Characterization of the two major merlin isoforms and merlin regulation of YAP

Abstract

Merlin is the protein encoded by the tumor suppressor gene NF2. Deletion or loss-of-function of NF2 leads to neurofibromatosis type 2, a disease characterized by the formation of multiple benign tumors of the nervous system. In addition to the genetic disorder, loss of merlin expression has been found in sporadically occurring schwannomas and meningiomas, as well as in mesothelioma. Merlin has two major isoforms that differ in only one exon at the C-terminal. Previous work hypothesized that isoform 11 is unable to suppress growth. In this thesis, I show that both of the major merlin isoforms are able to suppress growth in multiple cell lines, including mesothelioma. Merlin has been shown to suppress growth through multiple mechanisms, including upstream regulation of the oncogene YAP through stabilization of the Hippo-pathway kinase Lats, allowing Lats to phosphorylate and inhibit YAP. In this thesis I identify an additional mechanism for merlin regulation of YAP, which occurs independently of the Hippo-pathway-based regulation. I show that mesothelioma cells expressing merlin have lower YAP-driven transcriptional activity and that expression of merlin leads to cytoplasmic localization of YAP. Furthermore, I show that this regulation of YAP is not dependent on the major Lats phosphorylation sites, but does require the YAP WW domains. This thesis provides additional insight into how merlin controls cell growth, and into YAP regulation by merlin.