Rak functions as a tumor suppressor by regulating PTEN protein stability and function.
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.
Mesh Terms:
Animals, Bone Neoplasms, Breast, Breast Neoplasms, Cell Proliferation, Cell Transformation, Neoplastic, Cells, Cultured, Endosomal Sorting Complexes Required for Transport, Female, Genes, Tumor Suppressor, Humans, Immunoblotting, Immunoprecipitation, Mice, Mice, Nude, Mutation, Neoplasm Invasiveness, Neoplasm Proteins, Osteosarcoma, PTEN Phosphohydrolase, Phosphorylation, Protein-Tyrosine Kinases, RNA, Messenger, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Ubiquitin-Protein Ligases, Ubiquitination, src-Family Kinases
Animals, Bone Neoplasms, Breast, Breast Neoplasms, Cell Proliferation, Cell Transformation, Neoplastic, Cells, Cultured, Endosomal Sorting Complexes Required for Transport, Female, Genes, Tumor Suppressor, Humans, Immunoblotting, Immunoprecipitation, Mice, Mice, Nude, Mutation, Neoplasm Invasiveness, Neoplasm Proteins, Osteosarcoma, PTEN Phosphohydrolase, Phosphorylation, Protein-Tyrosine Kinases, RNA, Messenger, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Ubiquitin-Protein Ligases, Ubiquitination, src-Family Kinases
Cancer Cell
Date: Apr. 07, 2009
PubMed ID: 19345329
View in: Pubmed Google Scholar
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- Interactions 4
- PTM Genes 1