The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network

Song, M. S. et al. 2008. Nature 455:813-817.

Speaker: Huan Yun Chen (陳奐勻)                         Time: 13:00~14:00, Dec. 31, 2008

Commentator: Dr. Ai-Li Shiau (蕭璦莉 博士)               Place: Room 601

Abstract:

PTEN (phosphatase and tensin homolog deleted on chromosome10) is one of the most frequently mutated tumor suppressor in human cancer. PTEN is a plasma- membrane lipid-phosphatase that antagonizes the PI3K–Akt pathway. Upon PTEN loss, PIP₃ accumulates and promotes the recruitment of a subset of proteins including AKT which promotes cell survival, proliferation, growth, and angiogenesis. Previous studies have shown that the localization of the PTEN has been associated with tumorgenesis. However, the mechanisms leading to this aberrant PTEN localization in human cancers are currently unknown. Some studies suggested that PTEN ubiquitinylation at specific lysine residues may regulate its nuclear–cytoplasmic partitioning. In this study, the authors showed that promyelocytic leukaemia protein (PML) nuclear bodies co-ordinate PTEN localization by opposing the action of a previously unknown PTEN-deubiquitinylating enzyme, herpesvirus-associated ubiquitin-specific protease (HAUSP), and that the integrity of this molecular framework is required for PTEN to be able to enter the nucleus. In addition, the results also suggest that PML opposes the activity of HAUSP towards PTEN through a mechanism involving the adaptor protein DAXX (death domain-associated protein). Taken together, this work elucidates a earlier PML–DAXX–HAUSP molecular network controlling PTEN deubiquitinylation and trafficking, which is disturbed by oncogenic cues in human cancer, in turn defining a new deubiquitinylation-dependent model for PTEN subcellular compartmentalization.

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