Phosphatidylinositol-3 kinase activity in B cells is negatively regulated by Lyn tyrosine kinase.
Phosphatidylinositol-3 kinase (PI3K) activity is essential for normal B-cell receptor (BCR)-mediated responses. To understand the mechanisms of PI3K regulation during B-cell activation, we performed a series of biochemical analysis on primary B cells, and found that activity of Src family tyrosine kinases (SFK) is crucial for the activation of PI3K following BCR ligation and this is regulated by the SFK Lyn. We show that the hyperresponsive phenotype of B cells lacking Lyn is predicated on significantly increased basal and inducible PI3K activity that correlates with the constitutive hypophosphorylation of PAG/Cbp (phosphoprotein associated with glycosphingolipid-enriched microdomains/Csk-binding protein), a concomitant reduction in bound Csk in Lyn(-/-) B cells and elevated levels of active Fyn. Regulating SFK activity may thus be a central mechanism by which Lyn regulates PI3K activity in B cells. This study defines the molecular connection between the BCR and PI3K and reveals this to be a point of Lyn-mediated regulation.
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Yuekang
Y
Xu
Nicholas D
ND
Huntington
Kenneth W
KW
Harder
Harshal
H
Nandurkar
Margaret L
ML
Hibbs
David M
DM
Tarlinton
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology / Q000378:metabolism; D018448:Models, Immunological; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology* / Q000378:metabolism; D010750:Phosphoproteins / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D008565:Membrane Proteins; D016328:NF-kappa B; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; D011947:Receptors, Antigen, B-Cell; D019869:Phosphatidylinositol 3-Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1