TY - JOUR
T1 - The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein
AU - Chen, Muhan
AU - Nowak, Dawid G.
AU - Narula, Navneet
AU - Robinson, Brian
AU - Watrud, Kaitlin
AU - Ambrico, Alexandra
AU - Herzka, Tali M.
AU - Zeeman, Martha E.
AU - Minderer, Matthias
AU - Zheng, Wu
AU - Ebbesen, Saya H.
AU - Plafker, Kendra S.
AU - Stahlhut, Carlos
AU - Wang, Victoria M.Y.
AU - Wills, Lorna
AU - Nasar, Abu
AU - Castillo-Martin, Mireia
AU - Cordon-Cardo, Carlos
AU - Wilkinson, John E.
AU - Powers, Scott
AU - Sordella, Raffaella
AU - Altorki, Nasser K.
AU - Mittal, Vivek
AU - Stiles, Brendon M.
AU - Plafker, Scott M.
AU - Trotman, Lloyd C.
N1 - Publisher Copyright:
© 2017 Chen et al.
PY - 2017/3/6
Y1 - 2017/3/6
N2 - 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.
AB - 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.
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U2 - 10.1083/jcb.201604025
DO - 10.1083/jcb.201604025
M3 - Article
C2 - 28193700
AN - SCOPUS:85021848032
SN - 0021-9525
VL - 216
SP - 641
EP - 656
JO - The Journal of cell biology
JF - The Journal of cell biology
IS - 3
ER -
