overcoming contact inhibition, a fundamental growth control property of normal cells in culture in which proliferation stops after cells reach confluence.[20] This property is typically lost in cancerous cells, allowing them to proliferate in an uncontrolled manner.[21] In fact, YAP overexpression antagonizes contact inhibition.[22]

Many of the pathway components recognized as tumor suppressor genes are mutated in human cancers. For example, mutations in Fat4 have been found in breast cancer,[23] while NF2 is mutated in familial and sporadic schwannomas.[24] Additionally, several human cancer cell lines invoke mutations of the WW45 and MOBK1B proteins.[25][26]

Summary Table

Drosophila melanogaster Human ortholog(s) Protein Description & Role in Hippo Signaling Pathway
Dachsous (Ds) DCHS1, DCHS2 Atypical cadherin that may act as a ligand for the Fat receptor
Fat (Ft) FAT1, FAT2, FAT3, FAT4 (FATJ) Atypical cadherin that may act as a receptor for the Hippo pathway
Expanded (Ex) FRMD6/Willin FERM domain-containing apical protein that associates with Kibra and Mer as an upstream regulator of the core kinase cascade
Dachs (Dachs) Unconventional myosin that can bind Wts, promoting its degradation
Kibra (Kibra) WWC1 WW domain-containing apical protein that associates with Ex and Mer as an upstream regulator of the core kinase cascade
Merlin (Mer) NF2 FERM domain-containing apical protein that associates with Ex and Kibra as an upstream regulator of the core kinase cascade
Hippo (Hpo) MST1, MST2 Sterile-20-type kinase that phosphorylates and activates Wts
Salvador (Sav) WW45 (SAV1) WW domain-containing protein that may act as a scaffold protein, facilitating Warts phosphorylation by Hippo
Warts (Wts) LATS1, LATS2 Nuclear DBF-2-related kinase that phosphorylates and inactivates Yki
Mob as tumor suppressor (Mats) MOBKL1A, MOBKL1B Kinase that associates with Wts to potentiate its catalytic activity
Yorkie (Yki) YAP, TAZ Transcriptional coactivator that binds to Sd in its active, unphosphorylated form to activate expression of transcriptional targets that promote cell growth, cell proliferation, and prevent apoptosis
Scalloped (Sd) TEAD1, TEAD2, TEAD3, TEAD4 Transcription factor that binds Yki to regulate target gene expression

References

  1. ^ Saucedo, Leslie J.; Edgar, Bruce A. (2007). "Filling out the Hippo pathway". Nature Reviews Molecular Cell Biology 8 (8): 613–21.  
  2. ^ Dan, Ippeita; Watanabe, Norinobu M.; Kusumi, Akihiro (2001). "The Ste20 group kinases as regulators of MAP kinase cascades". Trends in Cell Biology 11 (5): 220–30.  
  3. ^ Ma, J.; Benz, C.; Grimaldi, R.; Stockdale, C.; Wyatt, P.; Frearson, J.; Hammarton, T. C. (2010). "Nuclear DBF-2-related Kinases Are Essential Regulators of Cytokinesis in Bloodstream Stage Trypanosoma brucei". Journal of Biological Chemistry 285 (20): 15356–68.  
  4. ^ Andre, B.; Springael, J.Y. (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.  
  5. ^ Wu, Shian; Huang, Jianbin; Dong, Jixin; Pan, Duojia (2003). "Hippo Encodes a Ste-20 Family Protein Kinase that Restricts Cell Proliferation and Promotes Apoptosis in Conjunction with salvador and warts". Cell 114 (4): 445–56.  
  6. ^ Wei, Xiaomu; Shimizu, Takeshi; Lai, Zhi-Chun (2007). "Mob as tumor suppressor is activated by Hippo kinase for growth inhibition in Drosophila". The EMBO Journal 26 (7): 1772–81.  
  7. ^ Huang, Jianbin; Wu, Shian; Barrera, Jose; Matthews, Krista; Pan, Duojia (2005). "The Hippo Signaling Pathway Coordinately Regulates Cell Proliferation and Apoptosis by Inactivating Yorkie, the Drosophila Homolog of YAP". Cell 122 (3): 421–34.  
  8. ^ Thompson, Barry J.; Cohen, Stephen M. (2006). "The Hippo Pathway Regulates the bantam microRNA to Control Cell Proliferation and Apoptosis in Drosophila". Cell 126 (4): 767–74.  
  9. ^ Nolo, Riitta; Morrison, Clayton M.; Tao, Chunyao; Zhang, Xinwei; Halder, Georg (2006). "The bantam MicroRNA is a Target of the Hippo Tumor-Suppressor Pathway". Current Biology 16 (19): 1895–904.  
  10. ^ Wang, Kainan; Degerny, Cindy; Xu, Minghong; Yang, Xiang-Jiao (2009). "YAP, TAZ, and Yorkie: A conserved family of signal-responsive transcriptional coregulators in animal development and human diseaseThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB's 51st Annual Meeting – Epigenetics and Chromatin Dynamics, and has undergone the Journal's usual peer review process". Biochemistry and Cell Biology 87 (1): 77–91.  
  11. ^ Badouel, Caroline; Garg, Ankush; McNeill, Helen (2009). "Herding Hippos: Regulating growth in flies and man". Current Opinion in Cell Biology 21 (6): 837–43.  
  12. ^ Cho, E.; Irvine, KD (2004). "Action of fat, four-jointed, dachsous and dachs in distal-to-proximal wing signaling". Development 131 (18): 4489–500.  
  13. ^ Baumgartner, Roland; Poernbacher, Ingrid; Buser, Nathalie; Hafen, Ernst; Stocker, Hugo (2010). "The WW Domain Protein Kibra Acts Upstream of Hippo in Drosophila". Developmental Cell 18 (2): 309–16.  
  14. ^ Pan, Duojia (2010). "The Hippo Signaling Pathway in Development and Cancer". Developmental Cell 19 (4): 491–505.  
  15. ^ Cho, Eunjoo; Feng, Yongqiang; Rauskolb, Cordelia; Maitra, Sushmita; Fehon, Rick; Irvine, Kenneth D (2006). "Delineation of a Fat tumor suppressor pathway". Nature Genetics 38 (10): 1142–50.  
  16. ^ http://www.uniprot.org/uniprot/Q45VV3
  17. ^ Kango-Singh, Madhuri; Singh, Amit (2009). "Regulation of organ size: Insights from theDrosophilaHippo signaling pathway". Developmental Dynamics 238 (7): 1627–37.  
  18. ^ Zender, Lars; Spector, Mona S.; Xue, Wen; Flemming, Peer;  
  19. ^ Steinhardt, Angela A.; Gayyed, Mariana F.; Klein, Alison P.; Dong, Jixin; Maitra, Anirban; Pan, Duojia; Montgomery, Elizabeth A.; Anders, Robert A. (2008). "Expression of Yes-associated protein in common solid tumors". Human Pathology 39 (11): 1582–9.  
  20. ^ Eagle, Harry; Levine, Elliot M. (1967). "Growth Regulatory Effects of Cellular Interaction". Nature 213 (5081): 1102–6.  
  21. ^ Hanahan, Douglas; Weinberg, Robert A (2000). "The Hallmarks of Cancer". Cell 100 (1): 57–70.  
  22. ^ Zhao, B.; Wei, X.; Li, W.; Udan, R. S.; Yang, Q.; Kim, J.; Xie, J.; Ikenoue, T. et al. (2007). "Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control". Genes & Development 21 (21): 2747.  
  23. ^ Qi, Chao; Zhu, Yiwei Tony; Hu, Liping; Zhu, Yi-Jun (2009). "Identification of Fat4 as a candidate tumor suppressor gene in breast cancers". International Journal of Cancer 124 (4): 793–8.  
  24. ^ Evans, D G. R; Sainio, M; Baser, ME (2000). "Neurofibromatosis type 2". Journal of Medical Genetics 37 (12): 897–904.  
  25. ^ Tapon, Nicolas; Harvey, Kieran F.; Bell, Daphne W.; Wahrer, Doke C.R.; Schiripo, Taryn A.; Haber, Daniel A.; Hariharan, Iswar K. (2002). "Salvador Promotes Both Cell Cycle Exit and Apoptosis in Drosophila and is Mutated in Human Cancer Cell Lines". Cell 110 (4): 467–78.  
  26. ^ Lai, Zhi-Chun; Wei, Xiaomu; Shimizu, Takeshi; Ramos, Edward; Rohrbaugh, Margaret; Nikolaidis, Nikolas; Ho, Li-Lun; Li, Ying (2005). "Control of Cell Proliferation and Apoptosis by Mob as Tumor Suppressor, Mats". Cell 120 (5): 675–85.  
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