Commentary: New insights into the complexity of phosphatidylinositol lipid signaling in B lymphocytes.
Stimulation of B cells through the B cell antigen receptor (BCR) leads to the activation of numerous intracellular signaling pathways including phosphoinositide (PI) 3-kinases (PI3K). These generate the 3-PI lipids which in turn act as critical second messengers. Gene-targeting experiments had shown that B cells deficient in p85alpha, an adaptor protein required for PI3K function, were defective in their ability to proliferate in response to BCR stimulation. In this issue of the European Journal of Immunology, Hess et al. report analysis of intracellular signaling pathways in p85alpha-deficient B cells and show that in the absence of p85alpha there is a partial impairment in BCR-induced calcium flux, and a reduction in activation of the transcription factor NF-kappaB. Unexpectedly, they show that while the BCR-induced phosphorylation of the PI3K-dependent kinase Akt is reduced in p85alpha-deficient cells, the phosphorylation of two downstream targets of Akt -- FOXO1 and ribosomal protein S6 -- is largely unaffected. Furthermore, they show that treatment of wild-type B cells with PI3K inhibitors had a more profound effect than disruption of the p85alpha gene. Taken together, these results indicate that in the absence of p85alpha, there is still significant residual PI3K activity. These results highlight the need for careful measurement of PI3K activity in gene-targeted mice and cells, by directly measuring levels of the 3-PI lipids.
Tybulewicz
Victor L J
VL
Division of Immune Cell Biology, National Institute for Medical Research, London, UK. vtybule@nimr.mrc.ac.uk
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D004789:Enzyme Activation; D007527:Isoenzymes; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D010716:Phosphatidylinositols / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015290:Second Messenger Systems / Q000276:immunology
D007527:Isoenzymes; D010716:Phosphatidylinositols; D011947:Receptors, Antigen, B-Cell; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase