Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction.

Cheng, Genhong; Ye, Zheng-Sheng; Baltimore, David

doi:10.1073/pnas.91.17.8152

Cited by 157 publications

(111 citation statements)

References 21 publications

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“…Recently, these data have been extended to include the adapter protein SAP, which activates and recruits Fyn to SLAM family receptors (5, 18 -20). Interestingly, Tec family kinases, specifically Btk and Itk, have been shown to bind to the Fyn Src homology 3 domain through an N-terminal region that is conserved between these kinases (59,60). Although these findings suggest a connection between Tec family kinases and the SLAM-SAP-Fyn pathway, this possibility seems unlikely.…”

Section: Discussionmentioning

confidence: 40%

The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival

Felices

Berg

2008

The Journal of Immunology

105

125

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The Tec kinases Itk and Rlk are required for efficient positive selection of conventional CD4+ and CD8+ T cells in the thymus. In contrast, recent studies have shown that these Tec kinases are dispensable for the development of CD8+ T cells with characteristics of innate T cells. These findings raise questions about the potential role of Itk and Rlk in NKT cell development, because NKT cells represent a subset of innate T cells. To address this issue, we examined invariant NKT cells in Itk−/− and Itk/Rlk−/− mice. We find, as has been reported previously, that Itk−/− mice have reduced numbers of NKT cells with a predominantly immature phenotype. We further show that this defect is greatly exacerbated in the absence of both Itk and Rlk, leading to a 7-fold reduction in invariant NKT cell numbers in the thymus of Itk/Rlk−/− mice and a more severe block in NKT cell maturation. Splenic Itk−/− and Itk/Rlk−/− NKT cells are also functionally defective, because they produce little to no cytokine following in vivo activation. Tec kinase-deficient NKT cells also show enhanced cell death in the spleen. These defects correlate with greatly diminished expression of CD122, the IL-2R/IL-15R β-chain, and impaired expression of the T-box transcription factor, T-bet. These data indicate that the Tec kinases Itk and Rlk provide important signals for terminal maturation, efficient cytokine production, and peripheral survival of NKT cells.

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Section: Discussionmentioning

confidence: 40%

The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival

Felices

Berg

2008

The Journal of Immunology

105

125

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“…Later, it was suggested that G␤␥ subunits induce coupling between heterotrimeric G-proteins and c-Src by mediating the formation of a Shc-Grb2-c-Src signaling complex (32). Alternatively, other investigators (38) have proposed that G␤␥ subunit-induced activation of Btk is caused by interaction with PH domains, which leads to a downstream activation of Src kinases via interaction with the SH3 domain.…”

Section: Discussionmentioning

confidence: 99%

Leukotriene D4 Triggers an Association between Gβγ Subunits and Phospholipase C-γ1 in Intestinal Epithelial Cells

Thodeti¹,

Adolfsson

Juhas

et al. 2000

Journal of Biological Chemistry

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The proinflammatory mediator leukotriene D 4 (LTD 4 ) binds to the seven-transmembrane receptor CYSLT 1 . Although this leukotriene plays an important biological role, its intracellular signaling pathways are only partly known. In previous experiments, we found that LTD 4 induced tyrosine phosphorylation and translocation of phospholipase (PLC)-␥1 to a plasma membrane fraction in a human epithelial cell line (Int 407). In the present study, we further examined these signaling events and found that LTD 4 induced a rapid interaction between G␤␥ subunits and PLC-␥1; results obtained with GST fusion proteins of PLC-␥1 suggest that this interaction is mediated via the pleckstrin homology domain of PLC-␥1. Moreover, LTD 4 induced an increased association of c-Src with PLC-␥1, and the selective Src family tyrosine kinase inhibitor PP1 blocked both LTD 4 -induced tyrosine phosphorylation of PLC-␥1 and the association of PLC-␥1 with G␤␥ subunits. The relevance of these observations in intracellular calcium signaling was investigated by microinjecting cells with anti-G␤, anti-PLC-␥1, or anti-c-Src antibodies and by pretreatment with PP1. LTD 4 -induced calcium mobilization was blocked by each of the indicated antibodies (but not isotypematched control antibodies) and by PP1. Our data suggest that G␤␥ subunits can, directly or indirectly, serve as membrane-bound partners for PLC-␥1 and c-Src and that each of these proteins is essential for LTD 4 -induced downstream PLC-␥1 signaling. Leukotrienes (LTs)1 are metabolites of the fatty acid arachidonate, produced by the activation of 5-lipoxygenase, and are powerful inflammatory mediators (1). LTs are extremely potent and exert a large number of functional effects; for example, they increase vascular permeability and cause contraction of smooth muscle cells, trachea, parenchyma, and ileum (2, 3).It is generally assumed that LT-induced effects are mediated via specific plasma membrane receptors. Yokomizo et al. (4) have cloned and sequenced the LTB 4 receptor from a cDNA library of a gene that encodes an orphan seven-spanning receptor on human B-lymphoblasts (5). In studying Chinese hamster ovary LTB 4 receptor cells, Yokomizo et al. (4) also noted that the LTB 4 receptor, which belongs to the seven-transmembrane-spanning receptor group, can bind to two different Gproteins, one that is sensitive and one that is insensitive to pertussis toxin. The former G-protein has been identified as ␣ i and the latter as ␣ 16 , and both appear to signal via phospholipase C-␤ (PLC-␤) in COS-7 cells (6). The LTD 4 receptor was also recently cloned and shown to belong to the seven-transmembrane group (7,8), which is in accordance with previous observations reported from our laboratory (10) and by other investigators (9) showing that LTD 4 signaling occurs through heterotrimeric G-proteins. We have also demonstrated (10), as have others (11), that the cytosolic free Ca 2ϩ concentration is increased in cells stimulated with LTD 4 . Furthermore, we have concluded that the LTD 4 -induced mobiliza...

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“…Membrane localization may be needed to regulate Itk function in response to Src family tyrosine kinases (8,9). The proline-rich region in the Tec homology domain can bind to Grb2 and the SH3 domain of Src family members, including Fyn, Lyn, and Hck (10). Several proteins, including CD28, Cbl, and Wiskott-Aldrich syndrome protein among others, have been shown to interact with the Itk SH3 domain in vitro (11,12).…”

mentioning

confidence: 99%

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

Khurana

Arneson

Schoon

et al. 2007

The Journal of Immunology

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NK cells are effector lymphocytes that can recognize and eliminate virally infected and transformed cells. NK cells express distinct activating receptors, including an ITAM-containing FcR complex that recognizes Ab-coated targets, and the DNAX-activating protein of 10 kDa-containing NKG2D receptor complex that recognizes stress-induced ligands. The regulatory role of specific tyrosine kinases in these pathways is incompletely understood. In this study, we show that, in activated human NK cells, the tyrosine kinase IL-2-inducible T cell kinase (Itk), differentially regulates distinct NK-activating receptors. Enhanced expression of Itk leads to increases in calcium mobilization, granule release, and cytotoxicity upon stimulation of the ITAM-containing FcR, suggesting that Itk positively regulates FcR-initiated cytotoxicity. In contrast, enhanced Itk expression decreases cytotoxicity and granule release downstream of the DNAX-activating protein of 10 kDa-containing NKG2D receptor, suggesting that Itk is involved in a pathway of negative regulation of NKG2D-initiated granule-mediated killing. Using a kinase mutant, we show that the catalytic activity of Itk is required for both the positive and negative regulation of these pathways. Complementary experiments where Itk expression was suppressed also showed differential regulation of the two pathways. These findings suggest that Itk plays a complex role in regulating the functions initiated by distinct NK cell-activating receptors. Moreover, understanding how these pathways may be differentially regulated has relevance in the setting of autoimmune diseases and antitumor immune responses where NK cells play key regulatory roles.

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Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction.

Cited by 157 publications

References 21 publications

The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival

The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival

Leukotriene D4 Triggers an Association between Gβγ Subunits and Phospholipase C-γ1 in Intestinal Epithelial Cells

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

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