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)

Bacteremia is one of the leading causes of death by infectious disease. To understand the immune mechanisms required for the rapid control of bacteremia, we studied Borrelia hermsii, a bacterial pathogen that colonizes the blood stream of humans and rodents to an extremely high density. A T cell-independent IgM response is essential and sufficient for controlling B. hermsii bacteremia. Mice deficient in Bruton's tyrosine kinase (Btk), despite their known defect in BCR signaling, generated B. hermsii-specific IgM and resolved bacteremia, suggesting that an alternative activation or costimulatory pathway remained functional for T cell-independent B cells in Btk(-/-) mice. B. hermsii contains putative ligands for TLRs, and we found that mice deficient in TLR1, TLR2, or the TLR adaptor MyD88 generated anti-B. hermsii IgM with delayed kinetics and suffered more severe episodes of bacteremia. In striking contrast to the anti-B. hermsii IgM response in mice deficient only in Btk, mice deficient in both Btk and MyD88 were entirely incapable of generating B. hermsii-specific Ab or resolving bacteremia. The response to a T cell-dependent model Ag was unaffected in Btk(-/-) x MyD88(-/-) mice. These results suggest that MyD88 specifically promotes T cell-independent BCR signaling and that, in the absence of Btk, this TLR-mediated stimulation is a required component of this signal.
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PMID:MyD88- and Bruton's tyrosine kinase-mediated signals are essential for T cell-independent pathogen-specific IgM responses. 1733 72

Malakoplakia is an uncommon granulomatous infectious disease that is found primarily in the genitourinary tract, but may rarely involve the skin. We report a case of cutaneous malakoplakia in an HIV-positive patient diagnosed on the basis of Michaelis-Gutman bodies. The patient presented with ulcers, draining sinuses and tender papules and nodules mainly on perigenital area, buttocks and right thigh.
Int J STD AIDS 2007 Jun
PMID:Cutaneous malakoplakia in an HIV-positive patient. 1760 43

Infection of keratinocytes with high risk human Papilloma virus causes immortalization, and when followed by further mutations, leads to cervical cancer and other anogenital tumors. Here we monitor the progressive loss of robustness in an in vitro model of the early stages of transformation that comprises normal keratinocytes and progressive passages of HPV16 immortalized cells. As transformation progresses, the cells acquire higher proliferation rates and gain the ability to grow in soft agar. Concurrently, the cells lose robustness, becoming more sensitive to serum starvation and DNA damage by Cisplatin. Loss of robustness in the course of transformation correlates with significant reductions in the activities of the anti-apoptotic proteins PKB/Akt, Erk, Jnk and p38 both under normal growth conditions and upon stress. In parallel, loss of robustness is manifested by the shrinkage of the number of growth factors that can rescue starving cells from apoptosis, with the emergence of dependence solely on IGF1. Treatment with IGF1 activates PKB/Akt and Jnk and through them inhibits p53, rescuing the cells from starvation. We conclude that transformation in this model induces higher susceptibility of cells to stress due to reduced anti-apoptotic signaling and hyper-activation of p53 upon stress.
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PMID:Loss of robustness and addiction to IGF1 during early keratinocyte transformation by human Papilloma virus 16. 1762 50

Understanding the epidemiologic definition of epidemic versus non-epidemic spread of an infectious disease agent and the different patterns of heterosexual HIV transmission are needed to fully understand the low potential for heterosexual HIV epidemics in most heterosexual populations. Epidemic sexual HIV transmission can occur only in populations where there are large numbers of persons who have unprotected sex with multiple and concurrent sex partners. How high HIV prevalence may reach in these populations depends on the size and overlap of sex networks, and the prevalence of facilitating and protective factors that can greatly increase or limit the amount of infected blood and sexual fluids exchanged during intercourse. The wide difference in potentials for heterosexual HIV epidemics that exists within and between countries must be recognized, accepted and monitored in order to design and focus prevention strategies where they are most needed and most effective.
Int J STD AIDS 2007 Aug
PMID:Heterosexual HIV transmission dynamics: implications for prevention and control. 1768 10

Reovirus infection provides a classic experimental model system for studying the pathogenesis of viral infections of the central nervous system (CNS), with apoptosis acting as the major mechanism of cell death. The authors have examined the role of signal transducer and activator of transcription (STAT)1, a component of Janus-activated kinase (JAK)-STAT signaling, a pathway implicated in antiviral responses and pathways regulating apoptosis, following reovirus infection. Infection of primary cortical neuron cultures with reovirus serotype 3 strain Abney (T3A) resulted in phosphorylation of STAT1 at sites critical for transcriptional activity. Activated STAT1 was also detected in the brain of neonatal mice following T3A infection, with a nuclear pattern of expression in areas of virus-induced injury. Activation of STAT proteins is typically mediated by JAKs. The authors observed JAK2 phosphorylation (Tyr 1007/1008) in brain lysates from T3A-infected mice. Inhibition of JAK activity with the inhibitor AG-490 blocked reovirus-induced STAT1 activation in neuronal cultures, indicating reovirus-induced STAT activation is JAK dependent. Pretreatment of neuronal cultures with antibody raised against interferon (IFN)-alpha/betaR2 inhibited T3A-induced STAT1 phosphorylation, whereas neither IFN-gamma or IFN-gammaR2 antibody pretreatment had any effect on T3A-induced STAT1 phosphorylation. Mice lacking the STAT1 gene demonstrated increased susceptibility to reovirus infection, with increased mortality and higher viral titers in the brain compared to wild-type animals. The results demonstrate activation of a type I IFN-mediated, JAK-dependent STAT signaling pathway following reovirus infection and suggest that STAT1 is a key component of host defense mechanisms against reovirus infection in the brain.
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PMID:JAK-STAT signaling pathways are activated in the brain following reovirus infection. 1784 21

Sexually transmitted infection (STI), including AIDS disproportionately affects minority women with a history of physical or sexual abuse. The objective of this study was to evaluate the efficacy of gender- and culture-specific behavioural interventions and interactive STI counselling for high-risk minority women with a history of physical or sexual abuse over two years. African- and Mexican-American women with a non-viral STI were enrolled in a randomized trial. Follow-up screens and interviews occurred at six months and one and two years. The primary outcome was subsequent infection with chlamydia and/or gonorrhoea. Secondary analysis of primary outcomes was made by self-reported physical or sexual abuse. Logistic regression was utilized on an intention-to-treat basis. Baseline data from 853 women were included; the retention rate was 91%. Infection rates were higher in abused women in Year 1 (29% vs. 23.8%, P=0.12), Year 2 (23.4% vs.17.6%, P=0.03) and cumulatively (43.8% vs. 33.0%, P=0.003). Unadjusted association between abuse and reinfection was stronger for adolescents (<19 years) than adults in Year 1 (42.7% vs. 30.8%, P=0.03), Year 2 (32.7% vs. 22.0%, P=0.03) and cumulatively (59.4% vs. 43.3%, P=0.004). Corresponding rates for adults were Year 1 (17.8% vs. 17.0%, P=0.84), Year 2 (17.4% vs. 12.7%, P=0.23) and cumulatively (30.7% vs. 22.3%, P=0.08). Reinfection rates were further stratified by adolescence and substance use. Abused adolescents had consistently higher reinfection than non-abused adolescents and abused adults. In conclusion, risk-reduction interventions decreased infective episodes with chlamydia and/or gonorrhoea in the two-year study period for non-abused women. Abused women, particularly adolescents and substance users, had increased episodes in these study periods.
Int J STD AIDS 2007 Nov
PMID:Behavioural interventions and abuse: secondary analysis of reinfection in minority women. 1800 8

The initial signalling events leading to Helicobacter pylori infection associated changes in motility, cytoskeletal reorganization and elongation of gastric epithelial cells remain poorly understood. Because focal adhesion kinase (FAK) is known to play important roles in regulating actin cytoskeletal organization and cell motility we examined the effect of H. pylori in gastric epithelial cells co-cultured with H. pylori or its isogenic cag pathogenicity island (PAI) or oipA mutants. H. pylori induced FAK phosphorylation at distinct tyrosine residues in a dose- and time-dependent manner. Autophosphorylation of FAK Y397 was followed by phosphorylation of Src Y418 and resulted in phosphorylation of the five remaining FAK tyrosine sites. Phosphorylated FAK and Src activated Erk and induced actin stress fibre formation. FAK knock-down by FAK-siRNA inhibited H. pylori-mediated Erk phosphorylation and abolished stress fibre formation. Infection with oipA mutants reduced phosphorylation of Y397, Y576, Y577, Y861 and Y925, inhibited stress fibre formation and altered cell morphology. cag PAI mutants reduced phosphorylation of only FAK Y407 and had less effect on stress fibre formation than oipA mutants. We propose that activation of FAK and Src are responsible for H. pylori-induced induction of signalling pathways resulting in the changes in cell phenotype important for pathogenesis.
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PMID:OipA plays a role in Helicobacter pylori-induced focal adhesion kinase activation and cytoskeletal re-organization. 1806 7

Human primary immunodeficiencies impairing myeloid and/or lymphoid cellular responses to activating receptors other than antigen receptors have recently been described in children with various infectious diseases. Germline mutations in NEMO and IKBA impair NF-kappaB-mediated signalling, at least in response to the stimulation of TLRs, IL-1Rs and TNFRs, and confer a broad predisposition to infections. Mutations in IRAK4 selectively impair TLRs other than TLR3 and most IL-1R responses, and confer a predisposition to pyogenic bacterial diseases, including invasive pneumococcal disease in particular. Mutations in TLR3 and UNC93B1 impair TLR3 responses and confer a predisposition to herpes simplex encephalitis. Mutations in STAT1 impair IFN-gamma and/or IFN-alpha/beta responses and predispose subjects to mycobacterial and viral diseases, respectively. Mutations in IFNGR1 and IFNGR2 impair IFN-gamma responses and confer a predisposition to mycobacterial diseases. Mutations in IL12B and IL12RB1 impair IL-12 and IL-23 responses and predispose subjects to infections caused by mycobacteria and Salmonella. Finally, mutations in TYK2 and STAT3 mostly impair IL-6R responses, conferring a predisposition to staphylococcal disease in particular. The infectious phenotypes associated with these novel leukocyte activation deficiencies are therefore collectively diverse, tightly dependent on the morbid gene and affected pathway, and individually narrow, often restricted to one or a few infectious diseases.
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PMID:Novel primary immunodeficiencies revealed by the investigation of paediatric infectious diseases. 1808 7

Applications of molecular diagnostics to oncology have been slow to make their way to the clinical laboratory. While numerous genes and mutation spectra have been found to be involved in tumorigenesis, it is only recently that these findings begin to become useful in a clinical setting. Building on the technical knowledge obtained from molecular infectious disease testing, new instruments and assays have been developed to answer similar questions regarding qualitative, quantitative and genotyping issues. In this manuscript we describe two current examples of clinical molecular diagnostic applications, the assessment of BCR-ABL in chronic myelogenous leukemia patients and the detection of tumor cells in the sentinel lymph nodes of breast cancer patients, to demonstrate the role of molecular techniques in a routine clinical setting.
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PMID:Molecular oncology: current trends in diagnostics. 1824 Oct 1

TGF-beta1 and its target gene encoding plasminogen activator inhibitor-1 (PAI-1) are major causative factors in the pathology of tissue fibrosis and vascular disease. The increasing complexity of TGF-beta1 action in the cardiovascular system requires analysis of specific TGF-beta1-initiated signaling events that impact PAI-1 transcriptional regulation in a physiologically-relevant cell system. TGF-beta1-induced PAI-1 expression in both primary cultures and in an established line (R22) of vascular smooth muscle cells (VSMC) was completely blocked by inhibition of epidermal growth factor receptor (EGFR) activity or adenoviral delivery of a kinase-dead EGFR(K721A) construct. TGF-beta1-stimulated PAI-1 expression, moreover, was preceded by EGFR phosphorylation on Y845 (a src kinase target residue) and required pp60(c-src) activity. Infection of VSMC with an adenovirus encoding the EGFR(Y845F) mutant or transfection with a dominant-negative pp60(c-src) (DN-Src) expression vector effectively decreased TGF-beta1-stimulated, but not PDGF-induced, PAI-1 expression implicating the pp60(c-src) phosphorylation site EGFR(Y845) in the inductive response. Consistent with these findings, TGF-beta1 failed to induce PAI-1 synthesis in src kinase-deficient (SYF(-/-/-)) fibroblasts and reexpression of a wild-type pp60(c-src) construct in SYF(-/-/-) cells rescued the PAI-1 response to TGF-beta1. TGF-beta1-induced EGFR activation, but not SMAD2 activation, moreover, was virtually undetectable in SYK(-/-/-) fibroblasts in comparison to wild type (SYK(+/+/+)) counterparts, confirming an upstream signaling role of src family kinases in EGFR(Y845) phosphorylation. Genetic EGFR deficiency or infection of VSMCs with EGFR(K721A) virtually ablated TGF-beta1-stimulated ERK1/2 activation as well as PAI-1 expression but not SMAD2 phosphorylation. Transient transfection of a dominant-negative RhoA (DN-RhoA) expression construct or pretreatment of VSMC with C3 transferase (a Rho inhibitor) or Y-27632 (an inhibitor of p160ROCK, a downstream effector of Rho) also dramatically attenuated the TGF-beta1-initiated PAI-1 inductive response. In contrast to EGFR pathway blockade, interference with Rho/ROCK signaling effectively inhibited TGF-betaR-mediated SMAD2 phosphorylation and nuclear accumulation. TGF-beta1-stimulated SMAD2 activation, moreover, was not sufficient to induce PAI-1 expression in the absence of EGFR signaling both in VSMC and mouse embryonic fibroblasts. Thus, two distinct pathways involving the EGFR/pp60(c-src)/MEK-ERK pathway and Rho/ROCK-dependent SMAD2 activation are required for TGF-beta1-induced PAI-1 expression in VSMC. The identification of such novel interactions between two TGF-beta1-activated signaling networks that specifically impact PAI-1 transcription in VSMC may provide therapeutically-relevant targets to manage the pathophysiology of PAI-1-associated cardiovascular/fibrotic diseases.
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PMID:TGF-beta1-induced plasminogen activator inhibitor-1 expression in vascular smooth muscle cells requires pp60(c-src)/EGFR(Y845) and Rho/ROCK signaling. 1825 94


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