HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 48, 48474-48484, November 28, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/48/48474    most recent M301350200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tkaczyk, C. Articles by Gilfillan, A. M. Search for Related Content PubMed PubMed Citation Articles by Tkaczyk, C. Articles by Gilfillan, A. M. Social Bookmarking                      What's this?

The Phospholipase C₁-dependent Pathway of FcRI-mediated Mast Cell Activation Is Regulated Independently of Phosphatidylinositol 3-Kinase^*

Christine Tkaczyk, Michael A. Beaven, Saskia M. Brachman¶||**, Dean D. Metcalfe, and Alasdair M. Gilfillan

From the Laboratory of Allergic Diseases, NIAID, Laboratory of Molecular Immunology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, the ^¶Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, and the ^||Institut fuer Biochemie, Freie Universitaet Berlin, Berlin, Germany

Mast cell degranulation following FcRI aggregation is generally believed to be dependent on phosphatidylinositide 3-kinase (PI 3-kinase)-mediated phospholipase C (PLC) activation. Here we report evidence that the PLC₁-dependent pathway of FcRI-mediated activation of mast cells is independent of PI 3-kinase activation. In primary cultures of human mast cells, FcRI aggregation induced a rapid translocation and phosphorylation of PLC₁, and subsequent inositol trisphosphate (IP₃) production, which preceded PI 3-kinase-related signals. In addition, although PI 3-kinase-mediated responses were completely inhibited by wortmannin, even at high concentrations, this PI 3-kinase inhibitor had no effect on parameters of FcRI-mediated PLC activation, and had little effect on the initial increase in intracellular calcium levels that correlated with PLC activation. Wortmannin, however, did produce a partial (50%) concentration-dependent inhibition of FcRI-mediated degranulation in human mast cells and a partial inhibition of the later calcium response at higher concentrations. Further studies, conducted in mast cells derived from the bone marrow of mice deficient in the p85 and p85 subunits of PI 3-kinase, also revealed no defects in FcRI-mediated PLC₁ activation. These data are consistent with the conclusion that the PLC-dependent component of FcRI-mediated calcium flux leading to degranulation of mast cells is independent of PI 3-kinase. However, PI 3-kinase may contribute to the later phase of FcRI-mediated degranulation in human mast cells.

Received for publication, February 6, 2003 , and in revised form, September 12, 2003.

^* This work was supported in part by the NIAID, National Institutes of Health Intramural Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** Supported by a fellowship from Boehringer Ingelheim Fonds.

To whom correspondence should be addressed: Laboratory of Allergic Diseases, NIAID, National Institutes of Health, Bldg. 10, Rm. 11C206, 10 Center Dr. MSC 1881, Bethesda, MD 20892-1881. Tel.: 301-496-8757; Fax: 301-480-8384; E-mail: agilfillan{at}niaid.nih.gov.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				H. S. Kuehn, E. J. Swindle, M.-S. Kim, M. A. Beaven, D. D. Metcalfe, and A. M. Gilfillan The Phosphoinositide 3-Kinase-Dependent Activation of Btk Is Required for Optimal Eicosanoid Production and Generation of Reactive Oxygen Species in Antigen-Stimulated Mast Cells J. Immunol., December 1, 2008; 181(11): 7706 - 7712. [Abstract] [Full Text] [PDF]

				E. Shumilina, R. S. Lam, F. Wolbing, N. Matzner, I. M. Zemtsova, M. Sobiesiak, H. Mahmud, U. Sausbier, T. Biedermann, P. Ruth, et al. Blunted IgE-Mediated Activation of Mast Cells in Mice Lacking the Ca2+-Activated K+ Channel KCa3.1 J. Immunol., June 15, 2008; 180(12): 8040 - 8047. [Abstract] [Full Text] [PDF]

				M.-S. Kim, H. S. Kuehn, D. D. Metcalfe, and A. M. Gilfillan Activation and Function of the mTORC1 Pathway in Mast Cells J. Immunol., April 1, 2008; 180(7): 4586 - 4595. [Abstract] [Full Text] [PDF]

				B. M. Jensen, M. A. Beaven, S. Iwaki, D. D. Metcalfe, and A. M. Gilfillan Concurrent Inhibition of Kit- and Fc{epsilon}RI-Mediated Signaling: Coordinated Suppression of Mast Cell Activation J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 128 - 138. [Abstract] [Full Text] [PDF]

				Y. Yamashita, N. Charles, Y. Furumoto, S. Odom, T. Yamashita, A. M. Gilfillan, S. Constant, M. A. Bower, J. J. Ryan, and J. Rivera Cutting Edge: Genetic Variation Influences Fc{epsilon}RI-Induced Mast Cell Activation and Allergic Responses J. Immunol., July 15, 2007; 179(2): 740 - 743. [Abstract] [Full Text] [PDF]

				J. A. Deane, M. G. Kharas, J. S. Oak, L. N. Stiles, J. Luo, T. I. Moore, H. Ji, C. Rommel, L. C. Cantley, T. E. Lane, et al. T-cell function is partially maintained in the absence of class IA phosphoinositide 3-kinase signaling Blood, April 1, 2007; 109(7): 2894 - 2902. [Abstract] [Full Text] [PDF]

				N. M. Kushnir-Sukhov, A. M. Gilfillan, J. W. Coleman, J. M. Brown, S. Bruening, M. Toth, and D. D. Metcalfe 5-Hydroxytryptamine Induces Mast Cell Adhesion and Migration J. Immunol., November 1, 2006; 177(9): 6422 - 6432. [Abstract] [Full Text] [PDF]

				Y. Furumoto, S. Brooks, A. Olivera, Y. Takagi, M. Miyagishi, K. Taira, R. Casellas, M. A. Beaven, A. M. Gilfillan, and J. Rivera Cutting Edge: Lentiviral Short Hairpin RNA Silencing of PTEN in Human Mast Cells Reveals Constitutive Signals That Promote Cytokine Secretion and Cell Survival J. Immunol., May 1, 2006; 176(9): 5167 - 5171. [Abstract] [Full Text] [PDF]

				H. Qiao, M. V. Andrade, F. A. Lisboa, K. Morgan, and M. A. Beaven Fc{epsilon}R1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells Blood, January 15, 2006; 107(2): 610 - 618. [Abstract] [Full Text] [PDF]

				S. Iwaki, C. Tkaczyk, A. B. Satterthwaite, K. Halcomb, M. A. Beaven, D. D. Metcalfe, and A. M. Gilfillan Btk Plays a Crucial Role in the Amplification of Fc{epsilon}RI-mediated Mast Cell Activation by Kit J. Biol. Chem., December 2, 2005; 280(48): 40261 - 40270. [Abstract] [Full Text] [PDF]

				B. J. Davis, B. F. Flanagan, A. M. Gilfillan, D. D. Metcalfe, and J. W. Coleman Nitric Oxide Inhibits IgE-Dependent Cytokine Production and Fos and Jun Activation in Mast Cells J. Immunol., December 1, 2004; 173(11): 6914 - 6920. [Abstract] [Full Text] [PDF]

				T. R. Hundley, A. M. Gilfillan, C. Tkaczyk, M. V. Andrade, D. D. Metcalfe, and M. A. Beaven Kit and Fc{epsilon}RI mediate unique and convergent signals for release of inflammatory mediators from human mast cells Blood, October 15, 2004; 104(8): 2410 - 2417. [Abstract] [Full Text] [PDF]

				M. V. M. Andrade, T. Hiragun, and M. A. Beaven Dexamethasone Suppresses Antigen-Induced Activation of Phosphatidylinositol 3-Kinase and Downstream Responses in Mast Cells J. Immunol., June 15, 2004; 172(12): 7254 - 7262. [Abstract] [Full Text] [PDF]