TEC-family kinases: regulators of T-helper-cell differentiation

Schwartzberg, Pamela L.; Finkelstein, Lisa D.; Readinger, Julie A.

doi:10.1038/nri1591

Cited by 152 publications

(158 citation statements)

References 118 publications

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“…Furthermore, ITK protein expression is increased during the commitment of Th0 cells to Th2 cells and the ITK promoter contains binding sites for the canonical regulator of Th2 differentiation, GATA-3 (28). Thus, ITK genedeficient mice have diminished responses to intracellular pathogens normally controlled by Th2 immunity and have decreased allergic airways responses to allergen challenge (28). The activity of ITK is therefore consistent with the hypothesis that TIM-1 is a driver of Th2 T cell differentiation.…”

Section: Discussionsupporting

confidence: 68%

“…Association of ITK and PI3K has been described previously in the context of CD28 signaling (26) and ITK is proposed to integrate TCR and calcium dependant signaling cascades in T cells (27). Furthermore, ITK protein expression is increased during the commitment of Th0 cells to Th2 cells and the ITK promoter contains binding sites for the canonical regulator of Th2 differentiation, GATA-3 (28). Thus, ITK genedeficient mice have diminished responses to intracellular pathogens normally controlled by Th2 immunity and have decreased allergic airways responses to allergen challenge (28).…”

Section: Discussionmentioning

confidence: 99%

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Human TIM-1 Associates with the TCR Complex and Up-Regulates T Cell Activation Signals

Binné

Scott

Rennert

2007

The Journal of Immunology

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The T cell, Ig domain, and mucin domain-1 (TIM-1) gene is associated with Th2 T cell responses and human atopic diseases. The mechanism by which TIM-1 influences T cell responses remains unknown. We demonstrate that TIM-1 is recruited to the TCR-signaling complex via association with CD3. TIM-1 up-regulates TCR-associated signaling events, including phosphorylation of Zap70 and IL-2-inducible T cell kinase. This activity requires TIM-1 tyrosine phosphorylation. TIM-1 expression induces formation of a novel complex that includes PI3K and ITK. Finally, the consequences of TIM-1 activation include increased expression of effector cytokines. These results demonstrate that TIM-1 is a critical component of the human T cell response and provide a mechanistic hypothesis for the role of TIM-1 in disease.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Human TIM-1 Associates with the TCR Complex and Up-Regulates T Cell Activation Signals

Binné

Scott

Rennert

2007

The Journal of Immunology

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“…Three members of this family [ITK, RLK (resting lymphocyte kinase), and Tec] are expressed in T cells (10). Among these, ITK is most strongly implicated in the regulation of PLC-␥1, because the tyrosine phosphorylation and activation of PLC-␥1 are diminished in T cells from ITK-deficient mice (11).…”

mentioning

confidence: 99%

“…Among these, ITK is most strongly implicated in the regulation of PLC-␥1, because the tyrosine phosphorylation and activation of PLC-␥1 are diminished in T cells from ITK-deficient mice (11). ITK comprises an N-terminal pleckstrin homology domain, a proline-rich Tec homology domain, an SH3 domain, an SH2 domain, and a C-terminal catalytic domain (10). It also contains two tyrosine phosphorylation sites that are thought to play a role in its activation (12): Y 511 , residing in the activation loop of the kinase domain; and Y 180 , residing in the SH3 domain.…”

mentioning

confidence: 99%

SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK

Bogin

Ainey

Beach

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

115

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“…Itk belongs to the Tec family of nonreceptor tyrosine kinases that also includes Btk, Tec, Rlk, and Bmx (12). The Tec kinases, like the larger protein kinase superfamily, control numerous cellular signaling networks by phosphorylating target amino acid side chains in a stringently specific manner.…”

mentioning

confidence: 99%

Itk tyrosine kinase substrate docking is mediated by a nonclassical SH2 domain surface of PLCγ1

Min

Joseph

Fulton

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Interleukin-2 tyrosine kinase (Itk) is a Tec family tyrosine kinase that mediates signaling processes after T cell receptor engagement. Activation of Itk requires recruitment to the membrane via its pleckstrin homology domain, phosphorylation of Itk by the Src kinase, Lck, and binding of Itk to the SLP-76/LAT adapter complex. After activation, Itk phosphorylates and activates phospholipase C-␥1 (PLC-␥1), leading to production of two second messengers, DAG and IP3. We have previously shown that phosphorylation of PLC-␥1 by Itk requires a direct, phosphotyrosine-independent interaction between the Src homology 2 (SH2) domain of PLC-␥1 and the kinase domain of Itk. We now define this docking interface using a combination of mutagenesis and NMR spectroscopy and show that disruption of the Itk/PLC␥1 docking interaction attenuates T cell signaling. The binding surface on PLC␥1 that mediates recognition by Itk highlights a nonclassical binding activity of the well-studied SH2 domain providing further evidence that SH2 domains participate in important signaling interactions beyond recognition of phosphotyrosine.substrate recognition ͉ T cell signaling ͉ Tec kinases I nterleukin-2 tyrosine kinase (Itk) is a nonreceptor protein tyrosine kinase that is expressed in T cells, mast cells and NK cells (1)(2)(3)(4)(5). Previous studies have shown that activation of Itk after T cell receptor engagement requires Itk recruitment to PIP3 in the membrane via its PH domain, binding of Itk to the SLP-76/LAT adapter complex, and phosphorylation of Itk by Lck at the activation loop tyrosine in its kinase domain (6). Activated Itk then phosphorylates its substrate, phospholipase C-␥1 (PLC-␥1), resulting in activation of PLC␥1 lipase activity and subsequent hydrolysis of PIP 2 to IP 3 and DAG. IP 3 and DAG stimulate the release of calcium ions from the endoplasmic reticulum and activate Protein Kinase C, respectively (7-11). The overall signaling pathway has been clearly delineated but many of the precise molecular details of the protein-protein interactions and enzyme/substrate interactions that control signal transduction after TCR engagement remain to be determined.Itk belongs to the Tec family of nonreceptor tyrosine kinases that also includes Btk, Tec, Rlk, and Bmx (12). The Tec kinases, like the larger protein kinase superfamily, control numerous cellular signaling networks by phosphorylating target amino acid side chains in a stringently specific manner. Based on results of combinatorial peptide library screens and structures of kinase/peptide substrate complexes, the view has emerged that the active sites of most kinases tolerate different sequences and are therefore not necessarily stringently specific for short peptide sequences (13,14). Stringent specificity is, however, a strict requirement of cellular signaling cascades and so these enzymes must have mechanisms to control substrate fidelity (14-22).The physiological substrate of Itk, PLC␥1, is a phospholipase that contains an amino-terminal PH domain, EF hand motif, a split c...

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TEC-family kinases: regulators of T-helper-cell differentiation

Cited by 152 publications

References 118 publications

Human TIM-1 Associates with the TCR Complex and Up-Regulates T Cell Activation Signals

Human TIM-1 Associates with the TCR Complex and Up-Regulates T Cell Activation Signals

SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK

Itk tyrosine kinase substrate docking is mediated by a nonclassical SH2 domain surface of PLCγ1

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