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PMID:18369314

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Citation

Lee, JH, Kim, TS, Yang, TH, Koo, BK, Oh, SP, Lee, KP, Oh, HJ, Lee, SH, Kong, YY, Kim, JM and Lim, DS (2008) A crucial role of WW45 in developing epithelial tissues in the mouse. EMBO J. 27:1231-42

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.

Links

PubMed PMC2367404 Online version:10.1038/emboj.2008.63

Keywords

Animals; Cell Cycle/genetics; Cell Cycle Proteins/biosynthesis; Cell Cycle Proteins/genetics; Cell Cycle Proteins/physiology; Cell Differentiation/genetics; Cells, Cultured; Epithelium/embryology; Epithelium/metabolism; Epithelium/pathology; Hepatocyte Growth Factor/genetics; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein-Serine-Threonine Kinases/metabolism; Protein-Serine-Threonine Kinases/physiology; Proto-Oncogene Proteins/genetics; Signal Transduction/genetics; Signal Transduction/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:YAP1

acts_upstream_of_or_within

GO:0030216: keratinocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • results_in_acquisition_of_features_of:(CL:0000312)

Seeded From UniProt

complete

MOUSE:YAP1

acts_upstream_of_or_within

GO:0030216: keratinocyte differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1333883
MGI:MGI:1354386
MGI:MGI:1927144
MGI:MGI:1929004

P

  • results_in_acquisition_of_features_of:(CL:0000312)

Seeded From UniProt

complete

MOUSE:YAP1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000312)

Seeded From UniProt

complete

MOUSE:YAP1

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000312)

Seeded From UniProt

complete

MOUSE:YAP1

acts_upstream_of_or_within

GO:0010837: regulation of keratinocyte proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:YAP1

acts_upstream_of_or_within

GO:0035329: hippo signaling

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1333883
MGI:MGI:1354386
MGI:MGI:1927144
MGI:MGI:1929004

P

  • occurs_in:(CL:0000312)

Seeded From UniProt

complete

MOUSE:LATS2

acts_upstream_of_or_within

GO:0030216: keratinocyte differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:103262
MGI:MGI:1927144
MGI:MGI:1929004

P

  • results_in_acquisition_of_features_of:(CL:0000312)

Seeded From UniProt

complete

MOUSE:LATS2

acts_upstream_of_or_within

GO:0035329: hippo signaling

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:103262
MGI:MGI:1927144
MGI:MGI:1929004

P

  • occurs_in:(CL:0000312)

Seeded From UniProt

complete

MOUSE:LATS1

acts_upstream_of_or_within

GO:0030216: keratinocyte differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:103262
MGI:MGI:1927144
MGI:MGI:1929004

P

Seeded From UniProt

complete

MOUSE:LATS1

acts_upstream_of_or_within

GO:0035329: hippo signaling

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:103262
MGI:MGI:1927144
MGI:MGI:1929004

P

Seeded From UniProt

complete

MOUSE:SAV1

acts_upstream_of_or_within

GO:0030216: keratinocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3790763

P

  • results_in_acquisition_of_features_of:(CL:0000312)

Seeded From UniProt

complete

MOUSE:SAV1

acts_upstream_of_or_within

GO:0030216: keratinocyte differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:103262
MGI:MGI:1333883
MGI:MGI:1354386
MGI:MGI:1929004

P

  • results_in_acquisition_of_features_of:(CL:0000312)

Seeded From UniProt

complete

MOUSE:SAV1

acts_upstream_of_or_within

GO:0001942: hair follicle development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3790763

P

  • results_in_development_of:(EMAPA:18771)

Seeded From UniProt

complete

MOUSE:SAV1

acts_upstream_of_or_within

GO:0050680: negative regulation of epithelial cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3790763

P

Seeded From UniProt

complete

MOUSE:SAV1

acts_upstream_of_or_within

GO:0060575: intestinal epithelial cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3790763

P

  • occurs_in:(EMAPA:16247)
  • results_in_acquisition_of_features_of:(CL:0000066)

Seeded From UniProt

complete

MOUSE:SAV1

acts_upstream_of_or_within

GO:0060487: lung epithelial cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3790763

P

  • occurs_in:(EMAPA:16728)
  • results_in_acquisition_of_features_of:(CL:0000082)

Seeded From UniProt

complete

MOUSE:SAV1

acts_upstream_of_or_within

GO:0043065: positive regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3790763

P

  • occurs_in:(EMAPA:17525)
  • regulates_o_occurs_in:(CL:0000312)

Seeded From UniProt

complete

MOUSE:SAV1

acts_upstream_of_or_within

GO:0035329: hippo signaling

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:103262
MGI:MGI:1333883
MGI:MGI:1354386
MGI:MGI:1929004

P

  • occurs_in:(CL:0000312)

Seeded From UniProt

complete

MOUSE:SAV1

acts_upstream_of_or_within

GO:2000036: regulation of stem cell population maintenance

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3790763

P

  • occurs_in:(EMAPA:17525)

Seeded From UniProt

complete

MOUSE:STK4

acts_upstream_of_or_within

GO:0030216: keratinocyte differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:103262
MGI:MGI:1333883
MGI:MGI:1354386
MGI:MGI:1927144
MGI:MGI:1929004

P

  • results_in_acquisition_of_features_of:(CL:0000312)

Seeded From UniProt

complete

MOUSE:STK4

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000312)

Seeded From UniProt

complete

MOUSE:STK4

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000312)

Seeded From UniProt

complete

MOUSE:STK4

acts_upstream_of_or_within

GO:0035329: hippo signaling

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:103262
MGI:MGI:1333883
MGI:MGI:1354386
MGI:MGI:1927144
MGI:MGI:1929004

P

  • occurs_in:(CL:0000312)

Seeded From UniProt

complete

MOUSE:STK4

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000312)

Seeded From UniProt

complete

MOUSE:STK4

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000312)

Seeded From UniProt

complete

MOUSE:STK4

acts_upstream_of_or_within

GO:0030216: keratinocyte differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:103262
MGI:MGI:1333883
MGI:MGI:1354386
MGI:MGI:1927144
MGI:MGI:1929004

P

results_in_acquisition_of_features_of:(CL:0000312)

Seeded From UniProt

complete

MOUSE:STK4

acts_upstream_of_or_within

GO:0035329: hippo signaling

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:103262
MGI:MGI:1333883
MGI:MGI:1354386
MGI:MGI:1927144
MGI:MGI:1929004

P

occurs_in:(CL:0000312)

Seeded From UniProt

complete


See also

References

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