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

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: Muhan Chen, Dawid G Nowak, Navneet Narula, Brian Robinson, Kaitlin Watrud, Alexandra Ambrico, Tali M Herzka, Martha E Zeeman, Matthias Minderer, Wu Zheng, Saya H Ebbesen, Kendra S Plafker, Carlos Stahlhut, Victoria M Y Wang, Lorna Wills, Abu Nasar, Mireia Castillo-Martin, Carlos Cordon-Cardo, John E Wilkinson, Scott Powers, Raffaella Sordella, Nasser K Altorki, Vivek Mittal, Brendon M Stiles, Scott M Plafker, Lloyd C Trotman
• Journal: The Journal of cell biology (J Cell Biol) Vol. 216 Issue 3 Pg. 641-656 (03 06 2017) ISSN: 1540-8140 [Electronic] United States
• PMID: 28193700 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural)
• Copyright: © 2017 Chen et al.

Chemical References

• Receptors, Cytoplasmic and Nuclear
• Tumor Suppressor Proteins
• beta Karyopherins
• Ubiquitin-Conjugating Enzymes
• PTEN Phosphohydrolase

Topics

• Animals
• Cell Line
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cytoplasm (metabolism)
• HeLa Cells
• Humans
• Lung Neoplasms (metabolism)
• Mice
• PTEN Phosphohydrolase (metabolism)
• Receptors, Cytoplasmic and Nuclear (metabolism)
• Tumor Suppressor Proteins (metabolism)
• Ubiquitin-Conjugating Enzymes (metabolism)
• beta Karyopherins (metabolism)