NEDD4L‐mediated Merlin ubiquitination facilitates Hippo pathway activation. (14th October 2020)

• Record Type: Journal Article
• Authors: Wei, Yiju; Yee, Patricia P; Liu, Zhijun; Zhang, Lei; Guo, Hui; Zheng, Haiyan; Anderson, Benjamin; Gulley, Melissa; Li, Wei
• Is Part Of: EMBO reports. Volume 21:Number 12(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-10-14
• Subjects: AMOTL1 -- Hippo pathway -- Merlin -- NEDD4L -- ubiquitination; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202050642
• Languages: English
• ISSNs: 1469-221X

Abstract

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 Ca 2+ 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. Synopsis: The Hippo pathway tumor suppressor Merlin/NF2 is known to be regulated by phosphorylation. Here, the E3 ubiquitin ligase NEDD4L is shown to promote Hippo pathway activation via ubiquitination of Merlin. Merlin ubiquitination is associated with Hippo pathway activation. Merlin ubiquitination is mediated by the E3 ubiquitin ligase NEDD4L and the scaffold protein AMOTL1. Merlin ubiquitination is important for its interaction with Lats1 and for Lats1 activation. Abstract : The Hippo pathway tumor suppressor Merlin/NF2 is known to be regulated by phosphorylation. Here, the E3 ubiquitin ligase NEDD4L is shown to promote Hippo pathway activation via ubiquitination of Merlin.