Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha.
Phosphoinositide 3-kinase (PI3K) activation has been implicated in many cellular responses, including fibroblast growth, transformation, survival, and chemotaxis. Although PI3K is activated by several agents that stimulate T and B cells, the role of PI3K in lymphocyte function is not clear. The mouse gene encoding the PI3K adapter subunit p85alpha and its splice variants p55alpha and p50alpha was disrupted. Most p85alpha-p55alpha-p50alpha-/- mice die within days after birth. Lymphocyte development and function was studied with the use of the RAG2-deficient blastocyst complementation system. Chimeric mice had reduced numbers of peripheral mature B cells and decreased serum immunoglobulin. The B cells that developed had diminished proliferative responses to antibody to immunoglobulin M, antibody to CD40, and lipopolysaccharide stimulation and decreased survival after incubation with interleukin-4. In contrast, T cell development and proliferation was normal. This phenotype is similar to defects observed in mice lacking the tyrosine kinase Btk.
Fruman
D A
DA
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. dfruman@bidmc.harvard.edu
Snapper
S B
SB
Yballe
C M
CM
Davidson
L
L
Yu
J Y
JY
Alt
F W
FW
Cantley
L C
LC
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D020134:Catalytic Domain; D002453:Cell Cycle; D002678:Chimera; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018390:Gene Targeting; D007136:Immunoglobulins / Q000097:blood*; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology
D000077329:Agammaglobulinaemia Tyrosine Kinase; D002867:Chromones; D004791:Enzyme Inhibitors; D007136:Immunoglobulins; D017493:Leukocyte Common Antigens; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one