Frontline: The p85alpha isoform of phosphoinositide 3-kinase is essential for a subset of B cell receptor-initiated signaling responses.
Phosphoinositide 3-kinase (PI3K) is a ubiquitously expressed signaling enzyme that plays an integral role in development and activation of B cells. B cell receptor (BCR)-driven proliferation is completely blocked either in cells lacking the p85alpha regulatory isoform of PI3K or in wild-type cells treated with pharmacological PI3K inhibitors. However, the contribution of p85alpha to early signaling events has not been fully investigated. Here we show that B cells lacking p85alpha have signaling impairments that are both quantitatively and qualitatively different from those in cells treated with PI3K inhibitors. Loss of p85alpha results in partial reductions in Ca2+ mobilization and IkappaB phosphorylation, whereas ERK phosphorylation is not diminished. Moreover, although Akt phosphorylation is partially reduced, phosphorylation of several proteins downstream of Akt is preserved. These partial impairments suggest that there are other routes to PI3K activation in B cells apart from p85alpha-associated catalytic subunits. Notably, addition of phorbol ester restores BCR-mediated proliferation in p85alpha-deficient cells but not wild-type cells treated with PI3K inhibitors. These findings suggest that the primary BCR signaling defect in B cells lacking p85alpha is a failure to activate diacylglycerol-regulated signaling enzymes, most likely protein kinase C.
Hess
Kristen L
KL
Center for Immunology, Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
Donahue
Amber C
AC
Ng
Kwan L
KL
Moore
Travis I
TI
Oak
Jean
J
Fruman
David A
DA
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D002118:Calcium / Q000276:immunology; D049109:Cell Proliferation; D004789:Enzyme Activation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D020672:I-kappa B Proteins / Q000276:immunology; D007527:Isoenzymes; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology; D000072000:NF-KappaB Inhibitor alpha; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000276:immunology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
D002118:Calcium; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007527:Isoenzymes; D048052:Mitogen-Activated Protein Kinase 3; D000072000:NF-KappaB Inhibitor alpha; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011947:Receptors, Antigen, B-Cell; C000606205:Nfkbia protein, mouse