BLNK mediates Syk-dependent Btk activation

Baba, Yoshifumi; Hirano, Shoji; Matsushita, M.; Watanabe, Dai; Kishimoto, Tadamitsu; Kurosaki, Tomohiro; Tsukada, Satoshi

doi:10.1073/pnas.051626198

Cited by 120 publications

(90 citation statements)

References 33 publications

(40 reference statements)

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“…Of course, these possibilities are not mutually exclusive. In a similar fashion, Bruton's tyrosine kinase requires the SLP-76 analog B cell linker protein to mediate its B cell antigen receptor-induced transtyrosine phosphorylation and autophosphorylation (33).…”

Section: Discussionmentioning

confidence: 99%

SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK

Bogin

Ainey

Beach

et al. 2007

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

115

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Section: Discussionmentioning

confidence: 99%

SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK

Bogin

Ainey

Beach

et al. 2007

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

115

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“…Once activated, Syk phosphorylates the adaptor protein BLNK, allowing it to scaffold PLC␥2 and transduce Syk-mediated BCR signaling to downstream effector molecules (30,31,47). Since it is a central molecule involved in transmitting BCR signaling, disruption of BLNK activity leads to inhibition of B cell activation (47,48).…”

Section: Discussionmentioning

confidence: 99%

B and T Lymphocyte Attenuator Regulates B Cell Receptor Signaling by Targeting Syk and BLNK

Vendel¹,

Calemine-Fenaux²,

Izrael-Tomasevic³

et al. 2009

The Journal of Immunology

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B and T lymphocyte attenuator (BTLA) functions as a negative regulator of T cell activation and proliferation. Although the role of BTLA in regulating T cell responses has been characterized, a thorough investigation into the precise molecular mechanisms involved in BTLA-mediated lymphocyte attenuation and, more specifically, its role in regulating B cell activation has not been presented. In this study, we have begun to elucidate the biochemical mechanisms by which BTLA functions to inhibit B cell activation. We describe the cell surface expression of BTLA on various human B cell subsets and confirm its ability to attenuate B cell proliferation upon associating with its known ligand, herpesvirus entry mediator (HVEM). BTLA associates with the BCR and, upon binding to HVEM, recruits the tyrosine phosphatase Src homology 2 domain-containing phosphatase 1 and reduces activation of signaling molecules downstream of the BCR. This is exemplified by a quantifiable decrease in tyrosine phosphorylation of the protein tyrosine kinase Syk, as measured by absolute quantification mass spectrometry. T he B and T lymphocyte attenuator (BTLA) 2 is an Ig superfamily coinhibitory receptor with structural and functional similarities to programmed cell death 1 (PD-1) and CTLA-4 (1-3). However, unlike PD-1 and CTLA-4, which bind members of the B7 Ig superfamily receptors, the established ligand for BTLA is the TNFR family member herpesvirus entry mediator (HVEM) (TNFRSF14) (3-5). HVEM binding leads to tyrosine phosphorylation of the cytoplasmic tail of BTLA, which contains a proposed Grb2/Grb2-related adaptor protein (Grap) docking site and two ITIMs (5-11). Biochemical analysis has revealed that phosphorylation at multiple tyrosines within the cytoplasmic tail of BTLA is necessary and required for efficient recruitment of protein tyrosine phosphatases and BTLA-mediated attenuation of T cell effector response and cell proliferation (5,8,10,11).The role of BTLA appears to be limited to lymphocyte activation as shown in BTLA-deficient mice, which present normal lymphoid organ development and near wild-type lymphocyte numbers. However, these mice display hyperproliferative T and B cell responses to TCR-and BCR-mediated activation, respectively (9, 11). Furthermore, loss of BTLA function leads to increased susceptibility to experimental autoimmune encephalomyelitis and MHC-mismatched allograft rejection, supporting the role of BTLA in modulating T cell activation and effector responses (11,12).Surface expression analysis of BTLA indicates that it is expressed on a wide number of lymphocytes in mice. It is most highly expressed on B cells, followed by CD4 ϩ T cells, and lower expression on CD8 ϩ T cells, macrophages, dendritic cells, and NK cells (9, 13). During murine B cell development, BTLA expression first appears in pre-B cells and shows increased expression through B cell maturation, with the highest expression on mature B cells (9). In this study, we show a detailed cell surface expression profile of BTLA during human B cell deve...

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“…Nucleotide sequences of these constructs were verified by sequencing. These constructs were transfected into STIM1-deficient DT40 B cells by electroporation as described (37). Transient transfection using HeLa or 293T cells was performed by FuGENE 6 reagent (Roche Applied Science) according to manufacturer protocols.…”

Section: Methodsmentioning

confidence: 99%

Coupling of STIM1 to store-operated Ca ²⁺ entry through its constitutive and inducible movement in the endoplasmic reticulum

Baba¹,

Hayashi

Fujii³

et al. 2006

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

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298

316

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Depletion of intracellular calcium (Ca 2؉ ) stores induces storeoperated Ca 2؉ (SOC) entry across the plasma membrane (PM). STIM1, a putative Ca 2؉ sensor in the endoplasmic reticulum (ER), has been recently shown to be necessary for SOC channel activation. Here we show that STIM1 dynamically moves in tubulovesicular shape on the ER and its subcompartment in resting living cells, whereas, upon Ca 2؉ store depletion, it is rapidly redistributed into discrete puncta that are located underneath, but not inserted into the PM. Normal constitutive movement of STIM1 is mediated through the coiled-coil and Ser͞Thr-rich C-terminal domains in the cytoplasmic region of STIM1, whereas subsequent inducible puncta formation further requires the sterile ␣ motif domain protruding into the ER lumen. Each of these three domains (coiled-coil, Ser͞Thr-rich, and sterile ␣ motif) was essential for activating SOC channels. Hence, our findings based on structure-function experiments suggest that constitutive dynamic movement of STIM1 in the ER and its subcompartment is obligatory for subsequent depletion-dependent redistribution of STIM1 into puncta underneath the PM and activation of SOC channels.B cell receptor ͉ calcium signaling ͉ DT40 ͉ store-operated calcium C ytosolic Ca 2ϩ signals are a key to the regulation of various physiological events (1, 2). Two stages of calcium mobilization have been distinguished in lymphocytes and other nonexcitable cells (3-5). The first stage involves activation of phospholipase C by trimeric G protein-or tyrosine kinase-coupled receptors. This enzyme hydrolyzes phosphatidylinositol bisphosphate to release the second messenger inositol-1,4,5-trisphosphate, which binds to its receptor in the endoplasmic reticulum (ER) membrane, thereby causing rapid but transient release of Ca 2ϩ from ER stores. The second stage involves a sustained influx of extracellular Ca 2ϩ across the plasma membrane (PM) in a process termed store-operated Ca 2ϩ (SOC) entry. In this process, depletion of Ca 2ϩ within the ER lumen serves as the primary trigger to open SOC channels residing in the PM.STIM1 has recently emerged to play a critical role in coupling the first and second stages of calcium mobilization (6, 7). The STIM1 protein is thought to function primarily as a sensor of Ca 2ϩ within the ER stores, because a single N-terminal EF-hand Ca 2ϩ binding motif is located within the ER lumen (7,8). The activation mechanism of STIM1, however, has remained elusive. For instance, Zhang and colleagues (9, 10) proposed that insertion of STIM1 from the ER to the PM, presumably through vesicular transport, would be a prerequisite for subsequent SOC channel activation. Furthermore, STIM1 in the PM has been reported to play a role for SOC activation (11). But others have shown that STIM1 redistributed into puncta near the PM without inserting into the PM and proposed that this aggregated STIM1 might activate SOC channels (7, 12).To elucidate the mechanisms by which STIM1 activates SOC channels, we have constructed STIM1 mutants and ...

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BLNK mediates Syk-dependent Btk activation

Cited by 120 publications

References 33 publications

SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK

SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK

B and T Lymphocyte Attenuator Regulates B Cell Receptor Signaling by Targeting Syk and BLNK

Coupling of STIM1 to store-operated Ca ²⁺ entry through its constitutive and inducible movement in the endoplasmic reticulum

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BLNK mediates Syk-dependent Btk activation

Cited by 120 publications

References 33 publications

SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK

SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK

B and T Lymphocyte Attenuator Regulates B Cell Receptor Signaling by Targeting Syk and BLNK

Coupling of STIM1 to store-operated Ca 2+ entry through its constitutive and inducible movement in the endoplasmic reticulum

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Coupling of STIM1 to store-operated Ca ²⁺ entry through its constitutive and inducible movement in the endoplasmic reticulum