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J Cell Biol. 2017 Mar 6;216(3):641-656. doi: 10.1083/jcb.201604025. Epub 2017 Feb 13.

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

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
2
Department of Pathology, Neuberger Berman Lung Cancer Research Center, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY 10065.
3
Department of Cell and Developmental Biology, Neuberger Berman Lung Cancer Research Center, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY 10065.
4
The Watson School of Biological Sciences, Cold Spring Harbor, NY 11724.
5
Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.
6
Department of Cardiothoracic Surgery, Neuberger Berman Lung Cancer Research Center, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY 10065.
7
Department of Pathology, Mount Sinai Medical School, New York, NY 10029.
8
Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
9
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724 trotman@cshl.edu.

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.

PMID:
28193700
PMCID:
PMC5350510
DOI:
10.1083/jcb.201604025
[Indexed for MEDLINE]
Free PMC Article

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