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.
Bibliographical noteFunding Information:
We thank Dr Xuejun Jiang (Memorial Sloan-Kettering Cancer Center) for pcDNA3.1-NEDD4-HA, Dr Dongeun Park (Seoul National University) for NEDD4 knockdown stable cell line, Dr Kenneth D. Irvine (Rutgers University) for anti-Wts antibody. We also thank Dr Raymond Deshaies (California Institute of Technology) for critical reading of our manuscript and valuable discussion. This study was supported by the Mid-career Researcher Program (No. 2014R1A2A2A01005258 to J.H.S.), Basic Research Laboratory Program (No. 2014R1A4A1005259 to J.H.S.), the National Creative Research Initiative Program (No. 20120000231 to W.-J.L.) and Basic Science Research Program (No. 2013R1A1A3011632 to M.K.; No. 2013R1A1A2013250 to S.-H.K.) from National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP).
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