Evidence of Autophosphorylation in Txk: Y91 Is an Autophosphorylation Site.

Kashiwakura, Jun‐ichi; Suzuki, Noboru; Takeno, Mitsuhiro; Itoh, Saotomo; Oku, Teruaki; Sakane, Tsuyoshi; Nakajin, Shizuo; Toyoshima, Satoshi

doi:10.1248/bpb.25.718

Cited by 13 publications

(14 citation statements)

References 33 publications

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“…All Tec family kinases are significantly involved in the lymphocyte signaling pathways. [39][40][41][42][43][44][45][46][47] Txk is a signal-transducing molecule, which consists of the tyrosine kinase cascade downstream from the T cell receptor when an antigen is presented to the T cell through the T cell receptor. Txk is phosphorylated and activated by Fyn, one of the Srk family kinases, and it phosphorylates downstream signal molecules.…”

Section: Txk Expression Of Peripheral Blood T Cells Skin and Intestimentioning

confidence: 99%

Skewed Th1 Responses Caused by Excessive Expression of Txk, a Member of the Tec Family of Tyrosine Kinases, in Patients with Behcet's Disease

Suzuki

Nara²,

Suzuki³

2006

Clinical Medicine & Research

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Behcet's disease (BD) is characterized by recurrent attacks of uveitis, oral aphtha, genital ulcers and skin lesions.The etiology and pathogenesis of BD are largely unknown. It has been reported that excessive Th1 cell function is involved in the pathogenesis of BD. Previously, we found that Txk, a member of the Tec family of tyrosine kinases, acts as a Th1 cell-specific transcription factor that is involved in the effector function of Th1 cells.Thus, we studied Th1 cytokine production and Txk expression of T-lymphocytes in patients with BD. Peripheral blood lymphocytes produced excessive Th1-associated cytokines including interferon-γ (IFN-γ) and interleukin (IL)-12 in patients with BD. Circulating CD3+ and purified CD4+ T cells expressed excessive Txk protein.The extent of IFN-γ production by the lymphocytes correlated with the expression of Txk protein in the immunoblotting analysis. The majority of cells infiltrating into the skin lesions of patients with BD expressed IFN-γ. IL-12 and IL-18 were found in the mononuclear cell aggregates in the skin and intestinal lesions of those with BD. Lymphocytes accumulating in the skin and intestinal lesions expressed higher levels of Txk as compared with other Th2-associated diseases. IFN-γ, IL-18 and IL-12 detected in skin lesions may induce preferential development of Th1 cells in patients with BD. Collectively,Th1 cells expressing Txk and Th1-associated cytokines may play a critical role in the development of skin and intestinal lesions in patients with BD. This review may serve as a reminder of the importance of excessive Th1 cell function in the pathogenesis of BD and may contribute to the discovery of new molecular targets for the development of a specific therapeutic strategy for BD.

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Section: Txk Expression Of Peripheral Blood T Cells Skin and Intestimentioning

confidence: 99%

Skewed Th1 Responses Caused by Excessive Expression of Txk, a Member of the Tec Family of Tyrosine Kinases, in Patients with Behcet's Disease

Suzuki

Nara²,

Suzuki³

2006

Clinical Medicine & Research

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“…1A) and each Tec kinase autophosphorylates a tyrosine residue within its own SH3 domain (Y180 in Itk) 19; 20; 21. Autophosphorylation occurs in an intramolecular fashion ( in cis ) 16 and depends on the presence of the SH2 domain 8.…”

Section: Resultsmentioning

confidence: 99%

SH2-Dependent Autophosphorylation within the Tec Family Kinase Itk

Joseph

Severin

Min

et al. 2009

Journal of Molecular Biology

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The Tec family kinase, Itk (interleukin-2 tyrosine kinase), undergoes an in cis autophosphorylation on Y180 within its Src homology 3 (SH3) domain. Autophosphorylation of the Itk SH3 domain by the Itk kinase domain is strictly dependent on the presence of the intervening Src homology 2 (SH2) domain. A direct docking interaction between the Itk kinase and SH2 domains brings the Itk SH3 domain into the active site where Y180 is then phosphorylated. We now identify the residues on the surface of the Itk SH2 domain responsible for substrate docking and show that this SH2 surface mediates autophosphorylation in the fulllength Itk molecule. The canonical phospholigand binding site on the SH2 domain is not involved in substrate docking, instead the docking site consists of side chains from three loop regions (AB, EF and BG) and part of the βD strand. These results are extended into Btk (Bruton's tyrosine kinase), a Tec family kinase linked to the B-cell deficiency X-linked agammaglobulinemia (XLA). Our results suggest that some XLA-causing mutations might impair Btk phosphorylation. AbstractThe Tec family kinase, Itk, undergoes an in cis autophosphorylation on Y180 within its SH3 domain. Autophosphorylation of the Itk SH3 domain by the Itk kinase domain is strictly dependent on the presence of the intervening SH2 domain. A direct docking interaction between the Itk kinase and SH2 domains brings the Itk SH3 domain into the active site where Y180 is then phosphorylated. We now identify the residues on the surface of the Itk SH2 domain responsible for substrate docking and show that this SH2 surface mediates autophosphorylation in the full length Itk molecule. The canonical phospholigand binding site on the SH2 domain is not involved in substrate docking, instead the docking site consists of side chains from three loop regions (AB, EF and BG) and part of the βD strand. These results are extended into Btk, a Tec family kinase linked to the B cell deficiency X-linked agammaglobulinemia (XLA). Our results suggest that some XLA causing mutations might impair Btk phosphorylation.

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“…Specifically, mutation of TXK does not prevent T cell development nor block TCR signaling but instead reduces TCR signaling in a manner that can alter thymocyte development and mature T cell differentiation and function 34 . Kashiwakura and colleagues 38 , showed that Y91 of TXK is an autophosphorylation site, important for the promotion of IFN-gamma synthesis, suggesting that phosphorylation of Y91 plays a positive regulatory role in TXK function. Phosphorylation at Y420 was identified as a transphosphorylation substrate for FYN 39 , but the other sites have yet to be characterized.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Phosphoproteomic Analysis of T Cell Receptor Signaling in Diabetes Prone and Resistant Mice

et al. 2010

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Type 1 diabetes, in human patients and NOD mice, results from immune attack on insulin-producing beta-cells of the pancreas by autoreactive T lymphocytes. In NOD mice, genetically-controlled perturbations in the signaling pathways downstream of the antigen-specific T cell receptor (TCR) may be instrumental in the altered responses of T cells, manifest as inefficient induction of apoptosis after recognition of self-antigens in the thymus, or as perturbed reactivity of mature T cells in peripheral organs. To map this signaling difference(s), we have used mass spectrometry-based quantitative phosphoproteomics to compare the activation of primary CD4+ T cells of diabetes-prone NOD and -resistant B6.H2g7 mice. Immunoprecipitation and IMAC purification of tyrosine-phosphorylated peptides, combined with a stable-isotope iTRAQ labeling, enabled us to identify and quantify over 77 phosphorylation events in 54 different proteins downstream of TCR stimulation of primary CD4+ T cells. This analysis showed a generally higher level of phosphotyrosine in activated NOD cells, as well as several phosphorylation sites that appeared to be differentially regulated in these two strains (involving TXK, CD5, PAG1, and ZAP-70). These data highlight the differences in signaling between CD4+ T cell compartments of NOD and B6g7 mice, and may underlie the dysregulation of T cells in NOD mice.

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Evidence of Autophosphorylation in Txk: Y91 Is an Autophosphorylation Site.

Cited by 13 publications

References 33 publications

Skewed Th1 Responses Caused by Excessive Expression of Txk, a Member of the Tec Family of Tyrosine Kinases, in Patients with Behcet's Disease

Skewed Th1 Responses Caused by Excessive Expression of Txk, a Member of the Tec Family of Tyrosine Kinases, in Patients with Behcet's Disease

SH2-Dependent Autophosphorylation within the Tec Family Kinase Itk

Quantitative Phosphoproteomic Analysis of T Cell Receptor Signaling in Diabetes Prone and Resistant Mice

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