Differential organization of tonic and chronic B cell antigen receptors in the plasma membrane

Signal transduction by antigen receptors and some Fc receptors requires the activation of a family of receptor-associated transmembrane accessory proteins. One common feature of the cytoplasmic domains of these accessory molecules is the presence is at least two YXXA repeats that are potential sites for interaction with Src homology 2 domain-containing proteins. However, the degree of similarity between the different receptor-associated proteins varies from that of T-cell receptor (TCR) zeta and Fc receptor RIIIA gamma chains, which are homologous, to the distantly related Ig alpha and Ig beta proteins of the B-cell antigen receptor. To determine whether T- and B-cell antigen receptors are in fact functionally homologous, we have studied signal transduction by chimeric immunoglobulins bearing the Ig alpha or Ig beta cytoplasmic domain. We found that Ig alpha and Ig beta cytoplasmic domains were able to activate Ca2+ flux, interleukin-2 secretion, and phosphorylation of the same group of cellular substrates as the TCR in transfected T cells. Chimeric proteins were then used to examine the minimal requirements for activation of the Fyn, Lck, and ZAP kinases in T cells. Both Ig alpha and Ig beta were able to trigger Fyn, Lck, and ZAP directly without involvement of TCR components. Cytoplasmic tyrosine residues in Ig beta were required for recruitment and activation of ZAP-70, but these amino acids were not essential for the activation of Fyn and Lck. We conclude that Fyn and Lck are able to recognize a clustered nonphosphorylated immune recognition receptor, but activation of these kinases is not sufficient to induce cellular responses such as Ca2+ flux and interleukin-2 secretion. In addition, the molecular structures involved in antigen receptor signaling pathways are conserved between T and B cells.

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Gab-Family Adapter Proteins Act Downstream of Cytokine and Growth Factor Receptors and T- and B-Cell Antigen Receptors

Blood ◽

10.1182/blood.v93.6.1809.406k35_1809_1816 ◽

1999 ◽

Vol 93 (6) ◽

pp. 1809-1816 ◽

Cited By ~ 191

Author(s):

Keigo Nishida ◽

Yuichi Yoshida ◽

Motoyuki Itoh ◽

Toshiyuki Fukada ◽

Takuya Ohtani ◽

...

Keyword(s):

B Cell ◽

Amino Acid Level ◽

Adapter Proteins ◽

Antigen Receptors ◽

Ph Domain ◽

Cell Antigen ◽

Sh2 Domains ◽

Common Receptor ◽

Erk2 Activation

We previously found that the adapter protein Gab1 (110 kD) is tyrosine-phosphorylated and forms a complex with SHP-2 and PI-3 kinase upon stimulation through either the interleukin-3 receptor (IL-3R) or gp130, the common receptor subunit of IL-6–family cytokines. In this report, we identified another adapter molecule (100 kD) interacting with SHP-2 and PI-3 kinase in response to various stimuli. The molecule displays striking homology to Gab1 at the amino acid level; thus, we named it Gab2. It contains a PH domain, proline-rich sequences, and tyrosine residues that bind to SH2 domains when they are phosphorylated. Gab1 is phosphorylated on tyrosine upon stimulation through the thrombopoietin receptor (TPOR), stem cell factor receptor (SCFR), and T-cell and B-cell antigen receptors (TCR and BCR, respectively), in addition to IL-3R and gp130. Tyrosine phosphorylation of Gab2 was induced by stimulation through gp130, IL-2R, IL-3R, TPOR, SCFR, and TCR. Gab1 and Gab2 were shown to be substrates for SHP-2 in vitro. Overexpression of Gab2 enhanced the gp130 or Src-related kinases–mediated ERK2 activation as that of Gab1 did. These data indicate that Gab-family molecules act as adapters for transmitting various signals.

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Actin-binding protein 1 links B-cell antigen receptors to negative signaling pathways

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1321971111 ◽

2014 ◽

Vol 111 (27) ◽

pp. 9881-9886 ◽

Cited By ~ 22

Author(s):

Margaret K. Seeley-Fallen ◽

Lisa J. Liu ◽

Melanie R. Shapiro ◽

Olusegun O. Onabajo ◽

Senthilkumar Palaniyandi ◽

...

Keyword(s):

B Cell ◽

Signaling Pathways ◽

Binding Protein ◽

Actin Binding ◽

Antigen Receptors ◽

Actin Binding Protein ◽

Cell Antigen

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Thiol-Protease Inhibitors Selectively Inhibit Presentation of Antigen Incorporated through B Cell Antigen Receptors

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1995.1664 ◽

1995 ◽

Vol 210 (2) ◽

pp. 324-328 ◽

Cited By ~ 1

Author(s):

K. Togashi ◽

J. Magae ◽

T. Kataoka ◽

K. Nagai

Keyword(s):

B Cell ◽

Protease Inhibitors ◽

Antigen Receptors ◽

Thiol Protease ◽

Cell Antigen

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TAPP1 and TAPP2 Are Targets of Phosphatidylinositol 3-Kinase Signaling in B Cells: Sustained Plasma Membrane Recruitment Triggered by the B-Cell Antigen Receptor

Molecular and Cellular Biology ◽

10.1128/mcb.22.15.5479-5491.2002 ◽

2002 ◽

Vol 22 (15) ◽

pp. 5479-5491 ◽

Cited By ~ 72

Author(s):

Aaron J. Marshall ◽

Allyson K. Krahn ◽

Kewei Ma ◽

Vincent Duronio ◽

Sen Hou

Keyword(s):

Plasma Membrane ◽

B Cell ◽

Antigen Receptor ◽

B Cell Antigen Receptor ◽

Ph Domain ◽

Phosphatidylinositol 3 Kinase ◽

Cell Antigen Receptor ◽

Membrane Recruitment ◽

Cell Antigen ◽

Phosphatidylinositol 3

ABSTRACT We report the characterization of two signal transduction proteins related to Bam32, known as TAPP1 and TAPP2. Bam32, TAPP1, and TAPP2 share several characteristics, including small size (32 to 47 kDa), lack of enzymatic domains, high conservation between humans and mice, and the presence of pleckstrin homology (PH) domains near their C termini which contain the 3-phosphoinositide-binding motif. Unlike Bam32, the N-terminal regions of TAPP1 and TAPP2 contain a second PH domain. TAPP1 and TAPP2 transcripts are expressed in a variety of tissues including lymphoid tissues. Using live-cell imaging, we demonstrate that TAPP1 and TAPP2 are recruited to the plasma membrane of BJAB human B-lymphoma cells upon activation through the B-cell antigen receptor (BCR). The C-terminal PH domain is necessary and sufficient for BCR-induced membrane recruitment of both TAPP1 and TAPP2. Blockade of phosphatidylinositol 3-kinase (PI3K) activity completely abolished BCR-induced recruitment of TAPP1 and TAPP2, while expression of active PI3K is sufficient to drive constitutive membrane localization of TAPP1 and TAPP2. TAPP1 and TAPP2 preferentially accumulate within ruffled, F-actin-rich areas of plasma membrane, suggesting a potential role in PI3K-driven cytoskeletal reorganization. Like Bam32, BCR-driven TAPP1 and TAPP2 recruitment is a relatively slow and sustained response, in contrast to Btk recruitment and Ca2+ mobilization responses, which are rapid and transient. Consistent with recent studies indicating that Bam32, TAPP1, and TAPP2 can bind to PI(3,4)P2, we find that membrane recruitment correlates well with production of PI(3,4)P2 but not with that of PI(3,4,5)P3. Our results indicate that TAPP1 and TAPP2 are direct targets of PI3K signaling that are recruited into plasma membranes with distinctive delayed kinetics and accumulate within F-actin-rich membrane ruffles. We postulate that the TAPPs function to orchestrate cellular responses during the sustained phase of signaling.

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Recognition of Syngeneic forms of L-Chain V-Region Peptides by T Helper Cells Suggests that B Cell Antigen Receptors are Processed and Reutilized in Cognate T-B Interaction

The Semiotics of Cellular Communication in the Immune System ◽

10.1007/978-3-642-73145-7_22 ◽

1988 ◽

pp. 233-243

Author(s):

Kristian Hannestad ◽

Gunn Kristoffersen ◽

Jean Paul Briand

Keyword(s):

B Cell ◽

T Helper Cells ◽

Antigen Receptors ◽

T Helper ◽

Cell Antigen ◽

Helper Cells ◽

V Region

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Signalling Function of the B-Cell Antigen Receptors

Immunological Reviews ◽

10.1111/j.1600-065x.1993.tb00840.x ◽

1993 ◽

Vol 132 (1) ◽

pp. 125-146 ◽

Cited By ~ 48

Author(s):

Kwang-Myong Kim ◽

Gottfried Alber ◽

Peter Weiser ◽

Michael Reth

Keyword(s):

B Cell ◽

Antigen Receptors ◽

Cell Antigen

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The Gab1 Docking Protein Links the B Cell Antigen Receptor to the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway and to the SHP2 Tyrosine Phosphatase

Journal of Biological Chemistry ◽

10.1074/jbc.m010590200 ◽

2001 ◽

Vol 276 (15) ◽

pp. 12257-12265 ◽

Cited By ~ 43

Author(s):

Robert J. Ingham ◽

Lorna Santos ◽

May Dang-Lawson ◽

Marina Holgado-Madruga ◽

Peter Dudek ◽

...

Keyword(s):

Plasma Membrane ◽

B Cell ◽

Tyrosine Phosphorylation ◽

Tyrosine Phosphatase ◽

B Cell Antigen Receptor ◽

Ph Domain ◽

Phosphatidylinositol 3 Kinase ◽

Cell Antigen ◽

Bcr Signaling ◽

Docking Protein

B cell antigen receptor (BCR) signaling causes tyrosine phosphorylation of the Gab1 docking protein. This allows phosphatidylinositol 3-kinase (PI3K) and the SHP2 tyrosine phosphatase to bind to Gab1. In this report, we tested the hypothesis that Gab1 acts as an amplifier of PI3K- and SHP2-dependent signaling in B lymphocytes. By overexpressing Gab1 in the WEHI-231 B cell line, we found that Gab1 can potentiate BCR-induced phosphorylation of Akt, a PI3K-dependent response. Gab1 expression also increased BCR-induced tyrosine phosphorylation of SHP2 as well as the binding of Grb2 to SHP2. We show that the pleckstrin homology (PH) domain of Gab1 is required for BCR-induced phosphorylation of Gab1 and for Gab1 participation in BCR signaling. Moreover, using confocal microscopy, we show that BCR ligation can induce the translocation of Gab1 from the cytosol to the plasma membrane and that this requires the Gab1 PH domain as well as PI3K activity. These findings are consistent with a model in which the binding of the Gab1 PH domain to PI3K-derived lipids brings Gab1 to the plasma membrane, where it can be tyrosine-phosphorylated and then act as an amplifier of BCR signaling.

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