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Phosphatidylinositol 3-kinase p85{alpha} subunit-dependent interaction with BCR/ABL-related fusion tyrosine kinases: molecular mechanisms and biological consequences.

http://www.ncbi.nlm.nih.gov/pubmed/16135792

The p85alpha subunit of phosphatidylinositol 3-kinase (PI-3k) forms a complex with a protein network associated with oncogenic fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGFbetaR, and NPM/ALK, resulting in constitutive activation of the p110 catalytic subunit of PI-3k. Introduction of point mutations in the N-terminal and C-terminal SH2 domain and SH3 domain of p85alpha, which disrupt their ability to bind phosphotyrosine and proline-rich motifs, respectively, abrogated their interaction with the BCR/ABL protein network. The p85alpha mutant protein (p85mut) bearing these mutations was unable to interact with BCR/ABL and other FTKs, while its binding to the p110alpha catalytic subunit of PI-3k was intact. In addition, binding of Shc, c-Cbl, and Gab2, but not Crk-L, to p85mut was abrogated. p85mut diminished BCR/ABL-dependent activation of PI-3k and Akt kinase, the downstream effector of PI-3k. This effect was associated with the inhibition of BCR/ABL-dependent growth of the hematopoietic cell line and murine bone marrow cells. Interestingly, the addition of interleukin-3 (IL-3) rescued BCR/ABL-transformed cells from the inhibitory effect of p85mut. SCID mice injected with BCR/ABL-positive hematopoietic cells expressing p85mut survived longer than the animals inoculated with BCR/ABL-transformed counterparts. In conclusion, we have identified the domains of p85alpha responsible for the interaction with the FTK protein network and transduction of leukemogenic signaling.

Pubmed ID: 16135792 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Animals | Cattle | Cell Line | Cell Transformation, Neoplastic | Fusion Proteins, bcr-abl | Humans | Leukemia | Mice | Mice, SCID | Mutation | Phosphatidylinositol 3-Kinases | Phosphotyrosine | Protein Interaction Mapping | src Homology Domains

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Associated grants

  • Agency: NIDDK NIH HHS, Id: P01 DK50654
  • Agency: NCI NIH HHS, Id: R01 CA83700

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