Phosphatidylinositol 3-kinase p85α subunit-dependent interaction with BCR/ABL-related fusion tyrosine kinases: Molecular mechanisms and biological consequences

Shu Yue Ren, Elisabeth Bolton, M. Golam Mohi, Andrea Morrione, Benjamin G. Neel, Tomasz Skorski

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

The p85α 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/PDGFβR, 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 p85α, which disrupt their ability to bind phosphotyrosine and proline-rich motifs, respectively, abrogated their interaction with the BCR/ABL protein network. The p85α mutant protein (p85mut) bearing these mutations was unable to interact with BCR/ABL and other FTKs, while its binding to the p110α catalytic subunit of PI-3k was intact. In addition, binding of She, 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 p85α responsible for the interaction with the FTK protein network and transduction of leukemogenic signaling.

Original languageEnglish
Pages (from-to)8001-8008
Number of pages8
JournalMolecular and Cellular Biology
Volume25
Issue number18
DOIs
StatePublished - Sep 2005

Keywords

  • Adaptor Proteins, Signal Transducing/metabolism
  • Animals
  • Cattle
  • Cell Line
  • Cell Transformation, Neoplastic/genetics
  • Fusion Proteins, bcr-abl/metabolism
  • Humans
  • Leukemia/genetics
  • Mice
  • Mice, SCID
  • Mutation
  • Phosphatidylinositol 3-Kinases/chemistry
  • Phosphotyrosine/metabolism
  • Protein Interaction Mapping
  • src Homology Domains

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