SLP-65: A New Signaling Component in B Lymphocytes which Requires Expression of the Antigen Receptor for Phosphorylation

Wienands, Jürgen; Schweikert, Jutta; Wollscheid, Bernd; Jumaa, Hassan; Nielsen, Peter; Reth, Michael

doi:10.1084/jem.188.4.791

Cited by 254 publications

(227 citation statements)

References 26 publications

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“…One prominent substrate of Syk is the adaptor protein SLP65/BLNK, a component of the calcium signalosome of B cells (Fu et al , 1998; Wienands et al , 1998). To test whether SLP65 is also required for Igβ signaling, we generated HLSLP65 triple KO Ramos B cells and verified the loss of SLP65 expression by Western blot (Appendix Fig S5).…”

Section: Resultsmentioning

confidence: 99%

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

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et al. 2018

The EMBO Journal

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Expression of the B‐cell antigen receptor (BCR) is essential not only for the development but also for the maintenance of mature B cells. Similarly, many B‐cell lymphomas, including Burkitt lymphoma (BL), require continuous BCR signaling for their tumor growth. This growth is driven by immunoreceptor tyrosine‐based activation motif (ITAM) and PI3 kinase (PI3K) signaling. Here, we employ CRISPR/Cas9 to delete BCR and B‐cell co‐receptor genes in the human BL cell line Ramos. We find that Ramos B cells require the expression of the BCR signaling component Igβ (CD79b), and the co‐receptor CD19, for their fitness and competitive growth in culture. Furthermore, we show that in the absence of any other BCR component, Igβ can be expressed on the B‐cell surface, where it is found in close proximity to CD19 and signals in an ITAM‐dependent manner. These data suggest that Igβ and CD19 are part of an alternative B‐cell signaling module that use continuous ITAM/PI3K signaling to promote the survival of B lymphoma and normal B cells.

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Section: Resultsmentioning

confidence: 99%

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

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Iype

et al. 2018

The EMBO Journal

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“…The linker molecule SLP65 (also known as BLNK (Fu et al, 1998), BASH (Hayashi et al, 2000) represents a critical component of the (pre-) B cell receptor signaling cascade (Wienands et al, 1998). Through a number of phosphorylated tyrosine residues, SLP65 can connect with upstream and downstream signaling molecules including SYK, BTK, NCK, VAV and PLCg2 .…”

Section: Introductionmentioning

confidence: 99%

The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells

et al. 2006

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SLP65 represents a critical component in (pre-) B cell receptor signal transduction but is compromised in a subset of pre-B cell-derived acute lymphoblastic leukemia. Based on these findings, we investigated (i.) whether SLP65-deficiency also occurs in mature B cell-derived lymphoma and (ii.) whether SLP65-deficient B cell lymphoma cells use an alternative B cell receptor signaling pathway in the absence of SLP65. Indeed, expression of SLP65 protein was also missing in a fraction of B cell lymphoma cases. While SLP65 is essential for B cell receptor-induced Ca 2 þ mobilization in normal B cells, B cell receptor engagement in SLP65-deficient as compared to SLP65-reconstituted B cell lymphoma cells resulted in an accelerated yet shortlived Ca 2 þ -signal. B cell receptor engagement of SLP65-deficient lymphoma cells involves SRC kinase activation, which is critical for B cell receptor-dependent Ca 2 þ -mobilisation in the absence but not in the presence of SLP65. As shown by RNA interference, the SRC kinase LYN is required for B cell receptor-induced Ca 2 þ release in SLP65-deficient B cell lymphoma cells but dispensable after SLP65-reconstitution. B cell receptor engagement in SLP65-deficient B cell lymphoma cells also resulted in tyrosine-phosphorylation of the proliferation-and survival-related MAPK1 and STAT5 molecules, which was sensitive to silencing of the SRC kinase LYN. Inhibition of SRC kinase activity resulted in growth arrest and cell death specifically in SLP65-deficient lymphoma cells. These findings indicate that LYN can short-circuit conventional B cell receptor signaling in SLP65-deficient B cell lymphoma cells and thereby promote activation of survival and proliferationrelated molecules.

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“…Among PTK substrates, recent studies have underscored the importance of linkers/adaptors [1] and coreceptors [2,3] in linking PTK activation to downstream effectors. BLNK, also named SLP-65 or BASH, consists of a basic and an acidic domain, a proline-rich region, and an SH2 domain, and is expressed in B cells [4][5][6]. Upon tyrosine phosphorylation by Syk, BLNK translocates to the membrane and binds various signaling components [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

“…BLNK, also named SLP-65 or BASH, consists of a basic and an acidic domain, a proline-rich region, and an SH2 domain, and is expressed in B cells [4][5][6]. Upon tyrosine phosphorylation by Syk, BLNK translocates to the membrane and binds various signaling components [4][5][6][7]. The importance of BLNK in B cell development and activation was further demonstrated: B cell development is blocked at the transition from pro-B to pre-B cells in BLNK-deficient mice [8,9], and BLNKdeficient B cells fail to increase intracellular calcium concentration ([Ca 2+ ] i ) and to activate MAPK following BCR ligation [7].…”

Section: Introductionmentioning

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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SLP-65: A New Signaling Component in B Lymphocytes which Requires Expression of the Antigen Receptor for Phosphorylation

Cited by 254 publications

References 26 publications

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells

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

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