LAB: A new membrane-associated adaptor molecule in B cell activation

Janssen, Erin; Zhu, Minghua; Zhang, Weijia; Koonpaew, Surapong; Zhang, Weiguo

doi:10.1038/ni882

Cited by 146 publications

(173 citation statements)

References 33 publications

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“…Recently, a novel adaptor molecule, linker of activation of B cells (LAB) or non-T cell activation linker, has been identified [46,47]. This adaptor is preferentially expressed in B cells and contains five Grb2-binding motifs.…”

Section: Discussionmentioning

confidence: 99%

SLP‐76 is recruited to CD22 and dephosphorylated by SHP‐1, thereby regulating B cell receptor‐induced c‐Jun N‐terminal kinase activation

et al. 2005

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Despite the important role in the development and activation of T cells, NK cells, mast cells, and macrophages, the expression and function of SLP-76 in B cells have been largely unknown. Here we demonstrate that SLP-76 is expressed in all mouse B cell lines tested and in normal splenic B cells, and serves as an SHP-1 substrate. Dephosphorylation of SLP-76 by SHP-1 inhibits its association with Nck, down-regulating cJun N-terminal kinase (JNK) activation and exerting a positive effect on apoptosis. Knockdown of SLP-76 in WEHI-231 cells by small interfering RNA attenuated JNK activation, but showed little effects on extracellular signal-regulated kinase (ERK) or p38 activation. Although WEHI-231 does not express linker for activation of T cells (LAT), SLP-76 localizes in membrane fraction, which increases following B cell receptor (BCR) cross-linking. Further analyses revealed that SLP-76 complexed with Gads is associated with tyrosine-phosphorylated CD22 through the SH2 domains of SLP-76 and Gads. Given that SHP-1 binds to CD22 upon BCR ligation, our findings suggest that dephosphorylation of SLP-76 recruited to CD22 by SHP-1 inhibits BCR-induced JNK activation, dictating apoptosis.

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Section: Discussionmentioning

confidence: 99%

SLP‐76 is recruited to CD22 and dephosphorylated by SHP‐1, thereby regulating B cell receptor‐induced c‐Jun N‐terminal kinase activation

et al. 2005

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“…A novel AML1/ETO target gene, localized on the long arm of chromosome 7, band q11.23, involved in the microdeletion of Williams Beuren Syndrome (Pober, 2010), termed non-T-cell activation linker (NTAL), linker for activation of B cells (LAB) or linker for activation of T cells family, member 2 (LAT2) codes for a 28-kDa membrane protein (Brdicka et al, 2002;Janssen et al, 2003;Zhu et al, 2006). LAT2 acts as an adaptor molecule, which is phosphorylated and activated by several membrane receptors, that is, FceR I and c-Kit receptor in mast cells (Tkaczyk et al, 2004;Volna et al, 2004;Zhu et al, 2004), B-and T-cell receptor in B and T cells, respectively (Janssen et al, 2003;Wang et al, 2005;Zhu et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…LAT2 acts as an adaptor molecule, which is phosphorylated and activated by several membrane receptors, that is, FceR I and c-Kit receptor in mast cells (Tkaczyk et al, 2004;Volna et al, 2004;Zhu et al, 2004), B-and T-cell receptor in B and T cells, respectively (Janssen et al, 2003;Wang et al, 2005;Zhu et al, 2006). After its phosphorylation and activation, LAT2 regulates several signalling pathways interacting with cytoplasmic partner proteins, including GRB2 (Brdicka et al, 2002;Stork et al, 2004) and CBL (Brdicka et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

et al. 2011

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The chromosomal translocation (8;21) fuses the hematopoietic transcription factor AML1 (RUNX1) with ETO (RUNX1T1, MTG8), resulting in the leukemia-specific chimeric protein AML1/ETO. This fusion protein has been implicated in epigenetic silencing, recruiting histone deacetylases (HDACs) and DNA methyltransferases to target promoters. Previously, we have identified a novel in vivo AML1/ETO target gene, LAT2 (NTAL/LAB/ WBSCR5), which is involved in FceR I, c-Kit, B-cell and T-cell receptor signalling. We have now addressed the molecular mechanisms of AML1/ETO-mediated LAT2 repression. In Kasumi-1 cells, where AML1/ETO bound to the LAT2 gene, small interfering RNA (siRNA)-mediated AML1/ETO depletion caused upregulation of LAT2, suggesting a possible direct mechanism of repression. Expression of AML1/ETO was associated with a decrease in acetylation of histones H3, H3K9 and H4, and an increase in H3K9 and H3K27 trimethylation. The class I-specific HDAC inhibitors entinostat (MS-275) and mocetinostat (MGCD0103) induced LAT2 expression specifically in AML1/ETO-expressing cells, resulting in induction of several activating histone marks on the LAT2 gene, including trimethylation of histone H3K4. The combination of entinostat and decitabine increased acetylation of histones H3 and H4, as well as LAT2 mRNA expression, in an at least additive fashion. In conclusion, several repressive histone modifications mark the LAT2 gene in the presence of AML1/ETO, and LAT2 gene derepression is achieved by pharmacological inhibition of HDACs.

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“…Both adaptors become rapidly tyrosine-phosphorylated upon FceRI aggregation. Phosphorylated NTAL is known to associate with cytoplasmic signaling molecules such as Grb2, Sos1 and Vav [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

The transmembrane adaptor protein NTAL signals to mast cell cytoskeleton via the small GTPase Rho

et al. 2010

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The transmembrane adaptor protein NTAL (non-T-cell activation linker) participates in signalosome assembly in hematopoietic cells, but its exact role in cell physiology remains enigmatic. We report here that BM-derived mast cells from NTAL-deficient mice, responding to Ag alone or in combination with SCF, exhibit reduced spreading on fibronectin, enhanced filamentous actin depolymerization and enhanced migration towards Ag relative to WT cells. No such differences between WT and NTAL À/À BM-derived mast cells were observed when SCF alone was used as activator. We have examined the activities of two small GTPases, Rac and Rho, which are important regulators of actin polymerization. Stimulation with Ag and/or SCF enhanced activity of Rac(1,2,3) in both NTAL À/À and WT cells. In contrast, RhoA activity decreased and this trend was much faster and more extensive in NTAL À/À cells, indicating a positive regulatory role of NTAL in the recovery of RhoA activity. After restoring NTAL into NTAL À/À cells, both spreading and actin responses were rescued. This is the first report of a crucial role of NTAL in signaling, via RhoA, to mast cell cytoskeleton.

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LAB: A new membrane-associated adaptor molecule in B cell activation

Cited by 146 publications

References 33 publications

SLP‐76 is recruited to CD22 and dephosphorylated by SHP‐1, thereby regulating B cell receptor‐induced c‐Jun N‐terminal kinase activation

SLP‐76 is recruited to CD22 and dephosphorylated by SHP‐1, thereby regulating B cell receptor‐induced c‐Jun N‐terminal kinase activation

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

The transmembrane adaptor protein NTAL signals to mast cell cytoskeleton via the small GTPase Rho

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