Home LiteratureArticle Details
PMID: 18369314 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

A crucial role of WW45 in developing epithelial tissues in the mouse.

The EMBO journal ·Vol. 27 ·No. 8 ·2008-04-23 ·Pages 1231-42

Lee JH, Kim TS, Yang TH, Koo BK, Oh SP, Lee KP, Oh HJ, Lee SH, Kong YY, Kim JM, Lim DS

Abstract

The role and molecular mechanisms of a new Hippo signalling pathway are not fully understood in mammals. Here, we generated mice that lack WW45 and revealed a crucial role for WW45 in cell-cycle exit and epithelial terminal differentiation. Many organs in the mutant mouse embryos displayed hyperplasia accompanied by defects in terminal differentiation of epithelial progenitor cells owing to impaired proliferation arrest rather than intrinsic acceleration of proliferation during differentiation. Importantly, the MST1 signalling pathway is specifically activated in differentiating epithelial cells. Moreover, WW45 is required for MST1 activation and translocation to the nucleus for subsequent LATS1/2 activation upon differentiation signal. LATS1/2 phosphorylates YAP, which, in turn, translocates from the nucleus into the cytoplasm, resulting in cell-cycle exit and terminal differentiation of epithelial progenitor cells. Collectively, these data provide compelling evidence that WW45 is a key mediator of MST1 signalling in the coordinate coupling of proliferation arrest with terminal differentiation for proper epithelial tissue development in mammals.

MeSH Terms
Animals Cell Cycle/genetics Cell Cycle Proteins/biosynthesis,genetics,physiology Cell Differentiation/genetics Cells, Cultured Epithelium/embryology,metabolism,pathology Hepatocyte Growth Factor/genetics Humans Mice Mice, Inbred C57BL Mice, Knockout Protein Serine-Threonine Kinases/metabolism,physiology Proto-Oncogene Proteins/genetics Signal Transduction/genetics,physiology
Chemicals
Cell Cycle Proteins Proto-Oncogene Proteins Sav1 protein, mouse macrophage stimulating protein Hepatocyte Growth Factor Lats1 protein, mouse Stk4 protein, mouse Protein Serine-Threonine Kinases
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Lee Joo-Hyeon
National Research Laboratory, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
Kim Tae-Shin
Yang Tae-Hong
Koo Bon-Kyoung
Oh Sang-Phil
Lee Kwang-Pyo
Oh Hyun-Jung
Lee Sang-Hee
Kong Young-Yun
Kim Jin-Man
Lim Dae-Sik
References (55)
55 references, click to expand
  1. TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm.
    Genes Dev. 2001 May 15;15(10):1229-41 PMID: 11358867
  2. Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma.
    Neurosci Res. 2006 Dec;56(4):450-8 PMID: 17049657
  3. Elucidation of a universal size-control mechanism in Drosophila and mammals.
    Cell. 2007 Sep 21;130(6):1120-33 PMID: 17889654
  4. The human tumour suppressor LATS1 is activated by human MOB1 at the membrane.
    Biochem Biophys Res Commun. 2006 Jun 23;345(1):50-8 PMID: 16674920
  5. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts.
    Cell. 2003 Aug 22;114(4):445-56 PMID: 12941273
  6. The Drosophila Ste20 family kinase dMST functions as a tumor suppressor by restricting cell proliferation and promoting apoptosis.
    Genes Dev. 2003 Oct 15;17(20):2514-9 PMID: 14561774
  7. YAP1 increases organ size and expands undifferentiated progenitor cells.
    Curr Biol. 2007 Dec 4;17(23):2054-60 PMID: 17980593
  8. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach.
    Cell. 2006 Jun 30;125(7):1253-67 PMID: 16814713
  9. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis.
    Nat Cell Biol. 2006 Jan;8(1):27-36 PMID: 16341207
  10. Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product.
    Oncogene. 1994 Aug;9(8):2145-52 PMID: 8035999
  11. The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation.
    Genes Dev. 1997 May 15;11(10):1253-65 PMID: 9171370
  12. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway.
    Nat Cell Biol. 2003 Oct;5(10):914-20 PMID: 14502294
  13. The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network.
    Nat Rev Cancer. 2007 Mar;7(3):182-91 PMID: 17318211
  14. The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila.
    Nat Cell Biol. 2003 Oct;5(10):921-7 PMID: 14502295
  15. The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1.
    Oncogene. 2005 Mar 17;24(12):2076-86 PMID: 15688006
  16. Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity.
    Nat Genet. 1999 Feb;21(2):177-81 PMID: 9988268
  17. The fat cadherin acts through the hippo tumor-suppressor pathway to regulate tissue size.
    Curr Biol. 2006 Nov 7;16(21):2090-100 PMID: 16996265
  18. Lats2/Kpm is required for embryonic development, proliferation control and genomic integrity.
    EMBO J. 2004 Sep 15;23(18):3677-88 PMID: 15343267
  19. The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation.
    Genes Dev. 1995 Mar 1;9(5):534-46 PMID: 7698644
  20. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors.
    Science. 2002 Jul 19;297(5580):365-9 PMID: 12130776
  21. Filling out the Hippo pathway.
    Nat Rev Mol Cell Biol. 2007 Aug;8(8):613-21 PMID: 17622252
  22. The tumor-suppressor gene fat controls tissue growth upstream of expanded in the hippo signaling pathway.
    Curr Biol. 2006 Nov 7;16(21):2081-9 PMID: 16996266
  23. Mob as tumor suppressor is activated by Hippo kinase for growth inhibition in Drosophila.
    EMBO J. 2007 Apr 4;26(7):1772-81 PMID: 17347649
  24. Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction.
    Nat Genet. 1999 Feb;21(2):182-6 PMID: 9988269
  25. Developmental gradient of cell cycle in the telencephalic roof of the fetal NMRI-mouse.
    Anat Embryol (Berl). 1983;167(3):355-64 PMID: 6625191
  26. The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila.
    Cell. 2006 Aug 25;126(4):767-74 PMID: 16923395
  27. Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase.
    Development. 1995 Apr;121(4):1053-63 PMID: 7743921
  28. Delineation of a Fat tumor suppressor pathway.
    Nat Genet. 2006 Oct;38(10):1142-50 PMID: 16980976
  29. Hippo signaling in organ size control.
    Genes Dev. 2007 Apr 15;21(8):886-97 PMID: 17437995
  30. Calcium regulation of growth and differentiation of mouse epidermal cells in culture.
    Cell. 1980 Jan;19(1):245-54 PMID: 6153576
  31. Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila.
    Development. 2002 Dec;129(24):5719-30 PMID: 12421711
  32. Proteolytic activation of MST/Krs, STE20-related protein kinase, by caspase during apoptosis.
    Oncogene. 1998 Jun 11;16(23):3029-37 PMID: 9662336
  33. Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers.
    Clin Cancer Res. 2005 Feb 15;11(4):1380-5 PMID: 15746036
  34. LATS1 tumor suppressor regulates G2/M transition and apoptosis.
    Oncogene. 2002 Feb 14;21(8):1233-41 PMID: 11850843
  35. Membrane organization and tumorigenesis--the NF2 tumor suppressor, Merlin.
    Genes Dev. 2005 Oct 1;19(19):2265-77 PMID: 16204178
  36. RASSF1A is part of a complex similar to the Drosophila Hippo/Salvador/Lats tumor-suppressor network.
    Curr Biol. 2007 Apr 17;17(8):700-5 PMID: 17379520
  37. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon.
    Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12405-10 PMID: 16894141
  38. Beta-catenin regulation during the cell cycle: implications in G2/M and apoptosis.
    Mol Biol Cell. 2003 Jul;14(7):2844-60 PMID: 12857869
  39. Fat cadherin modulates organ size in Drosophila via the Salvador/Warts/Hippo signaling pathway.
    Curr Biol. 2006 Nov 7;16(21):2101-10 PMID: 17045801
  40. Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65.
    Mol Cell Biol. 2006 Jan;26(1):77-87 PMID: 16354681
  41. Epithelial stem cells: turning over new leaves.
    Cell. 2007 Feb 9;128(3):445-58 PMID: 17289566
  42. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.
    Genes Dev. 2007 Nov 1;21(21):2747-61 PMID: 17974916
  43. LATS1 tumour suppressor affects cytokinesis by inhibiting LIMK1.
    Nat Cell Biol. 2004 Jul;6(7):609-17 PMID: 15220930
  44. NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions.
    Genes Dev. 2003 May 1;17(9):1090-100 PMID: 12695331
  45. RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein.
    Mol Cell. 2007 Sep 21;27(6):962-75 PMID: 17889669
  46. Stem cells, cancer, and cancer stem cells.
    Nature. 2001 Nov 1;414(6859):105-11 PMID: 11689955
  47. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP.
    Cell. 2005 Aug 12;122(3):421-34 PMID: 16096061
  48. A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator.
    EMBO J. 1999 May 4;18(9):2551-62 PMID: 10228168
  49. Reversible inhibition of normal human prokeratinocyte proliferation by type beta transforming growth factor-growth inhibitor in serum-free medium.
    Cancer Res. 1986 Apr;46(4 Pt 2):2068-71 PMID: 2418960
  50. salvador Promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines.
    Cell. 2002 Aug 23;110(4):467-78 PMID: 12202036
  51. Control of cell proliferation and apoptosis by mob as tumor suppressor, mats.
    Cell. 2005 Mar 11;120(5):675-85 PMID: 15766530
  52. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis.
    Cell. 2003 Aug 22;114(4):457-67 PMID: 12941274
  53. Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane.
    J Cell Biol. 2005 Oct 24;171(2):361-71 PMID: 16247032
  54. The bantam microRNA is a target of the hippo tumor-suppressor pathway.
    Curr Biol. 2006 Oct 10;16(19):1895-904 PMID: 16949821
  55. From cell structure to transcription: Hippo forges a new path.
    Cell. 2006 Jan 27;124(2):267-73 PMID: 16439203
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2008.63
Published
2008-04-23
Epub
2008-00-27
Pages
1231-42
Language
English
Region
England
NLM ID
8208664
PMCID
PMC2367404
Subset
IM
Grants
Wellcome Trust · 107633 · United Kingdom
External Links
PubMed source DOI: 10.1038/emboj.2008.63 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2