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Departments of
*
Microbiology and Immunology,
Medicine, and
Zoology, University of British Columbia, Vancouver, British Columbia, Canada; and
§
Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, CA 94305
We have previously shown that the B cell Ag receptor (BCR) activates phosphatidylinositol (PI) 3-kinase. We now show that a serine/threonine kinase called Akt or protein kinase B is a downstream target of PI 3-kinase in B cells. Akt has been shown to promote cell survival as well as the transcription and translation of proteins involved in cell cycle progression. Using an Ab that specifically recognizes the activated form of Akt that is phosphorylated on serine 473, we show that BCR engagement activates Akt in a PI 3-kinase-dependent manner. These results were confirmed using in vitro kinase assays. Moreover, BCR ligation also induced phosphorylation of Akt of threonine 308, another modification that is required for activation of Akt. In the DT40 chicken B cell line, phosphorylation of Akt on serine 473 was completely dependent on the Lyn tyrosine kinase, while the Syk tyrosine kinase was required for sustained phosphorylation of Akt. Complementary experiments in BCR-expressing AtT20 endocrine cells confirmed that Src kinases are sufficient for BCR-induced Akt phosphorylation, but that Syk is required for sustained phosphorylation of Akt on both serine 473 and threonine 308. In insulin-responsive cells, Akt phosphorylates and inactivates the serine/threonine kinase glycogen synthase kinase-3 (GSK-3). Inactivation of GSK-3 may promote nuclear accumulation of several transcription factors, including NF-ATc. We found that BCR engagement induced GSK-3 phosphorylation and decreased GSK-3 enzyme activity. Thus, BCR ligation initiates a PI 3-kinase/Akt/GSK-3 signaling pathway.
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A. Bernal, R. D. Pastore, Z. Asgary, S. A. Keller, E. Cesarman, H.-C. Liou, and E. J. Schattner Survival of leukemic B cells promoted by engagement of the antigen receptor Blood, November 15, 2001; 98(10): 3050 - 3057. [Abstract] [Full Text] [PDF]
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L. R. Stephens, K. E. Anderson, and P. T. Hawkins Src Family Kinases Mediate Receptor-stimulated, Phosphoinositide 3-Kinase-dependent, Tyrosine Phosphorylation of Dual Adaptor for Phosphotyrosine and 3-Phosphoinositides-1 in Endothelial and B Cell Lines J. Biol. Chem., November 9, 2001; 276(46): 42767 - 42773. [Abstract] [Full Text] [PDF]
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W. J. Bruyninckx, K. M. Comerford, D. W. Lawrence, and S. P. Colgan Phosphoinositide 3-kinase modulation of {beta}3-integrin represents an endogenous "braking" mechanism during neutrophil transmatrix migration Blood, May 15, 2001; 97(10): 3251 - 3258. [Abstract] [Full Text] [PDF]
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M. L. Lang, L. Shen, H. Gao, W. F. Cusack, G. A. Lang, and W. F. Wade Fc{{alpha}} Receptor Cross-Linking Causes Translocation of Phosphatidylinositol-Dependent Protein Kinase 1 and Protein Kinase B{{alpha}} to MHC Class II Peptide-Loading-Like Compartments J. Immunol., May 1, 2001; 166(9): 5585 - 5593. [Abstract] [Full Text] [PDF]
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T. Kaisho, K. Takeda, T. Tsujimura, T. Kawai, F. Nomura, N. Terada, and S. Akira I{kappa}b Kinase {alpha} Is Essential for Mature B Cell Development and Function J. Exp. Med., February 19, 2001; 193(4): 417 - 426. [Abstract] [Full Text] [PDF]
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R. Swart, I. K. Ruf, J. Sample, and R. Longnecker Latent Membrane Protein 2A-Mediated Effects on the Phosphatidylinositol 3-Kinase/Akt Pathway J. Virol., November 15, 2000; 74(22): 10838 - 10845. [Abstract] [Full Text]
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M. Merchant, R. G. Caldwell, and R. Longnecker The LMP2A ITAM Is Essential for Providing B Cells with Development and Survival Signals In Vivo J. Virol., October 1, 2000; 74(19): 9115 - 9124. [Abstract] [Full Text]
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S. Andjelic, C. Hsia, H. Suzuki, T. Kadowaki, S. Koyasu, and H.-C. Liou Phosphatidylinositol 3-Kinase and NF-{kappa}B/Rel Are at the Divergence of CD40-Mediated Proliferation and Survival Pathways J. Immunol., October 1, 2000; 165(7): 3860 - 3867. [Abstract] [Full Text] [PDF]
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J. Kitaura, K. Asai, M. Maeda-Yamamoto, Y. Kawakami, U. Kikkawa, and T. Kawakami Akt-Dependent Cytokine Production in Mast Cells J. Exp. Med., September 5, 2000; 192(5): 729 - 740. [Abstract] [Full Text] [PDF]
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D. J. Carver, M. J. Aman, and K. S. Ravichandran SHIP inhibits Akt activation in B cells through regulation of Akt membrane localization Blood, August 15, 2000; 96(4): 1449 - 1456. [Abstract] [Full Text] [PDF]
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E. M. Genot, C. Arrieumerlou, G. Ku, B. M. T. Burgering, A. Weiss, and I. M. Kramer The T-Cell Receptor Regulates Akt (Protein Kinase B) via a Pathway Involving Rac1 and Phosphatidylinositide 3-Kinase Mol. Cell. Biol., August 1, 2000; 20(15): 5469 - 5478. [Abstract] [Full Text]
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S. L. Pogue, T. Kurosaki, J. Bolen, and R. Herbst B Cell Antigen Receptor-Induced Activation of Akt Promotes B Cell Survival and Is Dependent on Syk Kinase J. Immunol., August 1, 2000; 165(3): 1300 - 1306. [Abstract] [Full Text] [PDF]
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M. J. Aman, S. F. Walk, M. E. March, H.-P. Su, D. J. Carver, and K. S. Ravichandran Essential Role for the C-Terminal Noncatalytic Region of SHIP in Fcgamma RIIB1-Mediated Inhibitory Signaling Mol. Cell. Biol., May 15, 2000; 20(10): 3576 - 3589. [Abstract] [Full Text]
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A. Brauweiler, I. Tamir, J. Dal Porto, R. J. Benschop, C. D. Helgason, R. K. Humphries, J. H. Freed, and J. C. Cambier Differential Regulation of B Cell Development, Activation, and Death by the Src Homology 2 Domain-Containing 5' Inositol Phosphatase (Ship) J. Exp. Med., May 1, 2000; 191(9): 1545 - 1554. [Abstract] [Full Text] [PDF]
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M. E. March, D. M. Lucas, M. J. Aman, and K. S. Ravichandran p135 Src Homology 2 Domain-containing Inositol 5'-Phosphatase (SHIPbeta ) Isoform Can Substitute for p145 SHIP in Fcgamma RIIB1-mediated Inhibitory Signaling in B Cells J. Biol. Chem., September 22, 2000; 275(39): 29960 - 29967. [Abstract] [Full Text] [PDF]
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D. C. Otero, S. A. Omori, and R. C. Rickert CD19-dependent Activation of Akt Kinase in B-lymphocytes J. Biol. Chem., January 5, 2001; 276(2): 1474 - 1478. [Abstract] [Full Text] [PDF]
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R. J. Ingham, L. Santos, M. Dang-Lawson, M. Holgado-Madruga, P. Dudek, C. R. Maroun, A. J. Wong, L. Matsuuchi, and M. R. Gold The Gab1 Docking Protein Links the B Cell Antigen Receptor to the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway and to the SHP2 Tyrosine Phosphatase J. Biol. Chem., April 6, 2001; 276(15): 12257 - 12265. [Abstract] [Full Text] [PDF]
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M.-Y. Cao, F. Shinjo, S. Heinrichs, J.-W. Soh, J. Jongstra-Bilen, and J. Jongstra Inhibition of Anti-IgM-induced Translocation of Protein Kinase C beta I Inhibits ERK2 Activation and Increases Apoptosis J. Biol. Chem., June 29, 2001; 276(27): 24506 - 24510. [Abstract] [Full Text] [PDF]
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D. A. Fruman, G. Z. Ferl, S. S. An, A. C. Donahue, A. B. Satterthwaite, and O. N. Witte Phosphoinositide 3-kinase and Bruton's tyrosine kinase regulate overlapping sets of genes in B lymphocytes PNAS, January 8, 2002; 99(1): 359 - 364. [Abstract] [Full Text] [PDF]
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