Redistribution of Bruton's tyrosine kinase by activation of phosphatidylinositol 3-kinase and Rho-family GTPases

Nore, Beston F.; Vargas, Leonardo; Mohamed, Abdalla J.; Brandén, Lars J.; Bäckesjö, Carl-Magnus; Islam, Tahmina; Mattsson, Per; Hultenby, Kjell; Christensson, Birger; Smith, C. I. Edvard

doi:10.1002/1521-4141(200001)30:1<145::aid-immu145>3.0.co;2-0

Cited by 108 publications

(93 citation statements)

References 6 publications

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“…Although SDF-1 stimulates membrane association of ectopically expressed Btk in non-lymphoid cells [56] and signals through Itk in T cells [35,36], to our knowledge this is the first demonstration that Btk is involved in SDF-1-induced chemotaxis in the B lineage. These observations contradict prior studies showing that neither Btk nor PLCc2 contributes to SDF-1 responses in chicken DT40 cells [57].…”

Section: Discussionmentioning

confidence: 75%

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: 75%

Btk and phospholipase Cγ2 can function independently during B cell development

et al. 2007

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“…We also observed the colocalization of Etk and FAK at membrane ru es where the F-actins are enriched. These data are consistent with the observations from others that Btk kinases are involved in integrin signaling and regulation of GTPases and actin bundle formation (Mao et al, 1998;Nore et al, 2000;Yao et al, 1999). The interaction between Etk and FAK is shown to depend on PH domain of Etk and FERM domain of FAK (Chen et al, submitted).…”

Section: Interaction With Fakmentioning

confidence: 99%

“…Recent work further showed that Etk/Bmx, in response to ®bronectin and integrin, is relocated to membrane ru ing together with FAK (Chen et al, submitted). In addition, in DT-40 cells lacking Btk, the actin pattern as well as Figure 2 A two-step model of the activation of Btk family kinases the ability of actin to aggregate di er from that in the wild-type cells (Nore et al, 2000). These observations suggest that Btk family kinases are involved in cytoskeletal reorganization and cell movement, and their aberrant activation may be related to metastasis of cancer cells.…”

Section: Downstream Signalmentioning

confidence: 99%

Signaling network of the Btk family kinases

Qiu¹,

2000

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The Btk family kinases represent new members of nonreceptor tyrosine kinases, which include Btk/Atk, Itk/ Emt/Tsk, Bmx/Etk, and Tec. They are characterized by having four structural modules: PH (pleckstrin homology) domain, SH3 (Src homology 3) domain, SH2 (Src homology 2) domain and kinase (Src homology 1) domain. Increasing evidence suggests that, like Srcfamily kinases, Btk family kinases play central but diverse modulatory roles in various cellular processes. They participate in signal transduction in response to virtually all types of extracellular stimuli which are transmitted by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen-receptors and integrins. They are regulated by many non-receptor tyrosine kinases such as Src, Jak, Syk and FAK family kinases. In turn, they regulate many of major signaling pathways including those of PI3K, PLCg and PKC. Both genetic and biochemical approaches have been used to dissect the signaling pathways and elucidate their roles in growth, di erentiation and apoptosis. An emerging new role of this family of kinases is cytoskeletal reorganization and cell motility. The physiological importance of these kinases was amply demonstrated by their link to the development of immunode®ciency diseases, due to germ-line mutations. The present article attempts to review the structure and functions of Btk family kinases by summarizing our current knowledge on the interacting partners associated with the di erent modules of the kinases and the diverse signaling pathways in which they are involved. Oncogene (2000) 19, 5651 ± 5661.

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“…It was proposed that membrane translocation is accompanied by activation (22)(23)(24)(25)(26). To investigate the activation mechanism further, we used fluorescence microscopy to analyze the subcellular distribution of Btk and Btk⌬PHTH after stimulation G␤␥ (Fig.…”

Section: G␤␥ Stimulates the Catalytic Activity Of Both Btk Andmentioning

confidence: 99%

“…4B, treatment with LY294002 blocked G␤␥-induced Btk-GFP membrane translocation. A role for PI 3-kinase in Btk activation had been observed for other types of receptors (22)(23)(24)(25)(26). Therefore, G␤␥-induced Btk membrane translocation depends on PI 3-kinase activation by G␤␥ and the generation of PIP 3 .…”

Section: G␤␥ Stimulates the Catalytic Activity Of Both Btk Andmentioning

confidence: 99%

G Protein βγ Subunits Act on the Catalytic Domain to Stimulate Bruton's Agammaglobulinemia Tyrosine Kinase

Lowry

Huang

2002

Journal of Biological Chemistry

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G proteins are critical cellular signal transducers for a variety of cell surface receptors. Both ␣ and ␤␥ subunits of G proteins are able to transduce receptor signals. Several direct effect molecules for G␤␥ subunits have been reported; yet the biochemical mechanism by which G␤␥ executes its modulatory role is not well understood. We have shown that G␤␥ could directly increase the kinase activity of Bruton's tyrosine kinase (Btk) whose defects are responsible for X chromosomelinked agammaglobulinemia in patients. The well characterized interaction of G␤␥ with the PH (pleckstrin homology)/TH (Tec-homology) module of Btk was proposed to be the underlying activation mechanism. Here we show that G␤␥ also interacts with the catalytic domain of Btk leading to increased kinase activity. Furthermore, we showed that the PH/TH module is required for G␤␥-induced membrane translocation of Btk. The membrane anchorage is also dependent on the interaction of Btk with phosphatidylinositol 3,4,5-trisphosphate, the product of phosphoinositide 3-kinase. These data support a dual role for G␤␥ in the activation of Btk signaling function, namely membrane translocation and direct regulation of Btk catalytic activity.Heterotrimeric (␣␤␥) GTP-binding regulatory proteins (G proteins) transduce signals from cell surface receptors across the membrane to the inside of cells (1). G proteins pass these extracellular signals to downstream effector molecules by directly interacting with these effectors. Both ␣ and ␤␥ subunits are able to interact with downstream effectors and actively participate in signal transduction (2). G␤␥ subunits have been demonstrated to interact with several proteins in the yeast mating pathway (3), G protein-gated potassium channels (4), certain isotypes of adenylyl cyclases (in the presence of G␣ s ) (5), certain isotypes of phospholipase C-␤ (6 -8), G protein-coupled receptor kinases (9), phosphoinositide 3-kinase-␥ (10), and Btk 1 (Bruton's tyrosine kinase) (11). However, the biochemical mechanism by which G␤␥ activates these effectors is not well understood.We have previously shown that G␤␥ could increase the kinase activity of Btk-family tyrosine kinases (11). Btk kinase was the first tyrosine kinase shown to be directly regulated by G proteins (11-13). The Btk family tyrosine kinases include Btk/Atk, Tec, Itk/Tsk, and Bmx/Etk (14). Defects in Btk are responsible for X chromosome-linked agammaglobulinemia in humans and X chromosome-linked immunodeficiency in mouse. G␤␥ subunits were shown to bind directly to the PH (pleckstrin homology) domain and its adjacent BM (Btk motif) domain (within the Tec-homology (TH) domain) of Btk (15,16). This interaction was assumed to be responsible for the G␤␥ activation of Btk. Here we show that G␤␥ can stimulate a purified recombinant Btk lacking the PH/TH module as well as full-length Btk, demonstrating that the effect of G␤␥ on Btk kinase activity is actually mediated by an alternate domain. In vitro binding studies further show that G␤␥ can bind to both the PH/TH module and...

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Redistribution of Bruton's tyrosine kinase by activation of phosphatidylinositol 3-kinase and Rho-family GTPases

Cited by 108 publications

References 6 publications

Btk and phospholipase Cγ2 can function independently during B cell development

Btk and phospholipase Cγ2 can function independently during B cell development

Signaling network of the Btk family kinases

G Protein βγ Subunits Act on the Catalytic Domain to Stimulate Bruton's Agammaglobulinemia Tyrosine Kinase

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