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.