Poster Presentation 27th Lorne Cancer Conference 2015

Cancer-associated PTEN mutants act in a dominant negative manner to suppress PTEN protein function (#329)

Antonella Papa 1 2 , Lixin Wan 3 , Massimo Bonora 4 , Leonardo Salmena 1 5 , Min Sup Song 1 6 , Robin M Hobbs 1 7 , Andrea Lunardi 1 , Kaitlyn Webster 1 , Christopher Ng 1 , Ryan H Newton 8 9 , Nicholas Knoblauch 3 , Jlenia Guarnerio 1 , Keisuke Ito 1 10 , Laurence A Turka 8 9 , Andy H Beck 3 , Paolo Pinton 4 , Roderick Bronson 11 , Wenyi Wei 3 , Pier Paolo Pandolfi 1
  1. Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, VIC, Australia
  2. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Melbourne, VIC, Australia
  3. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
  4. Department of Morphology, Surgery and Experimental Medicine Section of General Pathology, University of Ferrara, Ferrara, Italy
  5. Department of Pharmacology and Toxicology, University of Toronto and Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  6. Department of Molecular and Cellular Oncology, MD Anderson Cancer Center, Houstan, TX, USA
  7. Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia
  8. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
  9. Department of Surgery, Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  10. Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research and Departments of Medicine and Cell Biology, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA
  11. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA

PTEN dysfunction plays a crucial role in the pathogenesis of hereditary and sporadic cancers. Here we show that PTEN homo-dimerizes, and in this active conformation exerts lipid phosphatase activity on PtdIns(3,4,5)P3. We demonstrate that catalytically inactive cancer-associated PTEN mutants hetero-dimerize with wild-type PTEN and constrain its phosphatase activity in a dominant-negative manner. To study the consequences of homo- and hetero-dimerization of wild-type and mutant PTEN in vivo, we generated Pten knock-in mice harboring two cancer-associated PTEN mutations (PtenC124S and PtenG129E). Heterozygous PtenC124S/+ and PtenG129E/+ cells and tissues exhibit increased sensitivity to PI3-K/Akt activation compared to wild-type and Pten+/- counterparts, while this difference is no longer apparent between PtenC124S/- and Pten-/- cells. Notably, PtenKI mice are more tumor-prone and display features reminiscent of complete Pten loss. Our findings reveal that PTEN loss and PTEN mutations are not synonymous, and define a new working model for the function and regulation of PTEN.