scholarly journals Kidins220/ARMS binds to the B cell antigen receptor and regulates B cell development and activation

2015 ◽  
Vol 212 (10) ◽  
pp. 1693-1708 ◽  
Author(s):  
Gina J. Fiala ◽  
Iga Janowska ◽  
Fabiola Prutek ◽  
Elias Hobeika ◽  
Annyesha Satapathy ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
Antigen Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
B Cell Antigen Receptor ◽  
Independent Manner ◽  
Cell Antigen Receptor ◽  
Cell Antigen ◽  
Bcr Signaling

B cell antigen receptor (BCR) signaling is critical for B cell development and activation. Using mass spectrometry, we identified a protein kinase D–interacting substrate of 220 kD (Kidins220)/ankyrin repeat–rich membrane-spanning protein (ARMS) as a novel interaction partner of resting and stimulated BCR. Upon BCR stimulation, the interaction increases in a Src kinase–independent manner. By knocking down Kidins220 in a B cell line and generating a conditional B cell–specific Kidins220 knockout (B-KO) mouse strain, we show that Kidins220 couples the BCR to PLCγ2, Ca2+, and extracellular signal-regulated kinase (Erk) signaling. Consequently, BCR-mediated B cell activation was reduced in vitro and in vivo upon Kidins220 deletion. Furthermore, B cell development was impaired at stages where pre-BCR or BCR signaling is required. Most strikingly, λ light chain–positive B cells were reduced sixfold in the B-KO mice, genetically placing Kidins220 in the PLCγ2 pathway. Thus, our data indicate that Kidins220 positively regulates pre-BCR and BCR functioning.

scholarly journals The Immunoglobulin (Ig)α and Igβ Cytoplasmic Domains Are Independently Sufficient to Signal B Cell Maturation and Activation in Transgenic Mice

1997 ◽  
Vol 185 (10) ◽  
pp. 1753-1758 ◽  
Author(s):  
Yih-Miin Teh ◽  
Michael S. Neuberger
Keyword(s):  
B Cell ◽  
Transgenic Mouse ◽  
Critical Role ◽  
Antigen Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
Allelic Exclusion ◽  
B Cell Antigen Receptor ◽  
Cell Antigen Receptor ◽  
Cell Antigen

The B cell antigen receptor, composed of membrane immunoglobulin (Ig) sheathed by the Igα/Igβ heterodimer plays a critical role in mediating B cell development and responses to antigen. The cytoplasmic tails of Igα and Igβ differ substantially but have been well conserved in evolution. Transfection experiments have revealed that, while these tails share an esssential tyrosine-based activation motif (ITAM), they perform differently in some but not all assays and have been proposed to recruit distinct downstream effectors. We have created transgenic mouse lines expressing chimeric receptors comprising an IgM fused to the cytoplasmic domain of each of the sheath polypeptides. IgM/α and IgM/β chimeras (but not an IgM/β with mutant ITAM) are each independently sufficient to mediate allelic exclusion, rescue B cell development in gene-targeted Igμ− mice that lack endogenous antigen receptors, as well as signal for B7 upregulation. While the (IgM/α) × (IgM/β) double-transgenic mouse revealed somewhat more efficient allelic exclusion, our data indicate that each of the sheath polypeptides is sufficient to mediate many of the essential functions of the B cell antigen receptor, even if the combination gives optimal activity.

scholarly journals The B Cell Antigen Receptor Controls Integrin Activity through Btk and PLCγ2

2003 ◽  
Vol 198 (10) ◽  
pp. 1539-1550 ◽  
Author(s):  
Marcel Spaargaren ◽  
Esther A. Beuling ◽  
Mette L. Rurup ◽  
Helen P. Meijer ◽  
Melanie D. Klok ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
B Cell ◽  
Critical Role ◽  
Antigen Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
Mitogen Activated Protein Kinase ◽  
B Cell Antigen Receptor ◽  
Cell Antigen Receptor ◽  
Cell Antigen

Integrin-mediated adhesion and B cell antigen receptor (BCR) signaling play a critical role in B cell development and function, including antigen-specific B cell differentiation. Here we show that the BCR controls integrin α4β1 (VLA-4)-mediated adhesion of B cells to vascular cell adhesion molecule-1 and fibronectin. Molecular dissection of the underlying signaling mechanism by a combined biochemical, pharmacological, and genetic approach demonstrates that this BCR-controlled integrin-mediated adhesion requires the (consecutive) activation of Lyn, Syk, phosphatidylinositol 3-kinase, Bruton's tyrosine kinase (Btk), phospholipase C (PLC)γ2, IP3R-mediated Ca2+ release, and PKC. In contrast, activation of mitogen-activated protein kinase kinase (MEK) or extracellular signal–regulated kinase (ERK) is not required, and simultaneous activation of MEK, ERK, and PKB is not sufficient either. Furthermore, Btk is also involved in the control of integrin-mediated adhesion of preB cells. The control of integrin α4β1-mediated B cell adhesion by the BCR involves cytoskeletal reorganization and integrin clustering. These results reveal a novel function for the BCR and Btk, i.e., regulation of integrin α4β1 activity, thereby providing new insights into the control of B cell development and differentiation, as well as into the pathogenesis of the immunodeficiency disease X-linked agammaglobulineamia (XLA).

scholarly journals Acute Csk inhibition hinders B cell activation by constraining the PI3 kinase pathway

2021 ◽  
Vol 118 (43) ◽  
pp. e2108957118
Author(s):  
Wen Lu ◽  
Katarzyna M. Skrzypczynska ◽  
Arthur Weiss
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Antigen Receptor ◽  
Negative Regulator ◽  
B Cell Activation ◽  
Cell Antigen Receptor ◽  
Cell Antigen ◽  
Bcr Signaling

T cell antigen receptor (TCR) and B cell antigen receptor (BCR) signaling are initiated and tightly regulated by Src-family kinases (SFKs). SFKs positively regulate TCR signaling in naïve T cells but have both positive and negative regulatory roles in BCR signaling in naïve B cells. The proper regulation of their activities depends on the opposing actions of receptor tyrosine phosphatases CD45 and CD148 and the cytoplasmic tyrosine kinase C-terminal Src kinase Csk. Csk is a major negative regulator of SFKs. Using a PP1-analog-sensitive Csk (CskAS) system, we have previously shown that inhibition of CskAS increases SFK activity, leading to augmentation of responses to weak TCR stimuli in T cells. However, the effects of Csk inhibition in B cells were not known. In this study, we surprisingly found that inhibition of CskAS led to marked inhibition of BCR-stimulated cytoplasmic free calcium increase and Erk activation despite increased SFK activation in B cells, contrasting the effects observed in T cells. Further investigation revealed that acute CskAS inhibition suppressed BCR-mediated phosphatidylinositol 3,4,5-trisphosphate (PIP3) production in B cells. Restoring PIP3 levels in B cells by CD19 cross-linking or SHIP1 deficiency eliminated the negative regulatory effect of CskAS inhibition. This reveals the critical role of Csk in maintaining an appropriate level of SFK activity and regulating PIP3 amounts as a means of compensating for SFK fluctuations to prevent inappropriate B cell activation. This regulatory mechanism controlling PIP3 amounts may also contribute to B cell anergy and self-tolerance.

Synthetic biology of B cell activation: understanding signal amplification at the B cell antigen receptor using a rebuilding approach

2019 ◽  
Vol 400 (4) ◽  
pp. 555-563 ◽  
Author(s):  
Yogesh Kulathu ◽  
Christa Zuern ◽  
Jianying Yang ◽  
Michael Reth
Keyword(s):  
Synthetic Biology ◽  
B Cell ◽  
Signal Amplification ◽  
Cell Activation ◽  
Antigen Receptor ◽  
B Cell Antigen Receptor ◽  
B Cell Activation ◽  
Cell Antigen Receptor ◽  
Cell Antigen ◽  
Downstream Signaling

Abstract Upon activation of the B cell antigen receptor (BCR), the spleen tyrosine kinase (Syk) and the Src family kinase Lyn phosphorylate tyrosines of the immunoreceptor tyrosine-based activation motif (ITAM) of Igα and Igβ which further serve as binding sites for the SH2 domains of these kinases. Using a synthetic biology approach, we dissect the roles of different ITAM residues of Igα in Syk activation. We found that a leucine to glycine mutation at the Y+3 position after the first ITAM tyrosine prevents Syk binding and activation. However, a pre-activated Syk can still phosphorylate this tyrosine in trans. Our data show that the formation of a Syk/ITAM initiation complex and trans-ITAM phosphorylation is crucial for BCR signal amplification. In contrast, the interaction of Lyn with the first ITAM tyrosine is not altered by the leucine to glycine mutation. In addition, our study suggests that an ITAM-bound Syk phosphorylates the non-ITAM tyrosine Y204 of Igα only in cis. Collectively, our reconstitution experiments suggest a model whereby first trans-phosphorylation amplifies the BCR signal and subsequently cis-phosphorylation couples the receptor to downstream signaling elements.

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