NEDD4 E3 ligase inhibits the activity of the Hippo pathway by targeting LATS1 for degradation

Zaidoun Salah, Sherri Cohen, Ella Itzhaki, Rami I. Aqeilan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Proper regulation of cell proliferation, cell apoptosis, and cell death are vital for the development and survival of living organisms. Failure or dysfunction of any of these processes can have devastating effects, including cancer. The Hippo pathway, first discovered in Drosophila, has been found to be a major growth-regulatory signaling pathway that controls these crucial processes and has been implicated in cell-progress regulation and organ size determination. Abnormal regulation of this pathway has been found in several cancer types. However, the mechanisms that regulate the pathway and its core members yet have to be elucidated. One of the main core components of this pathway is LATS1, a serine/threonine kinase. Therefore, understanding how LATS1 activity is regulated is expected to shed light on new mechanisms that regulate the Hippo pathway. In the current work, we identified several potential LATS1 regulators and proved that NEDD4 E3 ubiquitin ligase controls LATS1 stability. We demonstrate that NEDD4 directly interacts with LATS1, leading to ubiquitination and decreased levels of LATS1 and, thus, increased YAP localization in the nucleus, which subsequently increases the transcriptional activity of YAP. As such, we show that NEDD4 acts as an additional regulator of the Hippo pathway on the protein level via interactions between WW domain-containing and PPxY motif-containing proteins. These findings might be applied in the development of new therapeutic approaches through the activation of LATS1.

Original languageAmerican English
Pages (from-to)3817-3823
Number of pages7
JournalCell Cycle
Volume12
Issue number24
DOIs
StatePublished - 15 Dec 2013

Bibliographical note

Funding Information:
Authors would like to thank all members of the Aqeilan lab for fruitful discussion. The research work was supported by funds from the Israel Science Foundation (ISF# 12-0542) to RI Aqeilan.

Keywords

  • Hippo pathway
  • LATS1
  • NEDD4
  • Protein-protein interaction
  • WW domain

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