A novel function for the Tec family tyrosine kinase Itk in activation of β1 integrins by the T-cell receptor

Woods, Melody L.; Kivens, Wendy J.; Adelsman, Margaret A.; Qiu, Yun; August, Avery; Shimizu, Yoji

doi:10.1093/emboj/20.6.1232

Cited by 92 publications

(84 citation statements)

References 73 publications

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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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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 reduced T cell infiltration may be the result of reduced chemokine and/or chemokine receptor expression in these mice that drive T cell recruitment to the lung (49) or reduced adhesion of these cells in the lung. Indeed, ITK has been shown to be involved in TCR-induced adhesion via the ␤ 1 integrins (34). Alternatively, the reduced production of IL-4 by ITK null T cells may underlie their lack of significant Ag-specific recruitment to the lung since IL-4 null T H 2 cells have been reported to be defective in this process (50).…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Immunological Symptoms of Allergic Asthma in Mice Lacking the Tyrosine Kinase ITK

Mueller

August

2003

The Journal of Immunology

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147

137

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Allergic asthma patients manifest airway inflammation and some show increases in eosinophils, TH2 cells, and cytokines, increased mucous production in the lung, and elevated serum IgE. This TH2-type response suggests a prominent role for TH2 cells and their cytokines in the pathology of this disease. The Tec family nonreceptor tyrosine kinase inducible T cell kinase (ITK) has been shown to play a role in the differentiation and/or function of TH2-type cells, suggesting that ITK may represent a good target for the control of asthma. Using a murine model of allergic asthma, we show here that ITK is involved in the development of immunological symptoms seen in this model. We show that mice lacking ITK have drastically reduced lung inflammation, eosinophil infiltration, and mucous production following induction of allergic asthma. Notably, T cell influx into the lung was reduced in mice lacking ITK. T cells from ITK−/− mice also exhibited reduced proliferation and cytokine secretion, in particular IL-5 and IL-13, in response to challenge with the allergen OVA, despite elevated levels of total IgE and increased OVA-specific IgE responses. Our results suggest that the tyrosine kinase ITK preferentially regulates the secretion of the TH2 cytokines IL-5 and IL-13 and may be an attractive target for antiasthmatic drugs.

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“…More recently, Itk-deficient cells have been shown to have defects in actin polarization and the localized activation of the Rho family GTPase Cdc42 (18,19). Overexpression of the Itk pleckstrin homology (PH) domain or Itk containing a mutation affecting the Src homology 2 (SH2) protein interaction domain in Jurkat cells also prevents TCR-induced actin polymerization (18,20), suggesting that the Tec kinases may have important functions in the regulation of the actin cytoskeleton. However, Itk deficiency also causes altered thymic development and selection, and mature cells from Itk Ϫ/Ϫ animals can express decreased TCR levels and altered cell surface markers (21,22), complicating interpretation of these results.…”

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“…However, Itk deficiency also causes altered thymic development and selection, and mature cells from Itk Ϫ/Ϫ animals can express decreased TCR levels and altered cell surface markers (21,22), complicating interpretation of these results. Experiments in cell culture have to date relied on overexpression of mutant versions of Itk, which also may not accurately reflect protein function in vivo (18,20,23). Indeed, the first report to address the role of Itk in actin reorganization and cell polarization concluded that Itk was not involved in this process because a kinase-inactive version of Itk failed to disrupt cell contact and polarization to the APC (23).…”

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confidence: 99%

Kinase-Independent Functions for Itk in TCR-Induced Regulation of Vav and the Actin Cytoskeleton

Dombroski

Houghtling

Labno

et al. 2005

The Journal of Immunology

126

132

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The Tec family kinase Itk is an important regulator of Ca2+ mobilization and is required for in vivo responses to Th2-inducing agents. Recent data also implicate Itk in TCR-induced regulation of the actin cytoskeleton. We have evaluated the requirements for Itk function in TCR-induced actin polarization. Reduction of Itk expression via small interfering RNA treatment of the Jurkat human T lymphoma cell line or human peripheral blood T cells disrupted TCR-induced actin polarization, a defect that correlated with decreased recruitment of the Vav guanine nucleotide exchange factor to the site of Ag contact. Vav localization and actin polarization could be rescued by re-expression of either wild-type or kinase-inactive murine Itk but not by Itk containing mutations affecting the pleckstrin homology or Src homology 2 domains. Additionally, we find that Itk is constitutively associated with Vav. Loss of Itk expression did not alter gross patterns of Vav tyrosine phosphorylation but appeared to disrupt the interactions of Vav with SLP-76. Expression of membrane-targeted Vav, Vav-CAAX, can rescue the small interfering RNA to Itk-induced phenotype, implicating the alteration in Vav localization as directly contributing to the actin polarization defect. These data suggest a kinase-independent scaffolding function for Itk in the regulation of Vav localization and TCR-induced actin polarization.

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A novel function for the Tec family tyrosine kinase Itk in activation of β1 integrins by the T-cell receptor

Cited by 92 publications

References 73 publications

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

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

Attenuation of Immunological Symptoms of Allergic Asthma in Mice Lacking the Tyrosine Kinase ITK

Kinase-Independent Functions for Itk in TCR-Induced Regulation of Vav and the Actin Cytoskeleton

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