c-Cbl acts as a mediator of Src-induced activation of the PI3K-Akt signal transduction pathway during TRAIL treatment

Cell Signal. 2010 Mar;22(3):377-85. doi: 10.1016/j.cellsig.2009.10.007.


We have previously observed that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces acquired TRAIL resistance by increasing Akt phosphorylation and Bcl-xL expression. In this study, we report that Src, c-Cbl, and PI3K are involved in the phosphorylation of Akt during TRAIL treatment. Data from immunoprecipitation and immunoblotting assay reveal that Src interacts with c-Cbl and PI3K. Data from immune complex kinase assay demonstrate that Src can directly phosphorylate c-Cbl and PI3K p85 subunit protein. Data from gene knockdown experiments with an RNA interference (RNAi) technique show that c-Cbl is involved in the interaction between Src and PI3K p85 during TRAIL treatment, playing an important role in TRAIL-induced Akt phosphorylation. Taken together, c-Cbl may act as a mediator to regulate the Src-PI3K-Akt signal transduction pathway during TRAIL treatment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caspase 8 / genetics
  • Caspase 8 / metabolism
  • Cell Line, Tumor
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / metabolism
  • Proto-Oncogene Proteins c-cbl / physiology*
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • RNA, Small Interfering / metabolism
  • Signal Transduction*
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*


  • RNA, Small Interfering
  • TNF-Related Apoptosis-Inducing Ligand
  • Proto-Oncogene Proteins c-cbl
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins pp60(c-src)
  • Proto-Oncogene Proteins c-akt
  • Caspase 8
  • CBL protein, human