Distinct roles of phosphoinositide-3 kinase and phospholipase Cgamma2 in B-cell receptor-mediated signal transduction.
During B-cell receptor (BCR) signaling, phosphoinositide-3 kinase (PI3K) is thought to function upstream of phospholipase Cgamma2 (PLCgamma2). PLCgamma2 deficiency specifically impedes transitional type 2 (T2) to follicular (FO) mature B-cell transition. Here, we demonstrate that PI3K deficiency specifically impaired T2-to-FO mature B-cell transition and marginal zone B-cell development. Furthermore, we investigated the functional relationship between PI3K and PLCgamma2 using PI3K-/-, PLCgamma2-/-, and PI3K-/- PLCgamma2-/- B cells. Interestingly, PLCgamma2 deficiency had no effect on BCR-mediated PI3K activation, whereas PI3K deficiency only partially blocked activation of PLCgamma2. Moreover, whereas PI3K-/- PLCgamma2-/- double deficiency did not affect hematopoiesis, it resulted in embryonic lethality. PI3K-/- PLCgamma2-/- fetal liver cells transplanted into B-cell null JAK3-/- mice failed to restore development of peripheral B cells and failed to progress through early B-cell development at the pro-B- to pre-B-cell transition, a more severe phenotype than was observed with either PI3K or PLCgamma2 single-deficiency B cells. Consistent with this finding, BCR signaling was more severely impaired in the absence of both PI3K and PLCgamma2 genes than in the absence of either one alone. Taken together, these results demonstrate that whereas PI3K functions upstream of PLCgamma2, activation of PLCgamma2 can occur independently of PI3K and that PI3K and PLCgamma2 also have distinct functions in BCR signal transduction.
Dai
Xuezhi
X
Blood Research Institute, 8727 Watertown Plank Rd., Milwaukee, WI 53226, USA.
Chen
Yuhong
Y
Schuman
James
J
Hua
Zichun
Z
Adamson
John W
JW
Wen
Renren
R
Wang
Demin
D
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000201:enzymology; D002454:Cell Differentiation; D004622:Embryo, Mammalian / Q000201:enzymology / Q000276:immunology; D047108:Embryonic Development / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation; D017353:Gene Deletion; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051966:Phospholipase C gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction
D011947:Receptors, Antigen, B-Cell; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma