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 distinct thiol redox status in macrophages, either elevated or reduced intracellular content of glutathione (GSH), was confirmed during aging in IL-2 receptor (IL-2R)gamma and Janus family tyrosine kinase (JAK)3 gene-disrupted mice. Oxidative macrophages (OMp) with reduced GSH dominated initially at a younger age in both mice. OMp-dominated JAK3 or IL-2R gamma chain-deficient mice showed shortened life longevity compared with wild-type littermates. These mice elicited spontaneous onsets of inflammatory bowel disease (IBD)-like symptoms accompanied with the conversion of the redox status of macrophages to reductive phenotypes with elevated intracellular GSH. Conversion of OMp to the reductive phenotype by GSH monoethyl ester or by a beta-(1-3)-glucan accelerated the disease onset, concomitant with the skewing from T(h)2 to T(h)1 responses. On the contrary, N,N'-diacetyl cystine dimethylester, which is capable of inducing OMp, delayed the incidence of IBD-like symptoms and improved the survival rate. This implies that the conversion of OMp/T(h)2 to reductive macrophages/T(h)1 may be critical for the disease progression. The study of these mice may provide insight into the mechanisms underlying Crohn's disease and ulcerative colitis.
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PMID:The conversion of redox status of peritoneal macrophages during pathological progression of spontaneous inflammatory bowel disease in Janus family tyrosine kinase 3(-/-) and IL-2 receptor gamma(-/-) mice. 1203 14

Altered mucosal integrity and increased cytokine production, including tumor necrosis factor (TNF), are the hallmarks of inflammatory bowel disease (IBD). In this study, we addressed the role of TNF receptors (TNFR) on intestinal epithelial cell migration in an in vitro wound closure model. With mouse TNFR1 or TNFR2 knockout intestinal epithelial cells, gene transfection, and pharmacological inhibitors, we show a concentration-dependent receptor-mediated regulation of intestinal cell migration by TNF. A physiological TNF level (1 ng/ml) enhances migration through TNFR2, whereas a pathological level (100 ng/ml) inhibits wound closure through TNFR1. Increased rate of wound closure by TNFR2 or inhibition by TNFR1 cannot be explained by either increased proliferation or apoptosis, respectively. Furthermore, inhibiting Src tyrosine kinase decreases TNF-induced focal adhesion kinase (FAK) tyrosine phosphorylation and cellular migration. We therefore conclude that TNFR2 activates a novel Src-regulated pathway involving FAK tyrosine phosphorylation that enhances migration of intestinal epithelial cells.
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PMID:Tumor necrosis factor regulates intestinal epithelial cell migration by receptor-dependent mechanisms. 1246 50

The short chain fatty acid butyrate promotes proliferation and survival of normal epithelial cells, but induces G(1) or G(2)-M arrest in transformed cells, which is coupled to differentiation and apoptosis. Local administration of butyrate has been shown to ameliorate inflammation in ulcerative colitis; however, the precise mechanism of its anti-inflammatory activity is not known. IFN-gamma is one of the principle cytokines secreted by lamina propria cells in inflamed mucosa and elevated levels of the transcription factor required for IFN-gamma signaling, STAT1 (signal transducer and activator of transcription 1), are present in the colonic mucosa of patients with ulcerative colitis and Crohn's disease. Here we report that butyrate is a strong inhibitor of signaling by IFN-gamma. We demonstrated that this short chain fatty acid inhibits IFN-gamma-induced tyrosine and serine phosphorylation of STAT1. IFN-gamma-induced JAK2 activation was inhibited by butyrate, implicating JAK2 as a target of butyrate action. Accordingly, STAT1 nuclear translocation and its DNA binding were completely inhibited in butyrate-treated cells. Transient transfection experiments using a reporter gene construct containing eight GAS sites (gamma-activated sites) revealed that butyrate inhibits IFN-gamma induced, STAT1-dependent, transcriptional activation. Proinflammatory cytokines, including IFN-gamma, play an important role in the pathogenesis of inflammatory bowel disease, and abnormal activity of STAT1 is associated with human malignancies and intestinal inflammatory diseases. Thus, our data suggest that butyrate negatively regulates mucosal inflammation through the inhibition of IFN-gamma/STAT1 signaling.
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PMID:Inhibition of interferon gamma signaling by the short chain fatty acid butyrate. 1451 48

High molecular weight kininogen (HK) is a plasma protein that is cleaved by plasma kallikrein in the clinical settings of sepsis and chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease. This proteolytic event results in a nonapeptide, bradykinin (BK), and a kinin-free derivative of HK, namely HKa. BK promotes angiogenesis by upregulation of bFGF through the B1 receptor or by stimulation of VEGF formation via the B2 receptor. Kininogen-deficient rats show diminished angiogenesis when neovascularization is stimulated. The formation of HKa results in exposure of domain 5 (D5). HKa or D5 inhibit endothelial cell migration and proliferation, both of which are needed for angiogenesis. In the chicken chorioallantoic membrane assay when neovascularization is stimulated by bFGF or VEGF, HKa or D5 inhibit angiogenesis. Monoclonal antibody C11C1, which prevents binding of HK to endothelial cells, also limits its conversion to BK thus downregulating angiogenesis. In vivo, mAb C11C1 inhibits tumor angiogenesis in mice as well as in experimental inflammatory arthritis and inflammatory bowel disease in Lewis rats. In vitro HKa or D5 inhibits endothelial cell adhesion to vitronectin and fibrinogen, resulting in anokis and apoptosis. The HKa receptor, uPAR, forms a signaling complex containing the integrin alphavbeta3 or alpha5beta1, caveolin, Src kinase Yes, focal adhesion kinase and paxcillin. HKa physically disrupts the complex by interfering with the binding of vitronectin to uPAR. Both mAb C11C1 and D5 have potential applications for controlling unwanted angiogenesis in inflammation and cancer.
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PMID:Regulation of angiogenesis by the kallikrein-kinin system. 1684 60

Altered transforming growth factor-beta (TGFbeta) expression may contribute to inflammatory bowel disease and modulate epithelial cell restitution. Interference with TGFbeta-mediated signaling inhibits excisional skin wound healing, but accelerates healing of incisional cutaneous wounds and wounds in some other tissues. Therefore, we sought to clarify the potential role of Smad3-dependent TGFbeta signaling in intestinal mucosal healing in Smad3 null mice. Jejunal serosal application of filter disks saturated with 75% acetic acid yielded a circumscribed reproducible ischemic mucosal ulcer 1 day later. We compared ulcer area at 3 and 5 days to day 1 in Smad3 knockout mice and syngeneic wild-type mice, and evaluated mucosal immunoreactivity at the ulcer edge for TGFbeta, phosphorylated (activated) focal adhesion kinase (pFAK), phosphorylated extracellular signal-related kinase (pERK), proliferating cell nuclear antigen and apoptosis by TUNEL. Ulcer healing in Smad3 null mice was 17% less at day 3 (n=14, P=0.022) and 15% less at day 5 (n=14, P=0.004) than in wild-type littermates. In wild-type mice, pFAK, pERK and TGFbeta immunoreactivity were elevated in epithelium immediately adjacent to the ulcer compared with more distant mucosa. However, this pattern of immunoreactivity for pFAK, pERK and TGFbeta was not observed in Smad3 null mice. Smad3 null mice exhibited increased epithelial proliferation and no differences in apoptotic cell death compared with wild types, suggesting that ulcer healing may reflect differences in restitutive cell migration. Thus, Smad3-dependent disruption of the TGFbeta signaling pathway impairs the healing of murine intestinal mucosal ulcers and alters patterns of activated FAK and ERK immunoreactivity important for cell migration at the ulcer edge. These studies suggest a significant role for Smad3-dependent TGFbeta signaling in intestinal mucosal healing.
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PMID:Smad3 knockout mice exhibit impaired intestinal mucosal healing. 1871 54

IL-24 is a member of the IL-10 family of cytokines. In this study, we investigated IL-24 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD), and characterized the molecular mechanisms responsible for IL-24 expression in human colonic subepithelial myofibroblasts (SEMFs). IL-24 expression in the IBD mucosa was evaluated by immunohistochemical methods. IL-24 mRNA and protein expression was determined by real-time PCR and ELISA, respectively. AP-1 and C/EBP DNA-binding activity and IL-24 promoter activity were assessed by EMSA analysis and a reporter gene assay, respectively. IL-24 mRNA expression was significantly elevated in active lesions from patients who have ulcerative colitis and Crohn's disease. Colonic SEMFs were identified as a major source of IL-24 in the mucosa. IL-1beta, but not IL-17A, TNF-alpha, or IFN-gamma, significantly enhanced IL-24 mRNA and protein expression in isolated colonic SEMFs. The IL-1beta-induced IL-24 mRNA expression was mediated by the activation of the transcription factors, AP-1 and C/EBP-beta. Induction of IL-24 mRNA stabilization was also involved in the effects of IL-1beta. IL-24 induced JAK1/STAT-3 phosphorylation and SOCS3 expression in HT-29 colonic epithelial cells. IL-24 did not modulate the proliferation of HT-29 cells, but significantly increased the mRNA expression of membrane-bound mucins (MUC1, MUC3, and MUC4). IL-24 derived from colonic SEMFs acts on colonic epithelial cells to elicit JAK1/STAT-3 activation and the expression of SOCS3 and mucins, supporting their suppressive effects on mucosal inflammation in IBD.
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PMID:Expression of IL-24, an activator of the JAK1/STAT3/SOCS3 cascade, is enhanced in inflammatory bowel disease. 1953 21

Epidemiological data, detailed molecular studies and recent genome-wide association studies strongly suggest that ulcerative colitis (UC) and Crohn's disease (CD) are related polygenic diseases that share some susceptibility loci, but differ at others. To date, there are more than 50 confirmed inflammatory bowel disease genes/loci, a number that is widely anticipated to at least double in the next 2 years. Germline variation in IL23R, IL12B, JAK2 and STAT3 is associated with inflammatory bowel disease susceptibility, consistent with the newly described role for IL23 signaling and Th17 cells in disease pathogenesis. Several genes involved in different aspects of bacterial handling are defective only in CD, including NOD2 and the autophagy genes ATG16L1 and IRGM. IL10 and ECM1 are associated with UC, while inherited variation at the HLA region is related to an inflammatory colonic phenotype. The application of genome-wide association studies to inflammatory bowel disease has been successful in defining the genetic architecture of CD and UC and in delivering genuinely novel and important insights into disease pathogenesis. This has unearthed a plethora of attractive targets for the development of future therapeutics. Insights into the natural history of these complex diseases will follow and may enable appropriate patient selection for early aggressive therapy with the view to modifying the disease course.
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PMID:Genetics of inflammatory bowel disease: implications for disease pathogenesis and natural history. 1981 73

The Signal Transducers and Activators of Transcription (STAT)-Janus kinase (JAK) pathway controls signal transduction between cell surface receptors and the nucleus. Two members of that pathway, STAT3 and JAK2, enhanced the risk of Crohn's disease (CD) in recent genome-wide association studies. We replicated these findings in a New Zealand Caucasian case-control cohort, by genotyping two single nucleotide polymorphisms (SNPs) in STAT3 (rs744166(G>A) and rs3816769(C>T)) and rs10758669(A>C) in JAK2, in 302 CD patients and 382 controls. For STAT3, there was a significant decrease in the frequency of the G allele of rs744166 and the C allele of rs3816769 in CD patients as compared with controls (OR=0.76, 95% CI=0.61-0.95, p=0.013; OR=0.71, 95% CI=0.56-0.89, p=0.003). For the JAK2 rs10758669 polymorphism, the homozygous C/C or heterozygous A/C genotypes increased the risk of having CD as compared with the homozygous A/A (OR=1.76, 95% CI=1.26-2.45 and OR=2.36, 95% CI=1.44-3.86, respectively, p=0.0003). Variant alleles in either gene significantly modified the likelihood of inflammatory disease in a colonic location, and of developing extra-intestinal manifestations. The JAK2 variant also strongly enhanced the risk of ileocolonic disease, with stricturing or ileal/stricturing behaviour, requiring a bowel resection. We further studied a subset of our control population, stratified for JAK2 rs10758669 and/or STAT3 rs3816769 genotype. Carrying either the JAK2 or STAT3 IBD risk allele was associated with significantly enhanced susceptibility to DNA damage, as estimated by comet assays in peripheral blood leukocytes, with or without a subsequent oxidative challenge. That is, both risk alleles enhance genomic instability. The JAK2 SNP is part of a haplotype previously associated with enhanced susceptibility to myeloproliferative neoplasms, but functional consequences of the STAT3 variant had not been previously demonstrated. It will be of interest to follow up CD patients carrying either JAK2 or STAT3 risk alleles for development of further secondary effects, including cancer.
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PMID:Genetic factors in chronic inflammation: single nucleotide polymorphisms in the STAT-JAK pathway, susceptibility to DNA damage and Crohn's disease in a New Zealand population. 2010 74

JAK2 and STAT3 polymorphisms have been implicated to be associated with inflammatory bowel disease, which might share common immunogenesis and genetic factors with AS. Here, we have investigated the possible relationship of JAK2 and STAT3 polymorphisms with AS in a Chinese Han population. We genotyped 200 AS patients and 200 healthy controls for 4 polymorphisms in JAK2 and 6 in STAT3 using the chip-based matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. There was no difference in the distribution of allele and genotype in either JAK2 or STAT3 between AS groups and controls. Haplotype analysis revealed an association of haplotype rs1536798/rs10119004/rs7857730-CGT in JAK2 locus with AS. In conclusion, we first demonstrated the association of JAK2 polymorphisms with the susceptibility of AS, which indicated that IL-23 pathway also was an important etiological factor in AS in Chinese population.
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PMID:Analysis of JAK2 and STAT3 polymorphisms in patients with ankylosing spondylitis in Chinese Han population. 2062 14

Chronic inflammation is commonly present in gastrointestinal mucosal sites at increased risk for cancer, such as in inflammatory bowel disease (IBD) or chronic gastritis caused by Helicobacter pylori infection. Why some patients have more mucosal inflammation than others, and why certain individuals with chronic inflammation develop cancer, are problems that have not been solved. Unlike the case for the syndromic forms of familial colorectal cancer (CRC), the risks for IBD and other forms of chronic inflammation have not been linked to highly penetrant single gene mutations. Single nucleotide polymorphisms (SNP) are variations in DNA sequence that can be linked to any phenotype (cancer, chronic inflammation, etc.) in genome-wide association studies (GWAS). CRC has been linked to several highly penetrant single gene loci, as well as multiple SNP. The propensity to develop IBD has not been linked to single gene mutations in most instances, but has been linked to SNP in the NOD2 locus (which appear to create hypomorphic alleles for this bacterial response gene), the IL23R locus, the autophagy gene ATG16L1 and a wide range of other loci including the Toll-like receptors, JAK2 and STAT3, and perhaps 70 more. At present, the problem in predicting risk for chronic inflammation is that there are many genetic polymorphisms with relatively modest individual effects. Our challenge is to understand how the SNPs that are linked to variations in the inflammatory response interact with one another (i.e. to understand the 'epistasis' involved), and to integrate this with the variety of individual environmental exposures. This represents an opportunity for informatics science to help personalize our approach to chronic inflammatory diseases of the gut and identify those at greatest risk for cancer.
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PMID:Chronic inflammation, colorectal cancer and gene polymorphisms. 2108 7


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