A crucial role of WW45 in developing epithelial tissues in the mouse.
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.
Lee
Joo-Hyeon
JH
National Research Laboratory, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
Kim
Tae-Shin
TS
Yang
Tae-Hong
TH
Koo
Bon-Kyoung
BK
Oh
Sang-Phil
SP
Lee
Kwang-Pyo
KP
Oh
Hyun-Jung
HJ
Lee
Sang-Hee
SH
Kong
Young-Yun
YY
Kim
Jin-Man
JM
Lim
Dae-Sik
DS
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004848:Epithelium / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D000099317:Hippo Kinases
D018797:Cell Cycle Proteins; D017228:Hepatocyte Growth Factor; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; C485935:Sav1 protein, mouse; C082332:macrophage stimulating protein; C490501:Lats1 protein, mouse; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases