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Phosphatidylinositol 3-Kinase p85 Subunit-Dependent Interaction with BCR/ABL-Related Fusion Tyrosine Kinases: Molecular Mechanisms and Biological Consequences

Molecular Carcinogenesis Section, Center for Biotechnology, College of Sciences and Technology, Temple University, Philadelphia, Pennsylvania 19122,¹ Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Institute of Medicine, Boston, Massachusetts 02215,² Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107³

Received 17 December 2004/ Returned for modification 1 February 2005/ Accepted 22 June 2005

The p85 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/PDGFßR, 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 p85, which disrupt their ability to bind phosphotyrosine and proline-rich motifs, respectively, abrogated their interaction with the BCR/ABL protein network. The p85 mutant protein (p85mut) bearing these mutations was unable to interact with BCR/ABL and other FTKs, while its binding to the p110 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 p85 responsible for the interaction with the FTK protein network and transduction of leukemogenic signaling.

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