Ubiquitin-specific protease 11 functions as a tumor suppressor by modulating Mgl-1 protein to regulate cancer cell growth.

Key-Hwan Lim,Bharathi Suresh,Suresh Ramakrishna,Young-Soo Kim,Jung-Hyun Park,Kwang-Hyun Baek

doi:10.18632/oncotarget.7581

Abstract

The Lethal giant larvae (Lgl) gene encodes a cortical cytoskeleton protein, Lgl, and is involved in maintaining cell polarity and epithelial integrity. Previously, we observed that Mgl-1, a mammalian homologue of the Drosophila tumor suppressor protein Lgl, is subjected to degradation via ubiquitin-proteasome pathway, and scaffolding protein RanBPM prevents the turnover of the Mgl-1 protein. Consequently, overexpression of RanBPM enhances Mgl-1-mediated cell proliferation and migration. Here, we analyzed the ability of ubiquitin-specific protease 11 (USP11) as a novel regulator of Mgl-1 and it requires RanBPM to regulate proteasomal degradation of Mgl-1. USP11 showed deubiquitinating activity and stabilized Mgl-1 protein. However, USP11-mediated Mgl-1 stabilization was inhibited in RanBPM-knockdown cells. Furthermore, in the cancer cell migration, the regulation of Mgl-1 by USP11 required RanBPM expression. In addition, an in vivo study revealed that depletion of USP11 leads to tumor formation. Taken together, the results indicated that USP11 functions as a tumor suppressor through the regulation of Mgl-1 protein degradation via RanBPM.

Highlights

Lethal giant larvae (Lgl) is an apical-basal polarity Drosophila gene, which functions as a tumor suppressor, controlling the self-renewal and differentiation of progenitor cells
To reconfirm the interaction between Mgl-1 and ubiquitin-specific protease 11 (USP11), we investigated the interaction between Mgl-1 and USP11 in a Glutathione S-transferase (GST) pull-down in vitro assay
Binding between Mgl-1 and USP11 was established with the GST-pull down assay, and the GST-Mgl-1 fusion protein was incubated with the USP11-transfected cell lysate

Summary

Introduction

Lethal giant larvae (Lgl) is an apical-basal polarity Drosophila gene, which functions as a tumor suppressor, controlling the self-renewal and differentiation of progenitor cells. Lgl plays a critical role in basal crescent formation [1, 2]. Lgl-1 depleted neural progenitor cells shows loss of cell polarity and asymmetric cell divisions which form neuroblastic rosette-like structures resembling primitive neuroectodermal tumors [3]. A direct interaction between apical proteins is required for basal crescent formation. Lgl-1 provides a functional link between polarity complexes, and this link is essential for cell polarization and asymmetric cell division [4]. Phosphorylation of Lgl-1 by aPKC is essential for Lgl-1 to perform its different functions. PKC phosphorylates Lgl-1 at the apical cortex of the cell, causing Lgl to disassociate from the cytoskeleton. Lgl-1 remains nonphosphorylated and basally localized in the cortical cytoskeleton, where it anchors for cell fate determinants [6]

Objectives

Methods

Results

Conclusion