[Frontiers in Bioscience S4, 321-334, January 1, 2012]

[Frontiers in Bioscience S4, 321-334, January 1, 2012]

The TRE17/USP6 Oncogene: a riddle wrapped in a mystery inside an enigma

Andre M. Oliveira¹, Margaret M. Chou²

1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, ²Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. TRE17/USP6 background: 3.1. Identification and expression of TRE17; 3.2. TRE17 and aneurysmal bone cyst; 3.3. Physiological function of TRE17; 3.4. Structure and evolution of TRE17 and its ancestor genes
4. Targets/binding partners of TRE17: 4.1. TBC domain targets; 4.2. USP substrates; 4.3. Additional binding partners
5. Cellular pathways and responses activated by TRE17: 5.1. Arf6 and endocytic trafficking; 5.2. Actin remodeling; 5.3. NFkB activation and matrix protease production
6. Mechanisms of Tumorigenesis: 6.1. Tumorigenesis requires TRE17's USP and TBC domains; 6.2. Cellular functions induced by TRE17: relevance to ABC and neoplasia
7. Concluding Remarks: 7.1. Novel therapeutics strategies; 7.2. Key issues for the future
8. Acknowledgments
9. References

1. ABSTRACT

De-ubiquitinating enzymes (DUBs) play critical roles in diverse cellular processes, including intracellular trafficking, protein turnover, inflammatory signaling, and cell transformation. The first DUB to be identified as an oncogene was TRE17/Ubiquitin-specific protease 6 (USP6)/Tre-2. In addition to encoding a USP, TRE17 also contains a TBC (Tre-2/Bub2/Cdc16) domain implicated in GTPase regulation and trafficking. Though first described almost two decades ago, remarkably little has been elucidated regarding TRE17's molecular and cellular functions. However, recent work has implicated TRE17 as a key etiological factor in aneurysmal bone cyst (ABC), a locally recurrent pediatric bone tumor, and identified potential pathways through which it acts. In this review, we discuss the most up-to-date findings on the molecular functions of TRE17, the role of its USP and TBC domains, and potential models for how it contributes to transformation and ABC pathogenesis.