title: NEDD4 controls intestinal stem cell homeostasis by regulating the Hippo signalling pathway.
abstract: The Hippo pathway plays crucial roles in regulating organ size and stem cell homeostasis. Although the signalling cascade of the core Hippo kinases is relatively well understood, little is known about the mechanisms that modulate the activity of the Hippo pathway. Here, we report identification of NEDD4, a HECT-type E3 ubiquitin ligase, as a regulatory component of the Hippo pathway. We demonstrate that NEDD4 ubiquitylates and destabilizes WW45 and LATS kinase, both of which are required for active Hippo signalling. Interestingly, MST1 protects WW45, but not LATS2, against NEDD4. We also provide evidence indicating that NEDD4 inactivation at high cell density is a prerequisite for the elevated Hippo activity linked to contact inhibition. Moreover, NEDD4 promotes intestinal stem cell renewal in Drosophila by suppressing Hippo signalling. Collectively, we present a regulatory mechanism by which NEDD4 controls the Hippo pathway leading to coordinated cell proliferation and apoptosis.
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Sung Jun
authors.initials: SJ
authors.lastname: Bae
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Myungjin
authors.initials: M
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Kwon
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Jaesang
authors.initials: J
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Chin Ha
authors.initials: CH
authors.lastname: Chung
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Won-Jae
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seol
mesh_terms: D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism* / Q000502:physiology; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D000075702:Nedd4 Ubiquitin Protein Ligases; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D017228:Hepatocyte Growth Factor; D047908:Intracellular Signaling Peptides and Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C415864:SAV1 protein, human; C082332:macrophage stimulating protein; C465504:sav protein, Drosophila; C000605755:Nedd4 protein, Drosophila; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; C092745:LATS1 protein, human; C093503:wts protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases