The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein. Academic Article uri icon

Overview

abstract

  • Phosphatase and tensin homologue (PTEN) protein levels are critical for tumor suppression. However, the search for a recurrent cancer-associated gene alteration that causes PTEN degradation has remained futile. In this study, we show that Importin-11 (Ipo11) is a transport receptor for PTEN that is required to physically separate PTEN from elements of the PTEN degradation machinery. Mechanistically, we find that the E2 ubiquitin-conjugating enzyme and IPO11 cargo, UBE2E1, is a limiting factor for PTEN degradation. Using in vitro and in vivo gene-targeting methods, we show that Ipo11 loss results in degradation of Pten, lung adenocarcinoma, and neoplasia in mouse prostate with aberrantly high levels of Ube2e1 in the cytoplasm. These findings explain the correlation between loss of IPO11 and PTEN protein in human lung tumors. Furthermore, we find that IPO11 status predicts disease recurrence and progression to metastasis in patients choosing radical prostatectomy. Thus, our data introduce the IPO11 gene as a tumor-suppressor locus, which is of special importance in cancers that still retain at least one intact PTEN allele.

authors

  • Chen, Muhan
  • Nowak, Dawid
  • Narula, Navneet
  • Robinson, Brian D.
  • Watrud, Kaitlin
  • Ambrico, Alexandra
  • Herzka, Tali M
  • Zeeman, Martha E
  • Minderer, Matthias
  • Zheng, Wu
  • Ebbesen, Saya H
  • Plafker, Kendra S
  • Stahlhut, Carlos
  • Wang, Victoria M Y
  • Wills, Lorna
  • Nasar, Abu
  • Castillo-Martin, Mireia
  • Cordon-Cardo, Carlos
  • Wilkinson, John E
  • Powers, Scott
  • Sordella, Raffaella
  • Altorki, Nasser K
  • Mittal, Vivek
  • Stiles, Brendon M
  • Plafker, Scott M
  • Trotman, Lloyd C

publication date

  • February 13, 2017

Research

keywords

  • PTEN Phosphohydrolase
  • Receptors, Cytoplasmic and Nuclear
  • Tumor Suppressor Proteins
  • beta Karyopherins

Identity

PubMed Central ID

  • PMC5350510

Scopus Document Identifier

  • 85021848032

Digital Object Identifier (DOI)

  • 10.1083/jcb.201604025

PubMed ID

  • 28193700

Additional Document Info

volume

  • 216

issue

  • 3