Rak Functions as a Tumor Suppressor by Regulating PTEN Protein Stability and Function

Cancer Cell. 2009 Apr 7;15(4):304-14. doi: 10.1016/j.ccr.2009.02.012.

Abstract

Expression of the PTEN tumor suppressor is frequently lost in breast cancer in the absence of mutation or promoter methylation through as yet undetermined mechanisms. In this study, we demonstrate that the Rak tyrosine kinase physically interacts with PTEN and phosphorylates PTEN on Tyr336. Knockdown of Rak enhanced the binding of PTEN to its E3 ligase NEDD4-1 and promoted PTEN polyubiquitination, leading to PTEN protein degradation. Notably, ectopic expression of Rak effectively suppressed breast cancer cell proliferation, invasion, and colony formation in vitro and tumor growth in vivo. Furthermore, Rak knockdown was sufficient to transform normal mammary epithelial cells. Therefore, Rak acts as a bona fide tumor suppressor gene through the mechanism of regulating PTEN protein stability and function.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Breast / cytology
  • Breast / metabolism
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • Endosomal Sorting Complexes Required for Transport
  • Female
  • Genes, Tumor Suppressor / physiology*
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Mice
  • Mice, Nude
  • Mutation
  • Nedd4 Ubiquitin Protein Ligases
  • Neoplasm Invasiveness
  • Neoplasm Proteins / physiology*
  • Osteosarcoma / genetics
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Phosphorylation
  • Protein-Tyrosine Kinases / physiology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • src-Family Kinases / physiology*

Substances

  • Endosomal Sorting Complexes Required for Transport
  • Neoplasm Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, human
  • Nedd4l protein, mouse
  • Ubiquitin-Protein Ligases
  • Protein-Tyrosine Kinases
  • FRK protein, human
  • Frk protein, mouse
  • src-Family Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Pten protein, mouse