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)

One of the main dilemma in T cell receptor (TCR) signal transduction is whether the presence of multiple Immunoreceptor Tyrosine-based Activation Motifs (ITAMs) within the TCR signaling module serves for signal amplification or signal distribution. To contribute to answer this question, we analyzed the effect of synthetic oligopeptides representing the three bi-phosphorylated zeta chain-ITAMs on the early signaling events in permeabilized leukemia T cells. Our main observations were as follows: 1/Stimulation of the cells with the bi-phosphorylated membrane proximal and central ITAMs (zeta (1)y(p)y(p) and zeta (2)y(p)y(p), respectively) resulted in a strong phosphorylation of proteins with a similar pattern. In contrast, the membrane distal ITAM, zeta (3)y(p)y(p) had a reduced ability to promote tyrosine phosphorylation and failed to induce the phosphorylation of a number of proteins. 2/ The phospho-peptide induced tyrosine phosphorylation events were at least partially mediated by p56(lck) and Syk/ZAP70 protein tyrosine kinases as it was shown in p56(lck) and Syk/ZAP70 deficient Jurkat variants. 3/The patterns of the association of the adaptor protein, Grb2 with tyrosine phosphorylated proteins following cell stimulation with the bi-phosphorylated membrane proximal or the central ITAMs were similar, while the membrane distal ITAM was unable to induce any of these associations. Our data provide additional evidence that the three zetaITAMs differ in their capacity to induce tyrosine phosphorylation of intracellular proteins in permeabilized T cells, depending to their primary sequence. The first and second ITAM sequences of the zeta chain may have similar but not totally overlapping functions. This conclusion results from their similar but not identical abilities to induce tyrosine phosphorylation and association of Grb-2 with intracellular phosphoproteins. In contrast, the third ITAM (zeta3) may have distinct functions since this peptide fails to induce tyrosine phosphorylation of a number of proteins compared to the other two ITAMs, and it is unable to induce either new association or the increase in the amount of Grb-2 associated phosphoproteins.
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PMID:Comparative study on the effect of phosphorylated TCR zeta chain ITAM sequences on early activation events in Jurkat T cells. 1178 78

A prospective study of 151 eyes, which underwent laser in situ keratomileusis, was done. Corneal flap creation was performed by using Moria LSK- One microkeratome (160 micrometers thickness) (distributed by Microtech, Inc., Moria, France). Flap thickness (measured by high frequency ultrasound), flap diameter (both horizontal and vertical), hinge size and pupillary hinge distance were recorded. The actual values from the measurement were compared to the predicted values from the microkeratome. The mean flap thickness was 161 +/- 38 micrometers compare to 160 micrometers predicted value. The mean diameter of the flap was 9.00 +/- 0.64 mm vertical and 8.94 +/- 0.54 mm horizontal compare to 9.00 mm predicted value. The hinge size was 4.75 +/- 0.84 mm. The pupillary-hinge distance was 3.35 +/- 0.61 mm. There was very high variable of the flap thickness, which can lead to miscalculation of the residual stroma. This miscalculation will be very critical if the residual stroma is left too thin. Caution should be made in higher level of myopia to avoid the serious complication such as keratectasia.
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PMID:Flap analysis: critical point in laser in situ keratomileusis. 1180 Mar 6

A 42-year-old woman with a refractive error of -10.00S - 2.00C x 105 degrees in the right eye underwent laser in situ keratomileusis (LASIK) at our hospital. LASIK was performed using the Schwind excimer laser (Keratom Multiscan, Schwind, Kleinostheim, Germany) and Moria LSK--One manual microkeratome with a 130 microns ablation plate. The uncorrected visual acuity improved postoperatively, and the patient was very satisfied. However, nine months later, she complained of sudden loss of visual acuity in the right eye. Indirect ophthalmoscopy revealed a giant retinal tear extending from 10:00 to 2:00 o'clock position with retinal detachment and vitreous hemorrhage. We performed scleral buckling procedure (with silicone band encircling), vitrectomy, and fluid-gas exchange with air/SF6 mixture. The retina attached postoperatively and remained so during 3-month follow-up period, but cellophane maculopathy was noted.
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PMID:Giant tear retinal detachment after laser in situ keratomileusis--a case report. 1185 68

Transformation of cells by src -like kinases leads to altered cell morphology associated with the disassembly of focal contacts and concomitant increase in tyrosine phosphorylation of pp125(FAK) x p56(lck) is a lymphocyte-specific member of the src family of protein tyrosine kinases that associates with cell surface glycoproteins such as CD4 and CD8. It phosphorylates and activates pp125(FAK) and increases its autokinase activity, thus pretreatment of pp125(FAK) with protein kinase C (PKC) markedly attenuates its phosphorylation and activation, suggesting a potential regulatory pathway of pp125(FAK) activation in focal contacts. p56(lck) further phosphorylates and activates actin binding protein (ABP-280; filamin) and controls its association with cell surface receptors such as beta-2 integrins, actin filament cross-linking, and possibly lipid membrane insertion.
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PMID:p56(lck) Controls phosphorylation of filamin (ABP-280) and regulates focal adhesion kinase (pp125(FAK)). 1217 Oct 35

The insect neuropeptides FMRF amide, leucomyosupressin (LMS) and neuropeptide analogues leucosulfakinins (FLSK and LSK II Ser (SO(3)H)), perisulfakinin (PSK), proleucosulfakinin (PLSK), 14A[phi1]WP-I, 542phi1, and 378A[5b]WP-I were assayed for their effects on the release of amylase and protease from the midgut tissue of larvae of Opisina arenosella. In the bioassay, empty midgut tubes ligated at both ends using hair were incubated with insect saline containing neuropeptides/analogues in a bioassay apparatus at 37 degrees C for 30 min. After incubation the contents of the midgut preparations were analyzed for amylase and protease activity. In control experiments, the midgut preparations were incubated in insect saline without neuropeptides. The results of the study reveal that for stimulating amylase release from midgut tissue, the peptides require an FXRF amide (X may be methionine or leucine) sequence at the C-terminal. The presence of HMRF amide at C-terminal of peptides may inhibit the release of amylase. Meanwhile, peptides with both FMRF and HMRF amide sequence at the C-terminal are found to be effective in stimulating protease release. The tetrapeptide segment at the C-terminal probably represent the active core of the neuropeptide.
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PMID:In vitro release of digestive enzymes by FMRF amide related neuropeptides and analogues in the lepidopteran insect Opisina arenosella (Walk.). 1238 63

This study analysed the T-cell receptor (TCR)-CD3 zeta complex and the signal transduction apparatus of T-acute lymphoblastic leukaemia (T-ALL) blasts, and investigated the function of the ubiquitin-proteasome system. In all nine T-ALL samples studied, the leukaemic cells showed a marked reduction in the expression of the zeta chain, while a variety of tyrosine kinases (p56lck, ZAP70 and SYK) were normally present. There was no expression of the FcepsilonRIgamma chain. To confirm that this aberration was specific to immature T-ALL blasts, we investigated two patients with lymphoproliferative disorders of granular lymphocytes (LDGL), characterized by the expansion of mature T lymphocytes and found normal zeta chain expression. The reduction of the zeta chain protein was not reversible after 72 h stimulation with the anti-CD3 monoclonal antibody and interleukin 2, either alone or in combination. Northern blot analysis indicated that the reduced protein expression did not correspond to a defect at the mRNA level, nor were mutations in the coding region of the zeta chain found. We, therefore, hypothesized that the observed reduction of protein expression in T-ALL blasts could be secondary to an increased degradation at the proteasome level. Following selective inhibition of the proteasome, a marked increase of the zeta chain expression was observed. Moreover, an increase in the surface expression of CD3 was also documented. Taken together, these results indicate that the expression of the zeta subunit of the TCR-CD3 complex is consistently reduced in T-ALL blasts and that degradation of the protein is mediated by the proteasome system.
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PMID:Defective expression of the T-cell receptor-CD3 zeta chain in T-cell acute lymphoblastic leukaemia. 1254 76

The Notch family of transmembrane receptors have been implicated in a variety of cellular decisions in different cell types. Here we investigate the mechanism underlying Notch-1-mediated anti-apoptotic function in T cells using model cell lines as the experimental system. Ectopic expression of the intracellular domain of Notch-1/activated Notch (AcN1) increases expression of anti-apoptotic proteins of the inhibitors of apoptosis (IAP) family, the Bcl-2 family, and the FLICE-like inhibitor protein (FLIP) and inhibits death triggered by multiple stimuli that activate intrinsic or extrinsic pathways of apoptosis in human and murine T cell lines. Numb inhibited the AcN1-dependent induction of anti-apoptotic proteins and anti-apoptotic function. Using pharmacological inhibitors and dominant-negative approaches, we describe a functional role for phosphatidylinositol 3-kinase (PI3K)-dependent activation of the serine-threonine kinase Akt/PKB in the regulation of AcN1-mediated anti-apoptotic function and the expression of FLIP and IAP family proteins. Using a cell line deficient for the T cell-specific, Src family protein, the tyrosine kinase p56(lck) and by reconstitution approaches we demonstrate that p56(lck) is required for the Notch-1-mediated activation of Akt/PKB function. Furthermore, the Src tyrosine kinase inhibitor, PP2, abrogated ectopically expressed AcN1-mediated anti-apoptotic function and phosphorylation of p56(lck). We present evidence that endogenous Notch-1 associates with p56(lck) and PI3K but that Akt/PKB does not co-immunoprecipitate with the Notch1.p56(lck).PI3K complex. Finally, we demonstrate that the Notch1.p56(lck).PI3K complex is present in primary T cells that have been activated in vitro and sustained in culture with the cytokine interleukin-2.
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PMID:The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells. 1458 9

Crosslinking of Fas (APO-1/CD95) on the surface of T cells initiates a biochemical cascade leading to programmed cell death. We have previously shown that crosslinking of Fas with an apoptosis-inducing IgM anti-Fas mAb results in suppression of the CD3-initiated cell signaling including Ca2+ mobilization and protein tyrosine phosphorylation. We conducted experiments to decipher the mechanisms whereby the cross talk between the Fas- and CD3 signaling pathways occur. We used lysates from Jurkat T and examined the composition of the TCR zeta chain-precipitated immune complexes using immunoblots. While crosslinking of Fas affected the association of p59fyn and p56lck tyrosine kinases with the TCR zeta chain to a limited degree, it dramatically inhibited the association of the protein tyrosine kinase ZAP70 with the zeta chain. In cells that were preincubated with an apoptosis-inducing anti-Fas mAb, the binding of the protein tyrosine phosphatases SHP-1 to the TCR zeta chain was increased. These experiments indicate that crosslinking of Fas interferes with early T cell signaling events by promoting the recruitment of SHP-1 and decreasing the association of protein tyrosine kinases with TCR zeta chain. Therefore, crosslinking of Fas antigen may regulate the antigen-induced T cell response and play an active role in the T cell anergy.
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PMID:Crosslinking of Fas/CD95 suppresses the CD3-mediated signaling events in Jurkat T cells by inhibiting the association of the T-cell receptor zeta chain with src-protein tyrosine kinases and ZAP70. 1463 36

Lysophospholipids, particularly lysophosphatidylcholine (lyso-PC), have been implicated in modulating T cell functions at the sites of inflammation and atherosclerosis. Although the chemotactic and immunomodulatory effects are well documented, the exact signaling pathway of lyso-PC action is poorly defined. In this work, we studied the earliest biochemical events in T cells triggered by lyso-PC. A marked and immediate tyrosine phosphorylation was induced in the leukemic T cell line, Jurkat. Phosphorylation of cellular substrates included src family kinase, p56(lck) and syk family kinase, ZAP70. The lyso-PC induced tyrosine phosphorylation was largely dependent on the presence of functional p56(lck). Tyrosine phosphorylation was followed by the elevation of intracellular Ca(2+) concentration. The magnitude of the mobilization of the intracellular Ca(2+) was similar in the absence of the p56(lck) activity in JCaM1.6 cells as in Jurkat cells, however, it was slightly but reproducibly delayed compared to that in the wild type cells. Inhibition of the Ser/Thr kinases and tyrosine kinases with staurosporine and genistein, respectively, decreased the rise in the intracellular Ca(2+) content. Moreover, pertussis toxin completely blocked the Ca(2+) signal supporting the role of the G-protein coupled LPC receptor in this event.
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PMID:Lysophosphatidylcholine is a regulator of tyrosine kinase activity and intracellular Ca(2+) level in Jurkat T cell line. 1475 65

The number of bone marrow hematopoietic stem and progenitor cells as defined by the lineage(-), Sca1(++), c-kit(+) (LSK) phenotype and their proliferative capacity in vitro are subject to quantitative genetic variation, and several quantitative trait loci (QTL) have been identified in young mice. Because some traits affecting hematopoiesis also change with age in a mouse strain-dependent fashion, we performed quantitative trait analysis in aged BXD recombinant inbred (RI) mice for the number and frequency of LSK cells, and for their proliferative capacity in vitro. Several novel QTL were identified. The number and frequency of LSK cells in old mice correlated inversely with lifespan. Furthermore, 4 of 7 lifespan QTL overlap with QTL contributing to the number, frequency, or proliferative capacity of LSK cells in young or old mice. Taken together, these data establish a close genetic, and perhaps functional, link between genetic variation in lifespan and characteristics of stem and progenitor cells.
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PMID:Quantitative genetic variation in the hematopoietic stem cell and progenitor cell compartment and in lifespan are closely linked at multiple loci in BXD recombinant inbred mice. 1498 59


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