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.
Highlights
The Hippo pathway plays crucial roles in regulating organ size and stem cell homeostasis
Our mass spectrometry data showed that WW45-immunoprecipitates contained MST1 and LATS2-(Ub)n α-HA (Ub) α-Xpress (LATS2), both of which are known to interact with WW45, as well as a novel interacting protein, NEDD4 E3 Ub-ligase (Fig. 1a)
Our results show that NEDD4 plays a crucial role in regulating cell proliferation and apoptosis in both mammalian cells and Drosophila
Summary
The Hippo pathway plays crucial roles in regulating organ size and stem cell homeostasis. 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. WW domain containing scaffold protein Salvador (Sav), Ste-20 family kinase Hippo (Hpo), NDR kinase Warts (Wts) and transcription co-activator Yorkie (Yki) are core components of the Hippo pathway in Drosophila[4,5,6]. This is supported by the observation that the NEDD4 knockout (KO) mouse shows apparent growth retardation compared with wild-type littermates and that NEDD4 KO mouse embryonic fibroblast cells grow slowly Such phenotypic outcomes originate from the NEDD4-mediated positive regulation of IGF-1 and insulin signalling[28]. NEDD4 negatively regulates the stability of WW45 and LATS kinase, which leads to alterations in cell proliferation and ISC homeostasis
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