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This article presents a study that shows that ubiquitin (Ub) charging of human class III ubiquitin-conjugating enzymes triggers their nuclear import. The Ub system plays a fundamental role in regulating many cellular processes. Ub is a 76-aa polypeptide that is conjugated onto the s-amino group of lysine residues. The covalent attachment of Ub to a target protein proceeds through a multi-enzyme cascade. Ub is first activated in an ATP-dependent manner by the Ub-activating enzyme. Subsequent to its activation, Ub is transferred to the active site cysteine of a Ub-conjugating enzyme in a transesterification reaction.

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. [ABSTRACT FROM AUTHOR]