Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signaling through the B cell receptor (BCR) is essential for B cell function and development. Despite the key role of Syk in BCR signaling, little is known about the mechanism by which Syk transmits downstream effectors. BLNK (B cell LiNKer protein), a substrate for Syk, is now shown to be essential in activating phospholipase C (PLC)gamma 2 and JNK. The BCR-induced PLC gamma 2 activation, but not the JNK activation, was restored by introduction of PLC gamma 2 membrane-associated form into BLNK-deficient B cells. As JNK activation requires both Rac1 and PLC gamma 2, our results suggest that BLNK regulates the Rac1-JNK pathway, in addition to modulating PLC gamma 2 localization.
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PMID:BLNK required for coupling Syk to PLC gamma 2 and Rac1-JNK in B cells. 1002 76

The entry of B lymphocytes into secondary lymphoid organs is a critical step in the development of an immune response, providing a site for repertoire shaping, antigen-induced activation and selection. These events are controlled by signals generated through the B cell antigen receptor (BCR) and are associated with changes in the migration properties of B cells in response to chemokine gradients. The chemokine stromal cell-derived factor (SDF)-1alpha is thought to be one of the driving forces during those processes, as it is produced inside secondary lymphoid organs and induces B lymphocyte migration that arrests upon BCR engagement. The signaling pathway that mediates this arrest was genetically dissected using B cells deficient in specific BCR-coupled signaling components. BCR-induced inhibition of SDF-1alpha chemotaxis was dependent on Syk, BLNK, Btk, and phospholipase C (Plc)gamma2 but independent of Ca2+ mobilization, suggesting that the target of BCR stimulation was a protein kinase C (PKC)-dependent substrate. This target was identified as the SDF-1alpha receptor, CXCR4, which undergoes PKC- dependent internalization upon BCR stimulation. Mutation of the internalization motif SSXXIL in the COOH terminus of CXCR4 resulted in B cells that constitutively expressed this receptor upon BCR engagement. These studies suggest that one pathway by which BCR stimulation results in inhibition of SDF-1alpha migration is through PKC-dependent downregulation of CXCR4.
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PMID:B cell antigen receptor engagement inhibits stromal cell-derived factor (SDF)-1alpha chemotaxis and promotes protein kinase C (PKC)-induced internalization of CXCR4. 1022 86

To explore the mechanism(s) by which phospholipase C (PLC)-gamma 2 participates in B cell Ag receptor (BCR) signaling, we have studied the function of PLC-gamma 2 mutants in B cells deficient in PLC-gamma 2. Mutation of the N-terminal Src homology 2 domain [SH2(N)] resulted in the complete loss of inositol 1,4, 5-trisphosphate generation upon BCR engagement. A possible explanation for the SH2(N) requirement was provided by findings that this mutation abrogates the association of PLC-gamma 2 with an adaptor protein BLNK. Moreover, expression of a membrane-associated form (CD16/PLC-gamma 2) with SH2(N) mutation required coligation of BCR and CD16 for inositol 1,4,5-trisphosphate generation. Together, our results suggest a central role for the SH2(N) domain in directing PLC-gamma 2 into the close proximity of BCR signaling complex by its association with BLNK, whereby PLC-gamma 2 becomes tyrosine phosphorylated and thereby activated.
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PMID:Cutting edge: association of phospholipase C-gamma 2 Src homology 2 domains with BLNK is critical for B cell antigen receptor signaling. 1043 4

B-cell receptor (BCR)-induced activation of phospholipase C-gamma1 (PLCgamma1) and PLCgamma2 is crucial for B-cell function. While several signaling molecules have been implicated in PLCgamma activation, the mechanism coupling PLCgamma to the BCR remains undefined. The role of PLCgamma1 SH2 and SH3 domains at different steps of BCR-induced PLCgamma1 activation was examined by reconstitution in a PLCgamma-negative B-cell line. PLCgamma1 membrane translocation required a functional SH2 N-terminal [SH2(N)] domain, was decreased by mutation of the SH3 domain, but was unaffected by mutation of the SH2(C) domain. Tyrosine phosphorylation did not require the SH2(C) or SH3 domains but depended exclusively on a functional SH2(N) domain, which mediated the association of PLCgamma1 with the adapter protein, BLNK. Forcing PLCgamma1 to the membrane via a myristoylation signal did not bypass the SH2(N) domain requirement for phosphorylation, indicating that the phosphorylation mediated by this domain is not due to membrane anchoring alone. Mutation of the SH2(N) or the SH2(C) domain abrogated BCR-stimulated phosphoinositide hydrolysis and signaling events, while mutation of the SH3 domain partially decreased signaling. PLCgamma1 SH domains, therefore, have interrelated but distinct roles in BCR-induced PLCgamma1 activation.
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PMID:Functional independence and interdependence of the Src homology domains of phospholipase C-gamma1 in B-cell receptor signal transduction. 1052 27

The SLP-76 (Src homology 2 domain-containing leukocyte protein of 76 kDa) adapter protein is expressed in T cells and myeloid cells, whereas its homologue BLNK (B cell linker protein) is expressed in B cells. SLP-76 and BLNK link immunoreceptor tyrosine-based activation motif-containing receptors to signaling molecules that include phospholipase C-gamma, mitogen-activated protein kinases, and the GTPases Ras and Rho. SLP-76 plays a critical role in T cell receptor, FcvarepsilonRI and gpVI collagen receptor signaling, and participates in signaling via FcgammaR and killer cell inhibitory receptors. BLNK plays a critical role in B cell receptor signaling. We show that murine bone marrow-derived macrophages express both SLP-76 and BLNK. Selective ligation of FcgammaRI and FcgammaRII/III resulted in tyrosine phosphorylation of both SLP-76 and BLNK. SLP-76(-/-) bone marrow-derived macrophages display FcgammaR-mediated tyrosine phosphorylation of Syk, phospholipase C-gamma2, and extracellular signal regulated kinases 1 and 2, and normal FcgammaR-dependent phagocytosis. These data suggest that both SLP-76 and BLNK are coupled to FcgammaR signaling in murine macrophages.
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PMID:Adapter proteins SLP-76 and BLNK both are expressed by murine macrophages and are linked to signaling via Fcgamma receptors I and II/III. 1067 25

Engagement of the B cell receptor (BCR) leads to the activation of tyrosine kinases and other signaling molecules that ultimately determine the type and magnitude of the B lymphocyte's cellular response. The adaptor protein BLNK/SLP-65 plays a pivotal role in BCR signal transduction by coupling Syk activation to downstream elements such as Grb2, phospholipase C-gamma, Vav and Nck. We have generated BLNK(-/-) mice to determine the physiological role of this protein in B cell development and activation. BLNK(-/-) mice exhibit an incomplete block in B cell development with a severe inhibition of pro-B to pre-B cell differentiation. BLNK(-/-) sIgM(+) cells can develop, seed the peripheral lymphoid tissues and accumulate in numbers overtime. However, these mutant B cells failed to mature and are non-responsive to BCR cross-linking in terms of proliferation and up-regulation of activation markers such as CD69 and CD86 (B7-2). In addition, the CD5(+) subset of B cells is absent. The immune response to T cell-independent antigen but not T cell-dependent antigen is also impaired. Overall, the phenotype of BLNK(-/-) mice bears a striking resemblance to that of xid mice which is the murine model of human XLA that has a mutation in Bruton's tyrosine kinase. This raises the interesting possibility that mutation in BLNK/SLP-65 may be responsible for certain human immunodeficiencies.
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PMID:B cell development and activation defects resulting in xid-like immunodeficiency in BLNK/SLP-65-deficient mice. 1070 Apr 74

In B lymphocytes, a signaling complex that contributes to cell fate decisions is the B-cell antigen receptor (BCR), with different extents of receptor engagement leading to such outcomes as cell death, survival, or proliferation. Here, based upon the available genetic and biochemical data of the BCR signal components, we discuss several mechanisms by which BCR signals are propagated and modified, with specific emphasis on the phospholipase C (PLC)-gamma2-calcium pathway Gene-targeting experiments in DT40 chicken B cells highlighted the importance of the intracellular protein tyrosine kinases Syk and Btk in PLC-gamma2 activation. Until recently, the molecular mechanism underlying the double requirement for Syk and Btk in PLC-gamma2 activation remained unclear, but new data suggest that an adapter molecule, B-cell linker protein (alternatively named SLP-65 or BASH), phosphorylated by Syk, provides docking sites for Btk SH2 domain as well as PLC-gamma2 SH2 domains, thus bringing Btk into close proximity with PLC-gamma2. The activated Btk then phosphorylates PLC-gamma2, leading to its activation. The activated PLC-gamma2 converts phosphatidylinositol 4,5-bisphosphate into the second messenger inositol 1,4,5-trisphosphate (IP3), which in turn binds to IP3 receptors located on the endoplasmic reticulum (ER). Binding of IP3 to the IP3 receptors is essential for triggering a calcium release from the ER and subsequent entry of extracellular calcium. Balancing these activation signals in the PLC-gamma2-calcium pathway are the inhibitory receptors expressed on B cells, FcyRII and paired immunoglobin-like receptor (PIR)-B. Although both FcyRII and PIR-B inhibits the BCR-mediated [Ca2+]i increase, the inhibitory mechanisms of these receptors are distinct. The FcyRII-mediated inhibitory signal is dependent on lipid phosphatase SHIP, whereas the PIR-B requires redundant functions of protein phosphatases SHP-1 and SHP-2. Thus, PIR-B and FcgammaRII inhibit calcium signals by utilizing two distinct signaling molecules, thereby contributing to setting threshold levels for activation signals as well as terminating activation responses.
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PMID:Regulation of the phospholipase C-gamma2 pathway in B cells. 1104 65

X-linked agammaglobulinemia (XLA) is caused by mutations in the Bruton's tyrosine kinase (Btk). The absence of functional Btk leads to failure of B-cell development that incapacitates antibody production in XLA patients leading to recurrent bacterial infections. Btk SH2 domain is essential for phospholipase C-gamma phosphorylation, and mutations in this domain were shown to cause XLA. Recently, the B-cell linker protein (BLNK) was found to interact with the SH2 domain of Btk, and this association is required for the activation of phospholipase C-gamma. However, the molecular basis for the interaction between the Btk SH2 domain and BLNK and the cause of XLA remain unclear. To understand the role of Btk in B-cell development, we have determined the stability and peptide binding affinity of the Btk SH2 domain. Our results indicate that both the structure and stability of Btk SH2 domain closely resemble with other SH2 domains, and it binds with phosphopeptides in the order pYEEI > pYDEP > pYMEM > pYLDL > pYIIP. We expressed the R288Q, R288W, L295P, R307G, R307T, Y334S, Y361C, L369F, and 1370M mutants of the Btk SH2 domain identified from XLA patients and measured their binding affinity with the phosphopeptides. Our studies revealed that mutation of R288 and R307 located in the phosphotyrosine binding site resulted in a more than 200-fold decrease in the peptide binding compared to L295, Y334, Y361, L369, and 1370 mutations in the pY + 3 hydrophobic binding pocket (approximately 3- to 17-folds). Furthermore, mutation of the Tyr residue at the betaD5 position reverses the binding order of Btk SH2 domain to pYIIP > pYLDL > pYDEP > pYMEM > pYEEI. This altered binding behavior of mutant Btk SH2 domain likely leads to XLA.
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PMID:Stability and peptide binding specificity of Btk SH2 domain: molecular basis for X-linked agammaglobulinemia. 1120 59

Splenic marginal zone (MZ) and follicular mantle (FO) B cells differ in their responses to stimuli in vitro and in vivo. We have previously shown that MZ cells exhibit greater calcium responses after ligation of membrane IgM (mIgM). We have now investigated the molecular mechanism underlying the difference in calcium responses following ligation of mIgM and studied the response to total B cell receptor ligation in these two subsets. We compared key cellular proteins involved in calcium signaling in MZ and FO cells. Tyrosine phosphorylation and activity of phospholipase C-gamma 2 and Syk protein tyrosine kinase were significantly higher in MZ cells than in FO cells after mIgM engagement, providing a likely explanation for our previous findings. Tyrosine phosphorylation of CD22 and expression of Src homology 2-containing inositol phosphatase and Src homology 2-containing protein tyrosine phosphatase-1 were also higher in the MZ cells. Expression and tyrosine phosphorylation of Btk, BLNK, Vav, or phosphatidylinositol 3-kinase were equivalent. In contrast, stimulation with anti-kappa induced equivalent increases in calcium and activation of Syk in the two subsets. These signals were also equivalent in cells from IgM transgenic, J(H) knockout mice, which have equivalent levels of IgM in both subsets. With total spleen B cells, Btk was maximally phosphorylated at a lower concentration of anti-kappa than Syk. Thus, calcium signaling in the subsets of mature B cells reflects the amount of Ig ligated more than the isotype or the subset and this correlates with the relative tyrosine phosphorylation of Syk.
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PMID:Antigen receptor proximal signaling in splenic B-2 cell subsets. 1120 64

To investigate the roles of various hematopoietic cell-specific adapter proteins in T cell receptor (TCR)-signaling leading to nuclear factor of activated T cell (NF-AT) and nuclear factor of kappaB (NF-kappaB) activation, we reconstituted TCR-signaling with CD8/zeta, various protein tyrosine kinases (PTKs), and adapter proteins in a non-lymphoid cell line, 293T. We show that SLP-76 and BLNK, but not LAT, effectively co-operated with Syk and Tec family PTKs to activate NF-AT and NF-kappaB. We also show that Tec family PTKs enhanced endogenous phospholipase C (PLC)-gamma1 phosphorylation induced by CD8/zeta and Syk in 293T cells. These results imply that PLC-gamma1 may play a critical role in a hematopoietic cell-specific adapter protein-mediated NF-AT and NF-kappaB activation in a non-lymphoid cell.
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PMID:Hematopoietic cell-specific adapter proteins, SLP-76 and BLNK, effectively activate NF-AT as well as NF-kappaB by Syk and Tec PTKs in non-lymphoid cell lines. 1124 Jan 41


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