Direct inhibition of Bruton's tyrosine kinase by IBtk, a Btk-binding protein

Liu, Weimin; Quinto, Ileana; Chen, Xueni; Palmieri, Camillo; Rabin, Ronald L.; Schwartz, Owen; Nelson, David L.; Scala, Giuseppe

doi:10.1038/ni1001-939

Cited by 76 publications

(82 citation statements)

References 49 publications

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“…Btk has been suggested to regulate phosphoinositide 3-kinase signaling via PIP5K [5] and may interact with other proteins as an adaptor. Previous studies also indicate that Btk binds to and/or phosphorylates several molecules not necessarily related to PLCc signaling pathways [41][42][43][44][45][46][47][48][49][50][51]. In addition, activation of splenic B cells by CD38 requires Btk but is not affected by the pan-PLCc inhibitor U73122 [52].…”

Section: Discussionmentioning

confidence: 99%

Btk and phospholipase Cγ2 can function independently during B cell development

et al. 2007

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The pre-BCR and the BCR regulate B cell development via a signalosome nucleated by the adaptor protein B cell linker protein (BLNK). Formation of this complex facilitates activation of phospholipase C (PLC) c2 by Bruton's tyrosine kinase (Btk). To determine whether Btk and PLCc2 also have separate functions, we generated Btk -/-PLCc2 -/-mice. They demonstrated a block in development at the pre-B stage and increased pre-BCR surface expression. This phenotype was more severe than that of Btk -/-or PLCc2 -/-mice. Although both Btk and PLCc2 were required for proliferation of splenic B cells in response to BCR cross-linking, they contributed differently to anti-IgM-induced phosphorylation of ERK. Btk -/-and PLCc2 -/-mice each had a reduced frequency of Igk-expressing B cells and impaired migration of pre-B cells towards stromal cellderived factor 1. However, the increase in pre-B cell malignancy that occurs in BLNK -/-mice in the absence of Btk was not observed in the absence of PLCc2. Thus, Btk and PLCc2 act both in concert and independently throughout B cell development. IntroductionSignals from the B cell antigen receptor (BCR) regulate multiple stages of B lymphopoiesis [1]. In pre-B cells, the pre-BCR signals for proliferation, allelic exclusion of the IgH locus, down-regulation of VpreB and k5 expression, and light chain rearrangement. The pre-BCR is predominantly intracellular and is believed to signal in a ligand-independent manner. The BCR is first expressed on the surface of immature B cells. Antigen encounter at this stage results in negative selection via deletion, anergy, or receptor editing. A tonic BCR signal is required for differentiation beyond the T2 stage in the periphery and survival of mature B cells. Mature B cells proliferate and differentiate upon stimulation with foreign antigen in the appropriate context. BCR and pre-BCR signaling is mediated by a signalosome composed of Syk, Bruton's tyrosine kinase (Btk), B cell linker protein (BLNK; also known as SLP65 and BASH), and phospholipase C (PLC) c2 [2-4]. Receptor cross-linking activates Syk, which phosphorylates the adaptor protein BLNK. Btk and PLCc2 bind to phosphorylated BLNK via their SH2 domains. Btk then phosphorylates and activates PLCc2, resulting in changes in intracellular Ca 2+ and the activation of protein kinase Cb. Btk can also mediate BCR-stimulated Ca 2+ flux [5] and B cell development [6] independently of its catalytic activity. Btk acts as an adaptor to recruit and activate phosphatidylinositol 4-phosphate 5-kinase (PIP5K) [5], which produces the substrate for PLCc2. Thus, Btk signals through PLCc2 directly, by phosphorylation, and indirectly, by increasing substrate availability.Loss of Btk function causes the human immunodeficiency X-linked agammaglobulinemia (XLA) [7,8], which is characterized by a block in B cell development at the pre-B stage. A similar disease results from

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Section: Discussionmentioning

confidence: 99%

Btk and phospholipase Cγ2 can function independently during B cell development

et al. 2007

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“…Confocal Microscopy-Confocal microscopy was performed as previously described (48). HeLa cells were seeded on poly-L-lysinetreated glass coverslips, fixed, and permeabilized using Cytofix/CytoPerm kit (BD Biosciences Pharmingen, San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

“…The Sequence of I B-␣ from Amino Acids 72 to 287 Is Required for Tat Inhibition-The sequence of I B-␣ encompassing amino acids 1-317 contains six ankyrins (amino acids 72-287), the NLS (amino acids 110 -120), the N-NES (amino acids [45][46][47][48][49][50][51][52][53][54][55], and the C-NES (amino acids 265-277) (Fig. 3A).…”

Section: Jurkat Cells Were Infected With the Wild Type Ltr Viruses (Nmentioning

confidence: 99%

IκB-α Represses the Transcriptional Activity of the HIV-1 Tat Transactivator by Promoting Its Nuclear Export

Puca

Fiume

Palmieri

et al. 2007

Journal of Biological Chemistry

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“…Cell Cultures and Transfection Experiments-Jurkat cells were cultured in RPMI 1640 medium supplemented with 10% fetal calf serum, 2 mM glutamine, and antibiotics as reported previously (65). For transfection experiments, 4 ϫ 10 6 cells were resuspended in 0.3 ml of RPMI 1640 medium and 20% fetal calf serum and subjected to a double electrical pulse at 200 V, 960 microfarads by a Bio-Rad apparatus (66).…”

Section: Figmentioning

confidence: 99%

“…Protein-Protein Interactions-For in vitro interaction studies, GST and GST-Tat proteins were produced and purified as described previously (29,65). For protein interaction, 5 g of purified GST and GSTTat proteins were incubated with 400 g of whole cellular extracts in binding buffer (20 mM Hepes, pH 7.9, 0.4 M KCl, 25% glycerol, 1 mM EDTA, 2 mM MgCl 2 , and 5 mM DTT).…”

Section: Figmentioning

confidence: 99%