NEDD4L‐mediated Merlin ubiquitination facilitates Hippo pathway activation
Abstract
The tumor suppressor Merlin/NF2, a key activator of the Hippo pathway in growth control, is regulated by phosphorylation. However, it is uncertain whether additional post‐translational modifications regulate Merlin. Here, we show that ubiquitination is required to activate Merlin in the Hippo pathway. Ubiquitinated Merlin is mostly conjugated by one or two ubiquitin molecules. Such modification is promoted by serine 518 dephosphorylation in response to Ca2+ signaling or cell detachment. Merlin ubiquitination is mediated by the E3 ubiquitin ligase, NEDD4L, which requires a scaffold protein, AMOTL1, to approach Merlin. Several NF2‐patient‐derived Merlin mutations disrupt its binding to AMOTL1 and its regulation by the AMOTL1‐NEDD4L apparatus. Lysine (K) 396 is the major ubiquitin conjugation residue. Disruption of Merlin ubiquitination by the K396R mutation or NEDD4L depletion diminishes its binding to Lats1 and inhibits Lats1 activation. These effects are also accompanied by loss of Merlin's anti‐mitogenic and tumor suppressive properties. Thus, we propose that dephosphorylation and ubiquitination compose an intramolecular relay to activate Merlin functions in activating the Hippo pathway during growth control.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 14, 2020
- Source ID
- 10.15252/embr.202050642
Entities
People
- Benjamin R Anderson
- Guo Hui
- Haiyan Zheng
- Lei Zhang
- Melissa Gulley
- Patricia P Yee
- Wei Li
- Yiju Wei
- Zhijun Liu
Organizations
- Huazhong University of Science and Technology
- Pennsylvania State University
- Robert Wood Johnson Medical School
- United States Department of Defense