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Science 15 January 1999:
Vol. 283. no. 5400, pp. 393 - 397
DOI: 10.1126/science.283.5400.393
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Reports

Impaired B Cell Development and Proliferation in Absence of Phosphoinositide 3-Kinase p85alpha

David A. Fruman, * Scott B. Snapper, Claudine M. Yballe, Laurie Davidson, Jonathan Y. Yu, Frederick W. Alt, Lewis C. Cantley

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.

D. A. Fruman. C. M. Yballe, J. Y. Yu, L. C. Cantley, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02215, and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. S. B. Snapper, Department of Medicine, Harvard Medical School, Boston, MA 02115; Howard Hughes Medical Institute, Children's Hospital, Boston, MA 02115; Center for Blood Research, Boston, MA 02115; and Gastrointestinal Unit (Medical Services), Massachusetts General Hospital, Boston, MA 02114, USA. L. Davidson, Howard Hughes Medical Institute, Children's Hospital, Boston, MA 02115, USA. F. W. Alt, Department of Genetics, Harvard Medical School, Boston, MA 02115; Howard Hughes Medical Institute, Children's Hospital, Boston, MA 02115; and Center for Blood Research, Boston, MA 02115, USA.
*   To whom correspondence should be addressed. E-mail: dfruman{at}bidmc.harvard.edu

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J. Immunol. 170, 5851-5860
   Abstract »    Full Text »    PDF »
Genetic evidence for convergence of c-Kit- and {alpha}4 integrin-mediated signals on class IA PI-3kinase and the Rac pathway in regulating integrin-directed migration in mast cells.
B. L. Tan, M. N. Yazicioglu, D. Ingram, J. McCarthy, J. Borneo, D. A. Williams, and R. Kapur (2003)
Blood 101, 4725-4732
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Smad3 Potentiates Transforming Growth Factor beta (TGFbeta )-induced Apoptosis and Expression of the BH3-only Protein Bim in WEHI 231 B Lymphocytes.
G. M. Wildey, S. Patil, and P. H. Howe (2003)
J. Biol. Chem. 278, 18069-18077
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Phosphatidylinositol 3-Kinase Regulates the CD4/CD8 T Cell Differentiation Ratio.
L. Rodriguez-Borlado, D. F. Barber, C. Hernandez, M. A. Rodriguez-Marcos, A. Sanchez, E. Hirsch, M. Wymann, C. Martinez-A., and A. C. Carrera (2003)
J. Immunol. 170, 4475-4482
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Critical Roles of Pten in B Cell Homeostasis and Immunoglobulin Class Switch Recombination.
A. Suzuki, T. Kaisho, M. Ohishi, M. Tsukio-Yamaguchi, T. Tsubata, P. A. Koni, T. Sasaki, T. W. Mak, and T. Nakano (2003)
J. Exp. Med. 197, 657-667
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B Cell Developmental Requirement for the G{alpha}i2 Gene.
H. Dalwadi, B. Wei, M. Schrage, T. T. Su, D. J. Rawlings, and J. Braun (2003)
J. Immunol. 170, 1707-1715
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Altered Signaling and Cell Cycle Regulation in Embryonal Stem Cells with a Disruption of the Gene for Phosphoinositide 3-Kinase Regulatory Subunit p85alpha.
D. Hallmann, K. Trumper, H. Trusheim, K. Ueki, C. R. Kahn, L. C. Cantley, D. A. Fruman, and D. Horsch (2003)
J. Biol. Chem. 278, 5099-5108
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Cross-linking of Surface IgM in the Burkitt's Lymphoma Cell Line ST486 Provides Protection against Arsenite- and Stress-induced Apoptosis That Is Mediated by ERK and Phosphoinositide 3-Kinase Sig