Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:Human TIM-1 associates with the TCR complex and up-regulates T cell activation signals. 1737 91

ITK (IL-2-inducible T cell kinase), a Tec family protein tyrosine kinase (PTK), is one of three PTKs required for T cell antigen receptor (TCR)-induced activation of phospholipase C-gamma1 (PLC-gamma1). Like Src and Abl family PTKs, ITK adopts an inactive, "closed" conformation, and its conversion to the active conformation is not well understood, nor have its direct substrates been identified. In a side-by-side comparison of ITK and ZAP-70 (zeta chain-associated protein kinase of 70 kDa), ITK efficiently phosphorylated Y(783) and Y(775) of PLC-gamma1, two phosphorylation sites that are critical for its activation, whereas ZAP-70 did not. SLP-76 (SH2-domain-containing leukocyte protein of 76 kDa), an adaptor required for TCR-induced activation of PLC-gamma1, was required for the phosphorylation of both PLC-gamma1 sites in intact cells. Furthermore, this event depended on the N-terminal tyrosines of SLP-76. Likewise, SLP-76, particularly its N-terminal tyrosines, was required for TCR-induced tyrosine phosphorylation and activation of ITK but was not required for the phosphorylation or activation of ZAP-70. Both ZAP-70 and ITK phosphorylated SLP-76 in vitro; thus, both PTKs are potential regulators of SLP-76, but only ITK is regulated by SLP-76. Upon TCR stimulation, a small fraction of ITK bound to SLP-76. This fraction, however, encompassed most of the catalytically active ITK. Catalytic activity was lost upon mild elution of ITK from the SLP-76-nucleated complex but was restored upon reconstitution of the complex. We propose that SLP-76 is required for ITK activation; furthermore, an ongoing physical interaction between SLP-76 and ITK is required to maintain ITK in an active conformation.
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PMID: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. 1742 Apr 79

Recent data from three laboratories have identified the TEC kinases, ITK and RLK, as crucial regulators of CD8(+) T-cell development into the conventional lymphocyte lineage. In the absence of ITK and RLK, CD4(+)CD8(+) thymocytes upregulate the T-box transcription factor eomesodermin, and develop into mature CD8(+) T cells that resemble memory cells, exhibit immediate effector cytokine production and depend on IL-15. Furthermore, the selection of these non-conventional 'innate' T cells results from interactions with haematopoietic cells in the thymus. These findings lead to the hypothesis that altered TCR signalling, together with distinct co-stimulatory signals, is the basis for the development of non-conventional T-cell lineages.
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PMID:Signalling through TEC kinases regulates conventional versus innate CD8(+) T-cell development. 1747 28

Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.
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PMID:Hit-to-lead studies on benzimidazole inhibitors of ITK: discovery of a novel class of kinase inhibitors. 1749 5

One of the most challenging problems in modern neuroimaging is detailed characterization of neurodegeneration. Quantifying spatial and longitudinal atrophy patterns is an important component of this process. These spatiotemporal signals will aid in discriminating between related diseases, such as frontotemporal dementia (FTD) and Alzheimer's disease (AD), which manifest themselves in the same at-risk population. Here, we develop a novel symmetric image normalization method (SyN) for maximizing the cross-correlation within the space of diffeomorphic maps and provide the Euler-Lagrange equations necessary for this optimization. We then turn to a careful evaluation of our method. Our evaluation uses gold standard, human cortical segmentation to contrast SyN's performance with a related elastic method and with the standard ITK implementation of Thirion's Demons algorithm. The new method compares favorably with both approaches, in particular when the distance between the template brain and the target brain is large. We then report the correlation of volumes gained by algorithmic cortical labelings of FTD and control subjects with those gained by the manual rater. This comparison shows that, of the three methods tested, SyN's volume measurements are the most strongly correlated with volume measurements gained by expert labeling. This study indicates that SyN, with cross-correlation, is a reliable method for normalizing and making anatomical measurements in volumetric MRI of patients and at-risk elderly individuals.
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PMID:Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain. 1765 98

The first aim of this pilot study was to determine if longitudinal change in caudate volume could be detected in chronic schizophrenic patients after 12 weeks of atypical antipsychotic treatment. A sub-aim of the first aim was to determine if similar results could be obtained from an operator-assisted segmentation tool for volumetric imaging (ITK-SNAP) and voxel-based morphometry (VBM) methods in the caudate. The second aim was to determine if frontal and temporal lobe grey matter, white matter, ventricular and sulcal cerebrospinal fluid volume change could be detected after 12 weeks of atypical antipsychotic treatment with VBM. Ten chronic schizophrenic inpatients, with illness duration averaging 10.6 years, underwent two MRI scans. The first scan was obtained after a mean of 39.4 days of antipsychotic withdrawal. The second MRI was obtained following twelve weeks of atypical antipsychotic treatment. Caudate volume change was first measured with ITK-SNAP. Then the location of grey matter volume change in the caudate was identified with VBM. Finally, the location of frontal and temporal lobe grey matter, white matter, ventricular and sulcal cerebrospinal fluid volume changes were identified with VBM. No longitudinal change in caudate volume or grey matter volume was observed after brief periods of atypical antipsychotic treatment. ITK-SNAP and VBM methods showed very similar results in the caudate. No statistically significant change was identified in the volume of frontal or temporal lobe grey matter, white matter, and lateral, third, or fourth ventricular cerebrospinal fluid. Although the results do not directly show that brief periods of atypical antipsychotic treatment are associated with basal ganglia and cortical volume change, there is much evidence to suggest that such an association exists.
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PMID:Absence of regional brain volume change in schizophrenia associated with short-term atypical antipsychotic treatment. 1855 74

The co-receptor CD28 binds to several intracellular proteins including PI3 kinase, Grb-2, Gads and ITK. Grb-2 and PI3 kinase binding has been mapped to the pYMNM motif within the cytoplasmic tail of CD28 and has been shown to play a role in co-stimulation. In this study, we demonstrate that amongst the Grb-2 family adapter proteins, CD28 precipitated Grb-2 and specifically co-operated in the up-regulation of NFAT/AP-1 transcription. By contrast, Gads and Grap either failed or only weakly collaborated with CD28 ligation. Further, the loss of Grb-2 binding interferes with the ability of Vav1 to co-operate with CD28. Anti-CD28 ligation alone was capable for co-operating with Grb-2 or Grb-2-Vav1. Our findings define a pathway involving CD28 binding to Grb-2 and its co-operativity with Vav1 in the regulation of T-cell co-stimulation.
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PMID:CD28 and Grb-2, relative to Gads or Grap, preferentially co-operate with Vav1 in the activation of NFAT/AP-1 transcription. 1829 96

Peripheral T-cell lymphomas (PTCLs) are fatal in the majority of patients and novel treatments, such as protein tyrosine kinase (PTK) inhibition, are needed. The recent finding of SYK/ITK translocations in rare PTCLs led us to examine the expression of Syk PTK in 141 PTCLs. Syk was positive by immunohistochemistry (IHC) in 133 PTCLs (94%), whereas normal T cells were negative. Western blot on frozen tissue (n=6) and flow cytometry on cell suspensions (n=4) correlated with IHC results in paraffin. Additionally, western blot demonstrated that Syk-positive PTCLs show tyrosine (525/526) phosphorylation, known to be required for Syk activation. Fluorescence in situ hybridization showed no SYK/ITK translocation in 86 cases. Overexpression of Syk, phosphorylation of its Y525/526 residues and the availability of orally available Syk inhibitors suggest that Syk merits further evaluation as a candidate target for pharmacologic PTK inhibition in patients with PTCL.
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PMID:Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas. 1840 19

A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared. In this report, we discuss the structure-activity relationship (SAR), selectivity, and cell-based activity for the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhibitors bound to ITK.
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PMID:Discovery, SAR and X-ray structure of 1H-benzimidazole-5-carboxylic acid cyclohexyl-methyl-amides as inhibitors of inducible T-cell kinase (Itk). 1881 99

Based on the information from molecular modeling and X-ray crystal structures, the kinase specificity pocket of ITK could be occupied upon extension of the right-hand-side of the 2-benzimidazole core of the inhibitors. 2-Aminobenzimidazoles with a trans-stilbene-like extension were designed and synthesized as novel ITK antagonists. Significant improvement on binding affinity and cellular activity were obtained through the trans-stilbene-like antagonists. Several compounds showed inhibitory activity in an IL-2 functional assay.
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PMID:2-Aminobenzimidazoles as potent ITK antagonists: trans-stilbene-like moieties targeting the kinase specificity pocket. 1893 Apr


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