title: 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 thatIpo11loss 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 thatIPO11status predicts disease recurrence and progression to metastasis in patients choosing radical prostatectomy. Thus, our data introduce theIPO11gene as a tumor-suppressor locus, which is of special importance in cancers that still retain at least one intactPTENallele.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Muhan
authors.initials: M
authors.lastname: Chen
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Dawid G
authors.initials: DG
authors.lastname: Nowak
authors.affiliation: Department of Pathology, Neuberger Berman Lung Cancer Research Center, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY 10065.|Department of Cell and Developmental Biology, Neuberger Berman Lung Cancer Research Center, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Navneet
authors.initials: N
authors.lastname: Narula
authors.affiliation: Department of Pathology, Neuberger Berman Lung Cancer Research Center, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY 10065.|Department of Cell and Developmental Biology, Neuberger Berman Lung Cancer Research Center, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Brian
authors.identifier: 0000-0001-5374-890X
authors.initials: B
authors.lastname: Robinson
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Watrud
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Alexandra
authors.identifier: 0000-0001-6372-1057
authors.initials: A
authors.lastname: Ambrico
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Tali M
authors.initials: TM
authors.lastname: Herzka
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Martha E
authors.identifier: 0000-0001-6904-021X
authors.initials: ME
authors.lastname: Zeeman
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Matthias
authors.identifier: 0000-0002-6428-8256
authors.initials: M
authors.lastname: Minderer
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Wu
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|The Watson School of Biological Sciences, Cold Spring Harbor, NY 11724.
authors.forename: Saya H
authors.initials: SH
authors.lastname: Ebbesen
authors.affiliation: Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.
authors.forename: Kendra S
authors.identifier: 0000-0001-8015-6168
authors.initials: KS
authors.lastname: Plafker
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Carlos
authors.identifier: 0000-0002-8472-7156
authors.initials: C
authors.lastname: Stahlhut
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Victoria M Y
authors.initials: VM
authors.lastname: Wang
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Lorna
authors.identifier: 0000-0003-2366-0610
authors.initials: L
authors.lastname: Wills
authors.affiliation: Department of Cardiothoracic Surgery, Neuberger Berman Lung Cancer Research Center, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Abu
authors.initials: A
authors.lastname: Nasar
authors.affiliation: Department of Pathology, Mount Sinai Medical School, New York, NY 10029.
authors.forename: Mireia
authors.identifier: 0000-0001-8926-6013
authors.initials: M
authors.lastname: Castillo-Martin
authors.affiliation: Department of Pathology, Mount Sinai Medical School, New York, NY 10029.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: John E
authors.initials: JE
authors.lastname: Wilkinson
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Scott
authors.initials: S
authors.lastname: Powers
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Sordella
authors.affiliation: Department of Cardiothoracic Surgery, Neuberger Berman Lung Cancer Research Center, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Nasser K
authors.initials: NK
authors.lastname: Altorki
authors.affiliation: Department of Cardiothoracic Surgery, Neuberger Berman Lung Cancer Research Center, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Vivek
authors.identifier: 0000-0002-4764-7413
authors.initials: V
authors.lastname: Mittal
authors.affiliation: Department of Cardiothoracic Surgery, Neuberger Berman Lung Cancer Research Center, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Brendon M
authors.initials: BM
authors.lastname: Stiles
authors.affiliation: Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.
authors.forename: Scott M
authors.identifier: 0000-0003-1998-8904
authors.initials: SM
authors.lastname: Plafker
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724 trotman@cshl.edu.
authors.forename: Lloyd C
authors.identifier: 0000-0002-4794-1559
authors.initials: LC
authors.lastname: Trotman
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D028961:beta Karyopherins / Q000378:metabolism*
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D025521:Tumor Suppressor Proteins; D028961:beta Karyopherins; D044763:Ubiquitin-Conjugating Enzymes; D051059:PTEN Phosphohydrolase