A role for C. elegans Eph RTK signaling in PTEN regulation.
PTEN is one of the most commonly lost tumor suppressors in human cancer and is known to inhibit insulin signaling. Eph receptor tyrosine kinases (RTKs) have also been implicated in cancer formation and progression, and they have diverse functions, including nervous and vascular system development. We show that in C. elegans, the VAB-1 Eph kinase domain physically interacts with and phosphorylates PTEN (DAF-18), diminishing its protein levels and function. vab-1 mutants show increased longevity and sensitivity to dauer conditions, consistent with increased DAF-18/PTEN activity and decreased insulin-like signaling. Moreover, daf-18 mutations suppress vab-1 oocyte maturation phenotypes independent of PI3K signaling. We also present evidence that DAF-18 has protein phosphatase activity to antagonize VAB-1 action. Possible implications for human cancers are discussed, based on the idea that mutually inhibitory interactions between PTEN and Eph RTKs may be conserved.
Department of Biology, Queen's University, 116 Barrie Street, Kingston, Ontario K7L 3N6, Canada.
Sarah
S
Brisbin
Jun
J
Liu
Jeff
J
Boudreau
Jimmy
J
Peng
Marie
M
Evangelista
Ian
I
Chin-Sang
D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007124:Immunoenzyme Techniques; D007328:Insulin / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D036081:Receptors, Eph Family / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques
D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; C116661:DAF-18 protein, C elegans; D007328:Insulin; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D036081:Receptors, Eph Family; C111040:vab-1 protein, C elegans; D051059:PTEN Phosphohydrolase