Syk Protein-tyrosine Kinase Is Regulated by Tyrosine-phosphorylated Iga/Ig/3 Immunoreceptor Tyrosine Activation Motif Binding and Autophosphorylation

Rowley, Roy; Burkhardt, Anne L.; Chao, Hann-Guang; Matsueda, Gary R.; Bolen, Joseph B.

doi:10.1074/jbc.270.19.11590

Cited by 261 publications

(180 citation statements)

References 23 publications

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“…Previous studies have demonstrated that the ITAM in the BCR subunit Ig␣ is required for the recruitment and activation of Syk (43,44,49). Activated Syk both initiates downstream signaling cascades and determines sorting of endocytosed complexes through early endosomes (34 -36).…”

Section: Discussionmentioning

confidence: 99%

“…1) (34). These phosphotyrosines function to recruit and activate Syk (43,44), which has also been implicated in receptor targeting (35,36). Other conserved tyrosines (Y 176 and Y 204 ) exist within the cytoplasmic tail of Ig␣, but their role in receptor trafficking has not been investigated.…”

Section: Receptor-facilitated Ag Presentation Requires Ig␣ Y 176 and mentioning

confidence: 99%

“…The recruitment and activation of Syk depend on the ITAMs in the Ig␣/Ig␤ cytoplasmic tails (43,44). To ensure that mutation of Y 176 /Y 204 did not perturb this function, immunoprecipitations of Syk from the lysates of cells stimulated through either chimeras of Ig␣/Ig␤, Ig␣(Y⌬F176,204)/Ig␤, or Ig␣(Y⌬F 182,193 )/Ig␤ were resolved by SDS-PAGE and transferred to PVDF membrane.…”

Section: Blnk Vav and Grb2 Are Recruited Upon Phosphorylation Of Igmentioning

confidence: 99%

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Receptor-Facilitated Antigen Presentation Requires the Recruitment of B Cell Linker Protein to Igα

Siemasko

Skaggs

Kabak

et al. 2002

The Journal of Immunology

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Ags that cross-link the B cell Ag receptor are preferentially and rapidly delivered to the MHC class II-enriched compartment for processing into peptides and subsequent loading onto MHC class II. Proper sorting of Ag/receptor complexes requires the recruitment of Syk to the phosphorylated immunoreceptor tyrosine-based activation motif tyrosines of the B cell Ag receptor constituent Igα. We postulated that the Igα nonimmunoreceptor tyrosine-based activation motif tyrosines, Y176 and Y204, contributed to receptor trafficking. Igα(YΔF176,204)/Igβ receptors were targeted to late endosomes, but were excluded from the vesicle lumen and could not facilitate the presentation of Ag to T cells. Subsequent analysis demonstrated that phosphorylation of Y176/Y204 recruited the B cell linker protein, Vav, and Grb2. Reconstitution of Igα(YΔF176,204)/Igβ with the B cell linker protein rescued both receptor-facilitated Ag presentation and entry into the MHC class II-enriched compartment. Thus, aggregation accelerates receptor trafficking by recruiting two separate signaling modules required for transit through sequential checkpoints.

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Section: Discussionmentioning

confidence: 99%

Section: Receptor-facilitated Ag Presentation Requires Ig␣ Y 176 and mentioning

confidence: 99%

Section: Blnk Vav and Grb2 Are Recruited Upon Phosphorylation Of Igmentioning

confidence: 99%

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Receptor-Facilitated Antigen Presentation Requires the Recruitment of B Cell Linker Protein to Igα

Siemasko

Skaggs

Kabak

et al. 2002

The Journal of Immunology

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“…The phosphorylation reaction is catalyzed by Src-family kinases such as Lyn. Upon phosphorylation of the BCR components, Syk kinase is recruited to the BCR signaling complex (9). Syk is essential for propagating BCR signaling (10,11).…”

mentioning

confidence: 99%

Sialylated multivalent antigens engage CD22in transand inhibit B cell activation

Courtney¹,

Puffer²,

Pontrello

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

121

178

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CD22 is an inhibitory coreceptor on the surface of B cells that attenuates B cell antigen receptor (BCR) signaling and, therefore, B cell activation. Elucidating the molecular mechanisms underlying the inhibitory activity of CD22 is complicated by the ubiquity of CD22 ligands. Although antigens can display CD22 ligands, the receptor is known to bind to sialylated glycoproteins on the cell surface. The propinquity of CD22 and cell-surface glycoprotein ligands has led to the conclusion that the inhibitory properties of the receptor are due to cis interactions. Here, we examine the functional consequences of trans interactions by employing sialylated multivalent antigens that can engage both CD22 and the BCR. Exposure of B cells to sialylated antigens results in the inhibition of key steps in BCR signaling. These results reveal that antigens bearing CD22 ligands are powerful suppressors of B cell activation. The ability of sialylated antigens to inhibit BCR signaling through trans CD22 interactions reveals a previously unrecognized role for the Siglec-family of receptors as modulators of immune signaling.B cell antigen receptor ͉ multivalency ͉ sialic acid ͉ siglec ͉ autoimmunity T he initiation of an immune response or the prevention of autoimmunity depends upon the ability of the B cell antigen receptor (BCR) to transmit signals that positively or negatively regulate B lymphocyte survival, proliferation, and differentiation (1). To avoid detrimental autoimmune responses, a means of differentiating between foreign and self-antigens is required; coreceptors that modulate BCR signaling can ensure that these distinctions are made. CD22 is an inhibitory coreceptor that can attenuate BCR signaling (2, 3). CD22 null mice possess hyperresponsive B cells (4), illustrating a role for CD22 in establishing a threshold for B cell activation. Specifically, an increase in intracellular Ca 2ϩ ion concentration is a hallmark of B cell activation (5, 6), and B cells isolated from CD22 null mice display increased Ca 2ϩ flux in response to antigen (4, 7). Thus, loss of CD22 results in a lowering of the threshold for B cell activation. Other data also support this conclusion: CD22 null mice exhibit increased serum IgM concentrations, decreased surface IgM levels on peripheral B cells, increased induction of apoptosis in response to BCR crosslinking, and increased serum autoantibody titers (8). These observations are consistent with the loss of CD22 leading to increased sensitivity and chronic B cell activation.The process of B cell activation ensues upon binding of multivalent antigen to the BCR. Antigen-induced clustering elicits phosphorylation of the cytoplasmic immunoreceptor tyrosinebased activation motifs (ITAMs), which are present in the BCRassociated signaling proteins Ig␣/␤. The phosphorylation reaction is catalyzed by Src-family kinases such as Lyn. Upon phosphorylation of the BCR components, Syk kinase is recruited to the BCR signaling complex (9). Syk is essential for propagating BCR signaling (10, 11). It acts along with...

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“…It is still unclear whether the enhanced association of syk is mediated through the phosphorylated ITAM of the ␥-chain, as reported in other systems [28,45]. A possible substrate for syk has been reported and identified as PLC-␥1 in response to the stimulation with aggregated IgA of human mesangial cells [46].…”

Section: Discussionmentioning

confidence: 99%

IgA Fc receptor (CD89) activation enables coupling to syk and Btk tyrosine kinase pathways: differential signaling after IFN-γ or phorbol ester stimulation

Launay

Lehuen

Kawakami

et al. 1998

Journal of Leukocyte Biology

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Syk Protein-tyrosine Kinase Is Regulated by Tyrosine-phosphorylated Iga/Ig/3 Immunoreceptor Tyrosine Activation Motif Binding and Autophosphorylation

Cited by 261 publications

References 23 publications

Receptor-Facilitated Antigen Presentation Requires the Recruitment of B Cell Linker Protein to Igα

Receptor-Facilitated Antigen Presentation Requires the Recruitment of B Cell Linker Protein to Igα

Sialylated multivalent antigens engage CD22in transand inhibit B cell activation

IgA Fc receptor (CD89) activation enables coupling to syk and Btk tyrosine kinase pathways: differential signaling after IFN-γ or phorbol ester stimulation

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