Phosphatidylinositol 3-kinase p85{alpha} subunit-dependent interaction with BCR/ABL-related fusion tyrosine kinases: molecular mechanisms and biological consequences.
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.
Ren
Shu-Yue
SY
Molecular Carcinogenesis Section, Center for Biotechnology, College of Science and Technology, Temple University, BLSB 419, 1900 N. 12th Street, Philadelphia, PA 19122, USA.
Bolton
Elisabeth
E
Mohi
M Golam
MG
Morrione
Andrea
A
Neel
Benjamin G
BG
Skorski
Tomasz
T
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism; D025941:Protein Interaction Mapping; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl