Phosphatidylinositol-3-kinase activity is required for the anti-ig-mediated growth inhibition of a human B-lymphoma cell line.
Stimulation of B lymphocytes through the Ig receptor initiates a cascade of biochemical changes, which can ultimately lead to either activation and growth, or cell-cycle arrest and cell death. One of the critical events that occurs in both cases is the activation of tyrosine kinases, and the resulting phosphorylation of a variety of proteins on tyrosine residues. In this report we identify one of the substrates of phosphorylation as the 85-kD subunit of the enzyme phosphatidylinositol-3 kinase (PI3K), and show that both anti-IgM and anti-IgD stimulation results in an increase in the anti-phosphotyrosine-precipitable PI3K activity. Furthermore, we show that the potent and specific inhibitor of PI3K, Wortmannin, can completely abrogate anti-Ig-mediated growth inhibition without affecting tyrosine kinase induction or protein kinase C (PKC) activation. Treatment of intact cells with Wortmannin results in an irreversible decrease in anti-Ig-induced PI3K activity, suggesting that the effect of Wortmannin on anti-Ig-mediated growth inhibition is caused by its inactivation of PI3K activity. Taken together, these data show that activation of PI3K is a critical component of the anti-Ig-initiated signaling cascade that leads to growth inhibition of human B lymphoma cells.
Biological Carcinogenesis and Development Program, Science Applications International Corporation/Frederick, MD, USA.
M
M
Beckwith
R G
RG
Fenton
I M
IM
Katona
D L
DL
Longo
D000730:Androstadienes / Q000494:pharmacology; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007072:Immunoglobulin D / Q000502:physiology*; D007075:Immunoglobulin M / Q000502:physiology*; D008024:Ligands; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology*; D009363:Neoplasm Proteins / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000730:Androstadienes; D000888:Antibodies, Anti-Idiotypic; D004791:Enzyme Inhibitors; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D008024:Ligands; D009363:Neoplasm Proteins; D011947:Receptors, Antigen, B-Cell; C039951:anti-IgD; C044203:anti-IgM; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D020794:Receptor Protein-Tyrosine Kinases; D000077191:Wortmannin