Internalization of B cell and pre‐B cell receptors is regulated by tyrosine kinase and phosphatase activities

Salamero, Jean; Fougereau, Michel; Seckinger, P

doi:10.1002/eji.1830251007

Cited by 25 publications

(21 citation statements)

References 33 publications

(17 reference statements)

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“…Despite a critical role of ITAMs of Ig␣ and Ig␤ in BCR signaling (3), the role of ITAMs in BCR internalization is controversial (4). However, activation of protein tyrosine kinases (PTKs) 3 is required for BCR internalization (5,6). Moreover, Src family PTKs, which are activated after BCR cross-linking, play a crucial role in BCR internalization (7)(8)(9), suggesting that BCR internalization is controlled by certain substrates phosphorylated by Src family PTKs.…”

mentioning

confidence: 99%

The B Lymphocyte Adaptor Molecule of 32 Kilodaltons (Bam32) Regulates B Cell Antigen Receptor Internalization

Niiro¹,

Allam

Stoddart

et al. 2004

The Journal of Immunology

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The B lymphocyte adaptor molecule of 32 kDa (Bam32) is an adaptor that plays an indispensable role in BCR signaling. In this study, we found that upon BCR ligation, Bam32 is recruited to the plasma membrane where it associates with BCR complexes and redistributes and internalizes with BCRs. BCR ligation induced colocalization of Bam32 with lipid rafts, clathrin, and actin filaments. An inhibitor of Src family protein tyrosine kinases (PTKs) blocked both BCR-induced tyrosine phosphorylation of Bam32 and BCR internalization. Moreover, BCR internalization is impaired in Bam32−/− and Lyn−/− cells, and expression of Bam32 with a mutation of its tyrosine phosphorylation site (Y139F) inhibited BCR internalization. These data suggest that Bam32 functions downstream of Src family PTKs to regulate BCR internalization. Bam32 deficiency does not affect tyrosine phosphorylation of clathrin or the association of clathrin with lipid rafts upon BCR cross-linking. However, BCR-induced actin polymerization is impaired in Bam32−/− cells. Collectively, these findings indicate a novel role of Bam32 in connecting Src family PTKs to BCR internalization by an actin-dependent mechanism.

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confidence: 99%

The B Lymphocyte Adaptor Molecule of 32 Kilodaltons (Bam32) Regulates B Cell Antigen Receptor Internalization

Niiro¹,

Allam

Stoddart

et al. 2004

The Journal of Immunology

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“…Salamero et al (13) demonstrated that only 2% of newly synthesized pre-BCR reached the cell surface in the human pre-B cell line, Nalm-6; the majority of pre-BCR remained in the cytoplasm. All published results indicate that there is relatively less pre-BCR expression on the surfaces of cell lines and normal pre-B cells.…”

mentioning

confidence: 99%

The Pre-B Cell Receptor Signaling for Apoptosis Is Negatively Regulated by FcγRIIB

Kato

Takai

Kudo

2002

The Journal of Immunology

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Many studies have shown that FcγRIIB is a negative regulator of B cell receptor signaling, and even though FcγRIIB is expressed through all developmental stages of the B cell lineage, its involvement in pre-B cell receptor (pre-BCR) signaling has not been examined. To investigate FcγRIIB function at the pre-B cell stage, we have established pre-BCR positive pre-B cell lines from normal mice and FcγRIIB-deficient mice, named PreBR and Fcγ−/−PreBR, respectively. These cell lines are able to differentiate into immature B cells in vitro by removal of IL-7. In PreBR, apoptosis was moderately induced by F(ab′)2 anti-μ Ab, but not by intact anti-μ Ab. Phosphorylation of SH2-containing inositol 5-phosphatase (SHIP) and Dok, which are involved in FcγRIIB signaling, was induced by anti-μ cross-linking in PreBR. In contrast, apoptosis was strongly induced by both the F(ab′)2 and intact anti-μ Abs in Fcγ−/−PreBR, and the level of phosphorylation of SHIP or Dok was much lower in Fcγ−/−PreBR than those observed in PreBR. Restoration of FcγRIIB to Fcγ−/−PreBR followed by anti-μ cross-linking blocked severe apoptosis, and up-regulated SHIP and Dok phosphorylation. The results demonstrate that FcγRIIB negatively regulates pre-BCR-mediated signaling for apoptosis.

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“…They have been mainly associated with the signal transduction pathway [20], but very recently their possible roles in antigen internalization and processing have been addressed in several studies. Some of these studies indicate that the heterodimer does indeed have a function in endocytosis of mIg [21][22][23], whereas others [24,25] found that internalization of mIg is independent from Ig-a/b. However, Weiser et al [24] transfected IgG2a into an mIg -cell line.…”

Section: Discussionmentioning

confidence: 99%

“…Our own results indicate that these findings may not be contradictory. Since endocytosis is dependent on phosphorylation and dephosphorylation activities [23,26], the function of Ig-a and Ig-b could be the independent linkage to src family and syk tyrosine kinases that induce internalization and signal transduction. The interaction of mIg molecules with the cytoskeleton is probably mediated by other, yet unknown, proteins.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Components of the Murine B Cell Receptor Complex and Their Role in Anti‐Ig Stimulation

1997

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Signal transduction in B cells is mediated by B cell receptor (BCR) complexes that are composed of membrane immunoglobulins (mIg) and additional proteins (e.g. Ig-a and Ig-b) that have been implicated with several aspects of B cell activation. In this paper, experiments are described that have been designed to characterize new components of the BCR and to elucidate their involvement in B cell activation directly after the binding of anti-Ig. The data obtained prove the assumption that IgM is degraded after internalization. Neither immunoglobulin nor the Ig-a/b heterodimer are re-expressed after they have disappeared from the cell surface. The newly detected Ig-associated proteins are neither degradation products of immunoglobulins nor different forms of Ig-a or Ig-b. In addition, they are not recognized by antibodies against any of the kinases known to date. The mIg molecules are linked to the cytoskeleton and internalized. On the other hand, the additional Ig-associated proteins as well as the Ig-a/b heterodimer could not be detected in the detergentinsoluble fraction. The former molecules remain on the B cell surface where they are attached to the unaffected isotype and might interact with downstream members of the signalling cascade. In addition, evidence is presented that the internalization of the receptor complex is not necessary for signal transduction and B cell activation. From these results the authors conclude that the BCR complexes are removed from the cell surface after binding of ligands, probably to prevent further activation of this cell, while the Ig-associated proteins interact with the intracellular components of the signal transduction pathway to promote the further activation of the B cells.

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Internalization of B cell and pre‐B cell receptors is regulated by tyrosine kinase and phosphatase activities

Cited by 25 publications

References 33 publications

The B Lymphocyte Adaptor Molecule of 32 Kilodaltons (Bam32) Regulates B Cell Antigen Receptor Internalization

The B Lymphocyte Adaptor Molecule of 32 Kilodaltons (Bam32) Regulates B Cell Antigen Receptor Internalization

The Pre-B Cell Receptor Signaling for Apoptosis Is Negatively Regulated by FcγRIIB

Characterization of Components of the Murine B Cell Receptor Complex and Their Role in Anti‐Ig Stimulation

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