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

Sung Jun Bae, Myungjin Kim, Sung-Hee Kim, Young Eun Kwon, Ji-Hoon Lee, Jaesang Kim, Chin Ha Chung, Won-Jae Lee () and Jae Hong Seol ()
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Sung Jun Bae: School of Biological Sciences, Seoul National University
Myungjin Kim: School of Biological Sciences, Seoul National University
Sung-Hee Kim: School of Biological Sciences, Seoul National University
Young Eun Kwon: School of Biological Sciences, Seoul National University
Ji-Hoon Lee: School of Biological Sciences, Seoul National University
Jaesang Kim: Ewha Womans University
Chin Ha Chung: School of Biological Sciences, Seoul National University
Won-Jae Lee: School of Biological Sciences, Seoul National University
Jae Hong Seol: School of Biological Sciences, Seoul National University

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7314

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