Figure 8: A proposed model for NEDD4 on regulating the Hippo signalling pathway.
From: NEDD4 controls intestinal stem cell homeostasis by regulating the Hippo signalling pathway
NEDD4 tightly regulates the Hippo pathway through WW45 and LATS destabilization. WW45 and LATS protein levels are maintained low by NEDD4-mediated degradation, which confers Hippo OFF state. YAP dominantly enters nuclei and induces its target gene expression by interacting with transcription factors, promoting cell proliferation or intestinal stem cell renewal. When cells receive the Hippo activation signalling (that is, ‘LATS phosphorylation’ and/or ‘LATS stabilization’), YAP is phosphorylated by LATS and subsequently sequestered in the cytoplasm. ‘LATS phosphorylation’ signal activates MST, and activated MST stabilizes WW45 by inhibiting NEDD4-mediated degradation. MST then phosphorylates LATS with WW45. On the other hand, ‘LATS stabilization’ signal inhibits NEDD4 activity, which leads to the elevated LATS as well as WW45 protein levels. As LATS activity is controlled dually by its phosphorylation and stabilization34,43, kinase-relayed phosphorylation signals and stabilization signals work in concert to fully activate LATS to its maximum extent followed by Hippo ON state.
