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 functional receptor for the flavivirus West Nile (WNV) infection has been characterized in this study with a combination of biochemical and molecular approaches. A 105-kDa protease-sensitive glycoprotein that binds WNV was isolated from the plasma membrane of cells permissive to WNV infection. The protein was subjected to peptide sequencing, and this glycoprotein was identified as a member of the integrin superfamily. Infection of WNV was shown to be markedly inhibited in Vero cells pretreated with blocking antibodies against alpha(v)beta(3) integrin and its subunits by receptor competition assay. It was also noted that cells pretreated with antibodies against alpha(v)beta(3) integrin can effectively inhibit flavivirus Japanese encephalitis but to a lesser extent flavivirus dengue infections. West Nile virus entry is independent of divalent cations and is not highly blocked by arginine-glycine-aspartic acid (RGD) peptides, suggesting that the interaction between the virus and alpha(v)beta(3) integrin is not highly dependent on the classical RGD binding motif. In addition, gene silencing of the beta(3) integrin subunit in cells has resulted in cells largely resistant to WNV infection. In contrast, expression of recombinant human beta(3) integrin substantially increased the permissiveness of CS-1 melanoma cells for WNV infection. Soluble alpha(v)beta(3) integrin can also effectively block WNV infection in a dose-dependent manner. Furthermore, WNV infection also triggered the outside-in signaling pathway via the activation of integrin-associated focal adhesion kinase. The identification of alpha(v)beta(3) integrin as a receptor for WNV provides insight into virus-receptor interaction, hence creating opportunities in the development of anti-viral strategies against WNV infection.
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PMID:Interaction of West Nile virus with alpha v beta 3 integrin mediates virus entry into cells. 1547 43

Theileria parasites infect and transform bovine lymphocytes, but host cell immortalization is reversible, as upon parasite death the lymphocytes rapidly die of apoptosis. Infection leads to a marked augmentation in the levels of lymphocyte c-Myc, and the parasite achieves this by inducing increased c-myc transcription and by prolonging the half-life of the transcription factor. Reduction in c-Myc turnover can be ascribed to CK2-mediated phosphorylation of the transcription factor. A parasite-dependent GM-CSF autocrine loop activates a JAK2/STAT3 signalling pathway that contributes to heightened c-myc transcription, and inhibition of the pathway leads to caspase 9 activation and apoptosis that can be directly ascribed to a reduction in c-Myc. An antiapoptotic role for c-Myc was clearly demonstrated by specific inhibition of c-myc expression with antisense oligonucleotides, and this correlates with loss of the antiapoptotic protein Mcl-1, and, consistently, ectopic expression of c-Myc abrogates B-cell death induced upon JAK2 inhibition. Thus, Theileria parasites ensure the survival of their host lymphocytes via specific activation of c-Myc.
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PMID:c-Myc activation by Theileria parasites promotes survival of infected B-lymphocytes. 1558 Feb 87

The current strategy of offering HIV testing to individuals with known risk has had no impact on the reduction in the number of patients diagnosed with immune suppression of infection. A prospective observational study to compare the baseline CD4+ T-cell counts in HIV-infected homosexual/bisexual men, intravenous drug users, heterosexual men and women diagnosed in GUM/RIDU and that of patients diagnosed during routine maternal screening for HIV between December 1999 and January 2003 was carried out at the Departments of Genitourinary Medicine (GUM), Regional Infectious Disease Unit (RIDU) and Obstetrics in Edinburgh. Late presentation was defined as positive HIV test with baseline CD4+ T-cell count of less than 200 cells/mL. During the study period, 189 patients tested in GUM/RIDU setting and 13 screened women were diagnosed with HIV infection. Thirty-four percent of the former and 38% of the latter group had CD4+ T-cell count of less than 200 cells/mL by the time of diagnosis. Heterosexual individuals contributed to 78% of HIV tests in the GUM/RIDU setting. Amongst the 78 HIV-infected heterosexual individuals diagnosed in GUM/RIDU 45% were late presenters. Significantly fewer homosexual men were late presenters. There was no difference between the proportion of late presenters amongst women screened at the antenatal (5/13) compared to heterosexual patients diagnosed in GUM/RIDU (35/78). A significant number of HIV infected heterosexual patients are late presenters in the HIV testing at GUM/RIDU. HIV screening programmes for heterosexual individuals in any medical encounter may reduce the number of late presenters.
Int J STD AIDS 2004 Dec
PMID:Heterosexual men and women with HIV test positive at a later stage of infection than homo- or bisexual men. 1560 87

Few studies have reported on sexually transmitted infections at the US-Mexico border, so the prevalence of Chlamydia trachomatis in this population remains uncertain. This binational project investigated the prevalence of, and risk factors for, C. trachomatis among women along the Arizona, US-Sonora, Mexico border. Women who self-referred for routine gynaecological care were invited to complete an interviewer-administered questionnaire and to undergo a Pap smear, C. trachomatis test, and HPV test. In 2270 women, C. trachomatis prevalence overall was 8.2% as measured by hybrid capture and 2.6% by enzyme immunoassay. Infection was associated with young age, a history of new sexual partner(s) in the previous three months, HPV infection, and proximity of clinic to the international border. Antibiotic use in the previous 30 days was associated with decreased odds of infection. Women in Arizona-Sonora border communities are at increased risk for C. trachomatis infection compared to women attending clinics in non-border locations.
Int J STD AIDS 2004 Dec
PMID:Chlamydial infection in women along the US-Mexico border. 1560 88

Philadelphia (Ph) chromosome-positive acute myelogenous leukemia (AML) is a rare disease that is resistant to conventional antitumor chemotherapy and has a poor prognosis. We describe a case of Ph chromosome-positive AML in which imatinib mesylate was used and a favorable outcome was obtained.A 64-year-old man was found to have Ph chromosome-positive, minor BCR-ABL-positive AML. Remission could not be induced by remission induction therapy with antitumor agents. Because the patient had a serious concomitant infectious disease, administration of 600 mg/day of imatinib mesylate, a specific inhibitor of BCR-ABL tyrosine kinase, was started after written informed consent was obtained. Complete cytogenetic response (CCR) was achieved without serious adverse events and persisted for more than 1 year. Our results suggested that imatinib mesylate was very useful for treating Ph chromosome-positive AML.
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PMID:Successful treatment with imatinib mesylate in a case of minor BCR-ABL-positive acute myelogenous leukemia. 1581 35

Development of strategies to prevent herpes simplex virus (HSV) infection requires knowledge of cellular pathways harnessed by the virus for invasion. This study demonstrates that HSV induces rapid phosphorylation of focal adhesion kinase (FAK) in several human target cells and that phosphorylation is important for entry post-binding. Nuclear transport of the viral tegument protein VP16, transport of viral capsids to the nuclear pore, and downstream events (including expression of immediate-early genes and viral plaque formation) were substantially reduced in cells transfected with dominant-negative mutants of FAK or small interfering RNA designed to inhibit FAK expression. These observations were substantiated using mouse embryonic fibroblast cells derived from embryonic FAK-deficient mice. Infection was reduced by >90% in knockout cells relative to control cells and was further reduced if the knockout cells were transfected with small interfering RNA targeting proline-rich tyrosine kinase-2, which was also phosphorylated in response to HSV. The knockout cells were permissive for viral binding, and virus triggered an intracellular calcium response, but nuclear transport was inhibited. Together, these results support a novel model for invasion that implicates FAK phosphorylation as important for delivery of viral capsids to the nuclear pore.
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PMID:Focal adhesion kinase plays a pivotal role in herpes simplex virus entry. 1599 12

Our objective was to analyse the characteristics of patients who were unaware of their HIV infection until they developed AIDS, in the period after introduction of highly active antiretroviral therapy. The complete national register of HIV and AIDS cases reported to the Department of Epidemiology at the Swedish Institute for Infectious Disease Control 1996-2002 was searched for cases diagnosed with HIV less than three months before AIDS diagnosis (so-called "late testers"). Of a total of 487 patients with AIDS, reported during the seven-year period, 219 (45%) were late testers. Their proportion of all AIDS cases increased from 22% in 1996 to 58% in 2002. Heterosexual route of transmission, age greater than 40 years, and foreign origin were all significant risk factors for being a late tester. Intravenous drug users were associated with a highly significant reduced risk. The group without previously known HIV infection represents an increasing part of all cases of AIDS. From a disease control and from a medical perspective, it is important to study this group further and discover what measures are needed for earlier identification and access to medical care.
Int J STD AIDS 2005 Oct
PMID:Patients unaware of their HIV infection until AIDS diagnosis in Sweden 1996-2002--a remaining problem in the highly active antiretroviral therapy era. 1621 20

During the past decade, we have observed advance in tuberculosis research including novel vaccines, innate immunity (TLR), SNIP analysis and molecular mechanism of drug resistance. Worldwide genome project enabled the whole genome sequence of host resistant against tuberculosis as well as the whole genome sequence of M. tuberculosis H37Rv. DNA technology has also provided a great impact on the development of novel vaccine against TB. In this symposium, we have invited leading researchers in the field of the frontier study of Mycobacterium research in order to provide general overview of the cutting edge of frontier research. Molecular mechanism of drug resistance of M. tuberculosis has been clarified. On the other hand, molecular mechanism of host-defence (insusceptibility of host) against M. tuberculosis has not yet elucidated. Dr. Taro Shirakawa (Kyoto University) reviewed the susceptibility genes of host in TB infection and presented candidate genes associated with multi-drug resistant tuberculosis. Dr. Naoto Keicho (International Medical Center of Japan) tried to identify host genetic factors involved in susceptibility to pulmonary Mycobacterium avium complex (MAC) infection by candidate gene approach and genome-wide approach. In Japan, Dr. Masaji Okada (National Hospital Organization Kinki-Chuo Chest Medical Center) has been engaged actively in the development of new tuberculosis vaccines (HVJ-liposome/Hsp65 DNA + IL-12 DNA vaccine and recombinant 72f BCG vaccine). He showed basic strategy for construction of new candidate vaccines and also showed significant efficacy on the protection of tuberculosis infection using cynomolgus monkeys, which are very similar to human tuberculosis. Dr. Hatsumi Taniguchi (University of Occupational and Environmental Health) presented that M. tuberculosis mIHF and the neighbor genes went into a dormacy-like state of M. smegmatis in J774 macrophage cells. This study might provide a weapon for elucidating the mechanism of dormacy of M. tuberculosis and the development of novel therapy. Dr. Chiyoji Abe (Nippon Becton Dickinson Co.) reviewed the molecular basis of the resistance to anti-tuberculosis drugs. Most cases of resistance are related to simple nucleotide substitutions rather than to acquisition of new elements. Dr. Kiyoshi Takeda (Kyushu University) showed interesting finding. He analyzed whether Toll-like receptor (TLR)-mediated activation of innate immunity in host defense against mycobacterial infection. MyD88/TRIF double defi-indicating that innate immunity is involved in anti-mycobacterial infection. (1) SNP (single nucleotide polymorphism) analysis in association with Mycobacterium tuberculosis: Taro SHIRAKAWA (Department of Health Promotion & Human Behavior, Kyoto University Medical School, and RIKEN SRC Center) Candidate gene approach was made on 18 SNPs in 11 genes in association with M. tuberculosis. Patients with multi-drug resistance against M. tuberculosis are also subjected. SNPs in NRAMP1 gene were associated with the disease, and drug resistance, its mechanisms remain unknown. (2) Search for genes susceptible to pulmonary Mycobacterium avium complex infection: Naoto KEICHO (Department of Respiratory Diseases, Research Institute, International Medical Center of Japan) Interaction among pathogens and host factors is important for development of infectious diseases. We are trying to identify host genetic factors involved in susceptibility to nonimmunocompromized pulmonary Mycobacterium avium complex (MAC) infection by candidate gene approach and genome-wide approach. Elucidation of functional significance of susceptibility gene polymorphisms will lead to a new strategy for control and prevention of the disease. (3) T cell immunity against Tuberculosis in host and the establishment of novel vaccine: Masaji OKADA (Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center) T cell (CTL, Th1) immunity including granulysin play an important role in host defense against tuberculosis (TB) in human. Patients with TB or Multi-drug resistant TB showed suppression of all these immunities. HVJ-liposome/Hsp65 DNA + IL-12 DNA vaccination was 100 fold more efficient than BCG on the elimination of Mycobacterium tuberculosis (M.TB) in the BALB/c mice. Cytotoxic T cells activity against M. TB was augmented. By using these new vaccines (Hsp 65 DNA + IL-12 DNA, recombinant 72f BCG) and the cynomolgus monkey models which are very similar to human tuberculosis, the prophylactic effect of vaccines was observed. Thus, these novel vaccines should provide a useful tool for the prevention of human TB infection. (4) Mycobacterium tuberculosis mIHF and the neighbor genes go into a dormancy-like state of M. smegmatis J15CS in J774 cells: Hatsumi TANIGUCHI (Department of Microbiology, School of Medicine, University of Occupational and Environmental Health) Mycobacterium smegmatis J15CS transformants harboring the mIHF gene or the mIHF-gmk-Rv1390 genes showed no difference in in vitro growth and acid-fastness. However, transformants harboring mIHF-gmk-Rv1390 formed short-rod cell morphology and decreased acid-fastness in the mouse macrophage-like cell line J774 compared to those of the other transformants, and the nuclei of the infected J774 cells also changed. Nevertheless, the colony forming units were similar. These indicate that mIHF and the neighbor genes of M. tuberculosis might regulate a growth of mycobacteria in macrophages. (5) Molecular basis of the resistance to anti-tuberculosis drugs: Chiyoji ABE (Nippon Becton Dickinson Company, Ltd.) Considerable progress has been made toward understanding the molecular basis of the resistance to anti-tuberculosis drugs. Most cases of resistance are related usually to simple nucleotide substitutions rather than to acquisition of new elements. Multi-drug resistant isolates of Mycobacterium tuberculosis arise a consequence of sequential accumulation of mutation conferring resistance to single therapeutic agents. The basis of resistance is not able to be explained yet in a substantial percentage of strains for other anti-tuberculosis drugs than rifampin and pyrazinamide. Further studies are required to fully understand the molecular mechanisms of resistance. (6) Toll-like receptors in anti-mycobacterial immune responses: Kiyoshi TAKEDA (Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University) Toll-like receptors (TLRs) play an essential role in the recognition of specific patterns of microbial components. TLRs mediate activation of innate immunity and further development of antigen-specific adaptive immunity. In TLR signaling pathways, Toll/IL-1 receptor (TIR) domain-containing adaptors, such as MyD88, TIRAP, TRIF, and TRAM, have been shown to play pivotal roles. Thus, the molecular mechanisms for TLR-mediated activation of innate immunity have been largely understood. We analyzed whether TLR-mediated activation of innate immunity is involved in host defense against mycobacterial infection. MyD88/TRIF double deficient mice, in which TLR-dependent activation of innate immunity is abolished, showed high sensitivity to mycobacterial infection, indicating that innate immunity is critically involved in anti-mycobacterial responses.
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PMID:[Frontier of mycobacterium research--host vs. mycobacterium]. 1624 93

Infection with cagA-positive Helicobacter pylori (H. pylori) is associated with atrophic gastritis, peptic ulcer, and gastric adenocarcinoma. The cagA gene product CagA is translocated from H. pylori into gastric epithelial cells and undergoes tyrosine phosphorylation by Src family kinases (SFKs). Tyrosine-phosphorylated CagA binds and activates SHP-2 phosphatase and the C-terminal Src kinase (Csk) while inducing an elongated cell shape termed the "hummingbird phenotype." Here we show that CagA reduces the level of focal adhesion kinase (FAK) tyrosine phosphorylation in gastric epithelial cells. The decrease in phosphorylated FAK is due to SHP-2-mediated dephosphorylation of FAK at the activating phosphorylation sites, not due to Csk-dependent inhibition of SFKs, which phosphorylate FAK. Coexpression of constitutively active FAK with CagA inhibits induction of the hummingbird phenotype, whereas expression of dominant-negative FAK elicits an elongated cell shape characteristic of the hummingbird phenotype. These results indicate that inhibition of FAK by SHP-2 plays a crucial role in the morphogenetic activity of CagA. Impaired cell adhesion and increased motility by CagA may be involved in the development of gastric lesions associated with cagA-positive H. pylori infection.
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PMID:Focal adhesion kinase is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA. 1635 97

Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8) interacts with cell surface alpha3beta1 integrin early during in vitro infection of human endothelial cells and fibroblasts and activates the focal adhesion kinase (FAK) that is immediately downstream in the outside-in signaling pathway by integrins, leading to the activation of several downstream signaling molecules. In this study, using real-time DNA and reverse transcription-PCR assays to measure total internalized viral DNA, viral DNA associated with infected nuclei, and viral gene expression, we examined the stage of infection at which FAK plays the most significant role. Early during KSHV infection, FAK was phosphorylated in FAK-positive Du17 mouse embryonic fibroblasts. The absence of FAK in Du3 (FAK(-/-)) cells resulted in about 70% reduction in the internalization of viral DNA, suggesting that FAK plays a role in KSHV entry. Expression of FAK in Du3 (FAK(-/-)) cells via an adenovirus vector augmented the internalization of viral DNA. Expression of the FAK dominant-negative mutant FAK-related nonkinase (FRNK) in Du17 cells significantly reduced the entry of virus. Virus entry in Du3 cells, albeit in reduced quantity, delivery of viral DNA to the infected cell nuclei, and expression of KSHV genes suggested that in the absence of FAK, another molecule(s) may be partially compensating for FAK function. Infection of Du3 cells induced the phosphorylation of the FAK-related proline-rich tyrosine kinase (Pyk2) molecule, which has been shown to complement some of the functions of FAK. Expression of an autophosphorylation site mutant of Pyk2 in which Y402 is mutated to F (F402 Pyk2) reduced viral entry in Du3 cells, suggesting that Pyk2 facilitates viral entry moderately in the absence of FAK. These results suggest a critical role for KSHV infection-induced FAK in the internalization of viral DNA into target cells.
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PMID:Focal adhesion kinase is critical for entry of Kaposi's sarcoma-associated herpesvirus into target cells. 1641 94


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