NEDD4 controls intestinal stem cell homeostasis by regulating the Hippo signalling pathway

• Published in: Nature communications 2015-02, Vol.6 (1), p.6314-6314, Article 6314
• Main Authors: Bae, Sung Jun, Kim, Myungjin, Kim, Sung-Hee, Kwon, Young Eun, Lee, Ji-Hoon, Kim, Jaesang, Chung, Chin Ha, Lee, Won-Jae, Seol, Jae Hong
• Format: Article
• Language: English
• Subjects: 14; 14/19; 38/109; 38/77; 38/89; 631/136/532/2437; 631/136/83/2360; 631/443/319/1557; 631/80/474/2073; 64/24; 82/80; 96/106; Animals; Apoptosis; Cell Cycle Proteins - metabolism; Cell Proliferation; Drosophila melanogaster - metabolism; Drosophila melanogaster - physiology; Drosophila Proteins - metabolism; Endosomal Sorting Complexes Required for Transport - metabolism; Gastrointestinal Tract - metabolism; Gene Expression Regulation; HEK293 Cells; Hepatocyte Growth Factor - metabolism; Homeostasis; Humanities and Social Sciences; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Mice; multidisciplinary; Nedd4 Ubiquitin Protein Ligases; NIH 3T3 Cells; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; RNA Interference; Science; Science (multidisciplinary); Signal Transduction; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7314

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. The Hippo pathway plays a role in regulating organ size and stem cell renewal but the regulatory mechanisms that fine-tune this pathway are not well understood. Here the authors report on the role of NEDD4 as a negative regulator of the Hippo signalling components, WW45 and LATS kinase, and in controlling cell proliferation and intestinal stem cell homeostasis.