Phosphatidylinositol 3-kinase-γ activates Bruton’s tyrosine kinase in concert with Src family kinases

Li, Zuomei; Wahl, Matthew I.; Eguinoa, Alicia; Stephens, Len R.; Hawkins, Phillip T.; Witte, Owen N.

doi:10.1073/pnas.94.25.13820

Cited by 190 publications

(163 citation statements)

References 60 publications

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“…In this regard, activation of Itk by a Src family kinase has been shown to require the Itk PH domain and PI3K activity (32). In addition, overexpression of PI3K␥, together with a Src family kinase, can directly activate Btk in fibroblast cells (36). Together, these data suggest that PI3K plays a role in regulating Tec-kinase activity downstream of an activated receptor.…”

Section: S Timulation Of the Tcr On Mature T Cells Induces A Seriesmentioning

confidence: 51%

Tec Kinase Signaling in T Cells Is Regulated by Phosphatidylinositol 3-Kinase and the Tec Pleckstrin Homology Domain

Yang

Ching

Tsoukas

et al. 2001

The Journal of Immunology

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Tec, the prototypical member of the Tec family of tyrosine kinases, is abundantly expressed in T cells and other hemopoietic cell types. Although the functions of Itk and Txk have recently been investigated, little is known about the role of Tec in T cells. Using antisense oligonucleotide treatment to deplete Tec protein from primary T cells, we demonstrate that Tec plays a role in TCR signaling leading to IL-2 gene induction. Interestingly, Tec kinases are the only known family of tyrosine kinases containing a pleckstrin homology (PH) domain. Using several PH domain mutants overexpressed in Jurkat T cells, we show that the Tec PH domain is required for Tec-mediated IL-2 gene induction and TCR-mediated Tec tyrosine phosphorylation. Furthermore, we show that Tec colocalizes with the TCR after TCR cross-linking, and that both the Tec PH and Src homology (SH) 2 domains play a role in this association. Wortmannin, a phosphatidylinositol 3-kinase inhibitor, abolishes Tec-mediated IL-2 gene induction and Tec tyrosine phosphorylation, and partially suppresses Tec colocalization with the activated TCR. Thus, our data implicate the Tec kinase PH domain and phosphatidylinositol 3-kinase in Tec signaling downstream of the TCR.

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Section: S Timulation Of the Tcr On Mature T Cells Induces A Seriesmentioning

confidence: 51%

Tec Kinase Signaling in T Cells Is Regulated by Phosphatidylinositol 3-Kinase and the Tec Pleckstrin Homology Domain

Yang

Ching

Tsoukas

et al. 2001

The Journal of Immunology

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“…A number of proteins containing a PH domain are shown to bind phosphatidyl inositol polyphosphates and to be activated by PI3-kinase. These include rac-GEF, unconventional PKCs, Akt/PKB, PDK2 and the Btk family of tyrosine kinases (Franke et al, 1995;Cross et al, 1995;August et al, 1997;Li et al, 1997;Qiu et al, 1998;Ma et al, 1998;Falasca et al, 1998;Van Lint et al, 1998). Much of the attention has recently been focused on Akt as a protector against apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…It was shown that the metabolic products of PI3-kinase, phosphatidyl inositol phosphates, bind a protein modular structure, called the pleckstrin-homology (PH) domain . Several PH-domain-containing proteins are found to be e ectors for PI3-kinase (Franke et al, 1995;Cross et al, 1995;August et al, 1997;Li et al, 1997;Qiu et al, 1998). Of particular relevance is Akt/PKB, a serine/ threonine kinase with an N-terminal PH domain, which was recently shown to phosphorylate and inactivate Bad, a protein involved in the apoptosis pathway.…”

Section: Introductionmentioning

confidence: 99%

Etk/Bmx, a PH-domain containing tyrosine kinase, protects prostate cancer cells from apoptosis induced by photodynamic therapy or thapsigargin

Xue

Qiu

et al. 1999

Oncogene

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Prostate carcinoma (PCA) is the most frequently diagnosed malignancy in American men. PCA at advanced stages can both proliferate abnormally and resist apoptosis. Among the many known signal transduction pathways, phosphatidylinositide-3'OH kinase (PI3-kinase) has been shown to play an important role in cell survival and resistance to apoptosis. In this study, we investigate the involvement of Etk/Bmx, a newly discovered tyrosine kinase that is a substrate of PI3-kinase, in protection of prostate cancer cells from apoptosis. Parental LNCaP cells and two derivative cell lines, one overexpressing wild type Etk (Etkwt) and the other expressing a dominant negative Etk (EtkDN), were used to study the function of Etk. The cells were treated with photodynamic therapy (PDT), a newly approved cancer treatment which employs a photosensitizer and visible light to produce an oxidative stress in cells, often leading to apoptosis. Our results indicate that PDT induces apoptosis in LNCaP cells, as measured by DNA fragmentation and by cleavage of poly(ADP-ribose) polymerase (PARP), and moreover, the extent of apoptosis was much reduced in Etkwt cells as compared to LNCaP or EtkDN cells. Assay of overall cell viability con®rmed that Etkwt cells were considerably less sensitive to PDT than were the parental LNCaP or EtkDN cells. Similar results were found in response to thapsigargin (TG). A speci®c inhibitor of PI3-kinase, LY294002, abolished Etk activity and markedly increased TG-induced PARP cleavage. The results suggest that Etk/Bmx is an e cient e ector of PI3-kinase and that the newly described PI3-kinase/Etk pathway is involved in the protection of prostate carcinoma cells from apoptosis in response to PDT or TG.

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“…To further test the possibility that interaction between Itk molecules in the cytoplasm could occur, we generated an Itk mutant, R29C, which disrupts the ability of the PH domain to interact with lipids, rendering this mutant unable to be recruited to the membrane (29,30). Thus, this mutant is totally constrained to the cytoplasm.…”

Section: Resultsmentioning

confidence: 99%

Tec Kinase Itk Forms Membrane Clusters Specifically in the Vicinity of Recruiting Receptors

Sahu

August

2006

Journal of Biological Chemistry

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The Tec family of tyrosine kinases transduces signals from antigen and other receptors in cells of the hematopoietic system. In particular, interleukin-2 inducible T cell kinase (Itk) plays an important role in modulating T cell development and activation. Itk is activated by receptors via a phosphatidylinositol 3-kinase-mediated pathway, which results in recruitment of Itk to the plasma membrane via its pleckstrin homology domain. We show here that membrane localization of Itk results in the formation of clusters of at least two molecules within 80 Å of each other, which is dependent on the integrity of its pleckstrin homology domain. By contrast, the proline-rich region within the Tec homology domain, SH3 or SH2 domains, or kinase activity were not required for this event. More importantly, these clusters of Itk molecules form in distinct regions of the plasma membrane as only receptors that recruit phosphatidylinositol 3-kinase reside in the same membrane vicinity as the recruited Itk. Our results indicate that Itk forms dimers in the membrane and that receptors that recruit Itk do so to specific membrane regions.The Tec family of non-receptor tyrosine kinases is the second largest family of non-receptor tyrosine kinases (1). This family, which includes Itk, 2 is involved in transducing signals from a number of receptors, including the T cell receptor, B cell receptor, Fc⑀R, c-Kit, CD28, CD2, CD32, and the erythropoietin receptor (1-6). These kinases play important roles in regulating cytokine and immune receptor signals that regulate the immune response (7,8). Itk in particular is involved in early T cell receptor signaling and regulates increases in intracellular calcium and activation of the nuclear factor of activated T cells family of transcription factors (9, 10). In addition, Itk regulates the development of Th2 cells and their subsequent cytokine secretion, thereby modulating the immune response (10 -13). A common feature of these kinases is that they require the activation of PI3 kinase, as well as Src kinase activation for their activity (14 -17). These kinases, including Itk, have a PH domain that allows them to be recruited to the plasma membrane by an activated PI3 kinase (1). Thus, membrane recruitment is a critical component of their activation, and Itk can be found at the plasma membrane of cells, although other events are required for its full activity (17)(18)(19). It is, however, not clear whether this is general membrane localization of the protein in anticipation of activation or a specific localization in certain regions of the plasma membrane.The structure of Itk in cells is not known, although it has been suggested to form dimers in its inactive state, with a resultant monomerization upon activation (20,21). We have examined these issues using a split YFP system (22) and find that Itk forms dimers or higher order clusters; however, it does so only at the plasma membrane and only in the vicinity of a receptor that can recruit PI3 kinase. Our data shed new light on the regulation, struct...

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Phosphatidylinositol 3-kinase-γ activates Bruton’s tyrosine kinase in concert with Src family kinases

Cited by 190 publications

References 60 publications

Tec Kinase Signaling in T Cells Is Regulated by Phosphatidylinositol 3-Kinase and the Tec Pleckstrin Homology Domain

Tec Kinase Signaling in T Cells Is Regulated by Phosphatidylinositol 3-Kinase and the Tec Pleckstrin Homology Domain

Etk/Bmx, a PH-domain containing tyrosine kinase, protects prostate cancer cells from apoptosis induced by photodynamic therapy or thapsigargin

Tec Kinase Itk Forms Membrane Clusters Specifically in the Vicinity of Recruiting Receptors

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