Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function

Antonella Papa, Lixin Wan, Massimo Bonora, Leonardo Salmena, Min Sup Song, Robin M. Hobbs, Andrea Lunardi, Kaitlyn Webster, Christopher Ng, Ryan H. Newton, Nicholas Knoblauch, Jlenia Guarnerio, Keisuke Ito, Laurence A. Turka, Andy H. Beck, Paolo Pinton, Roderick T. Bronson, Wenyi Wei, Pier Paolo Pandolfi

Research output: Contribution to journalArticle

137 Scopus citations

Abstract

PTEN dysfunction plays a crucial role in the pathogenesis of hereditary and sporadic cancers. Here, we show that PTEN homodimerizes and, in this active conformation, exerts lipid phosphatase activity on PtdIns(3,4,5)P3. We demonstrate that catalytically inactive cancer-associated PTEN mutants heterodimerize with wild-type PTEN and constrain its phosphatase activity in a dominant-negative manner. To study the consequences of homo- and heterodimerization of wild-type and mutant PTEN in vivo, we generated Pten knockin 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, whereas this difference is no longer apparent between PtenC124S/- and Pten-/- cells. Notably, Pten KI 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 working model for the function and regulation of PTEN.

Original languageEnglish (US)
Pages (from-to)595-610
Number of pages16
JournalCell
Volume157
Issue number3
DOIs
StatePublished - Apr 24 2014

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Papa, A., Wan, L., Bonora, M., Salmena, L., Song, M. S., Hobbs, R. M., Lunardi, A., Webster, K., Ng, C., Newton, R. H., Knoblauch, N., Guarnerio, J., Ito, K., Turka, L. A., Beck, A. H., Pinton, P., Bronson, R. T., Wei, W., & Pandolfi, P. P. (2014). Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function. Cell, 157(3), 595-610. https://doi.org/10.1016/j.cell.2014.03.027