Deubiquitination and stabilization of PTEN by USP13

The tumour suppressor PTEN is frequently lost in human cancers. In addition to gene mutations and deletions, recent studies have revealed the importance of post-translational modifications, such as ubiquitylation, in the regulation of PTEN stability, activity and localization. However, the deubiquitylase that regulates PTEN polyubiquitylation and protein stability remains unknown. Here we screened a total of 30 deubiquitylating enzymes (DUBs) and identified five DUBs that physically associate with PTEN. One of them, USP13, stabilizes the PTEN protein through direct binding and deubiquitylation of PTEN. Loss of USP13 in breast cancer cells promotes AKT phosphorylation, cell proliferation, anchorage-independent growth, glycolysis and tumour growth through downregulation of PTEN. Conversely, overexpression of USP13 suppresses tumorigenesis and glycolysis in PTEN-positive but not PTEN-null breast cancer cells. Importantly, USP13 protein is downregulated in human breast tumours and correlates with PTEN protein levels. These findings identify USP13 as a tumour-suppressing protein that functions through deubiquitylation and stabilization of PTEN.

[1]  Xinjiang Wang,et al.  Post-translational regulation of PTEN , 2008, Oncogene.

[2]  Peijing Zhang,et al.  LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker , 2012, Nature Medicine.

[3]  J. Sarkaria,et al.  WWP2 is an E3 ubiquitin ligase for PTEN , 2011, Nature Cell Biology.

[4]  Pier Paolo Pandolfi,et al.  The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network , 2008, Nature.

[5]  M. Waterfield,et al.  Signalling through phosphoinositide 3-kinases: the lipids take centre stage. , 1999, Current opinion in cell biology.

[6]  H. Ressom,et al.  Activation of p53-Dependent Growth Suppression in Human Cells by Mutations in PTEN or PIK3CA , 2006, Molecular and Cellular Biology.

[7]  M. Ghosh,et al.  The Chaperone-assisted E3 Ligase C Terminus of Hsc70-interacting Protein (CHIP) Targets PTEN for Proteasomal Degradation* , 2012, The Journal of Biological Chemistry.

[8]  Steven P Gygi,et al.  Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry , 2007, Nature Methods.

[9]  V. Leblanc,et al.  X-linked Inhibitor of Apoptosis Protein (XIAP) Regulates PTEN Ubiquitination, Content, and Compartmentalization* , 2009, The Journal of Biological Chemistry.

[10]  B. Paluch,et al.  PTEN at a glance , 2012, Journal of Cell Science.

[11]  J. Cheville,et al.  USP10 Regulates p53 Localization and Stability by Deubiquitinating p53 , 2010, Cell.

[12]  W. K. Alfred Yung,et al.  Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers , 1997, Nature Genetics.

[13]  P. Dennis,et al.  PTEN loss in the continuum of common cancers, rare syndromes and mouse models , 2011, Nature Reviews Cancer.

[14]  B. Weigelt,et al.  PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs , 2011, Oncogene.

[15]  Jing Li,et al.  Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome , 1997, Nature Genetics.

[16]  Lewis C. Cantley,et al.  AKT/PKB Signaling: Navigating Downstream , 2007, Cell.

[17]  D. Chaudhari,et al.  Cowden syndrome , 2015, Indian Journal of Gastroenterology.

[18]  O. Warburg.  [Origin of cancer cells]. , 1956, Oncologia.

[19]  Pier Paolo Pandolfi,et al.  Nuclear PTEN Regulates the APC-CDH1 Tumor-Suppressive Complex in a Phosphatase-Independent Manner , 2011, Cell.

[20]  T. Waldman,et al.  PTEN Gene Targeting Reveals a Radiation-Induced Size Checkpoint in Human Cancer Cells , 2004, Cancer Research.

[21]  Tomohiko Maehama,et al.  Crystal Structure of the PTEN Tumor Suppressor Implications for Its Phosphoinositide Phosphatase Activity and Membrane Association , 1999, Cell.

[22]  A. Alavi,et al.  Akt Stimulates Aerobic Glycolysis in Cancer Cells , 2004, Cancer Research.

[23]  P. Pandolfi,et al.  NEDD4-1 Is a Proto-Oncogenic Ubiquitin Ligase for PTEN , 2007, Cell.

[24]  Pier Paolo Pandolfi,et al.  Subtle variations in Pten dose determine cancer susceptibility , 2010, Nature Genetics.

[25]  D. Fisher,et al.  Regulation of MITF stability by the USP13 deubiquitinase. , 2011, Nature communications.

[26]  J. Fata,et al.  Nongenomic Mechanisms of PTEN Regulation , 2012, International journal of cell biology.

[27]  A. Shevchenko,et al.  Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. , 1996, Analytical chemistry.

[28]  Tom Misteli,et al.  Ubiquitination Regulates PTEN Nuclear Import and Tumor Suppression , 2007, Cell.

[29]  A. Giaccia,et al.  The complexity of p53 modulation: emerging patterns from divergent signals. , 1998, Genes & development.

[30]  Pier Paolo Pandolfi,et al.  Tenets of PTEN Tumor Suppression , 2008, Cell.

[31]  Mieke Schutte,et al.  Phosphatidylinositol-3-OH Kinase or RAS Pathway Mutations in Human Breast Cancer Cell Lines , 2007, Molecular Cancer Research.

[32]  L. Skoog,et al.  PIK3CA Mutations and PTEN Loss Correlate with Similar Prognostic Factors and Are Not Mutually Exclusive in Breast Cancer , 2007, Clinical Cancer Research.

[33]  Carlos Cordon-Cardo,et al.  Pten is essential for embryonic development and tumour suppression , 1998, Nature Genetics.

[34]  P. Pandolfi,et al.  Systemic Elevation of PTEN Induces a Tumor-Suppressive Metabolic State , 2012, Cell.

[35]  Tomohiko Maehama,et al.  The Tumor Suppressor, PTEN/MMAC1, Dephosphorylates the Lipid Second Messenger, Phosphatidylinositol 3,4,5-Trisphosphate* , 1998, The Journal of Biological Chemistry.

[36]  K. Wilkinson.  Regulation of ubiquitin‐dependent processes by deubiquitinating enzymes , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[37]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.