Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD44 is involved in leukocyte migration and activation and has recently been reported to contribute to leukocyte extravasation by associating with CD49d. We explored whether similar changes in CD44 activity are seen in vivo using murine alopecia areata (AA) as a chronic, organ-related autoimmune disease model system. Expression of the activated, hyaluronan-binding form of CD44, and of CD49d, was elevated in draining lymph node cells (LNC) of AA-affected mice as compared to control mice. LNC of AA mice displayed increased motility, proliferative activity and apoptosis resistance, which were equally well inhibited by anti-CD44 and anti-CD49d. The latter is the sequelae of the association between CD44 and CD49d that is seen in activated lymphocytes. Significantly, due to CD44-CD49d complex formation, CD44 gains access to focal adhesion kinase and CD49d gains access to CD44-associated lck and ezrin, such that downstream kinases become activated via CD44 or CD49d engagement. Thus, by their association, CD44 and CD49d mutually avail themselves of the partner's signaling pathways and the ligand binding of each one triggers signaling pathways of both. This strongly influences the lymphocytes' activation state and function.
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PMID:In vivo CD44-CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance. 1703 68

PF-956980 is a selective inhibitor of JAK3, related in structure to CP-690550, a compound being evaluated in clinical trials for rheumatoid arthritis and prevention of allograft rejection. PF-956980 has been evaluated against a panel of 30 kinases, and found to have nanomolar potency against only JAK3. Cellular and whole blood activity of this compound parallels its potency and selectivity in enzyme assays. It was effective in vivo at inhibiting the delayed type hypersensivity reaction in mice. We compared 2 commercially available JAK3 inhibitors (WHI-P131 and WHI-P154) in the same panel of biochemical and cellular assays and found them to be neither potent nor selective for JAK3. Both were found to be nanomolar inhibitors of the EGF receptor family of kinases. As these compounds have been used in numerous publications in the transplant and autoimmune disease literature, their specificity should be considered when interpreting these results.
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PMID:The specificity of JAK3 kinase inhibitors. 1809 29

Ligation of T cell receptor (TCR) alone is insufficient to induce full activation of T lymphocytes. Additional ligand-receptor interactions (costimulation) on antigen presenting cells (APCs) and T cells are required. T cell costimulation has been shown to be essential for eliciting efficient T cell responses, involving all phases during T cell development. However, the mechanisms by which costimulation affects the function of T cells still need to be elucidated. In recent years, advances have been made in studies of costimulation as potential therapies in cancer, infectious disease as well as autoimmune disease. In this review, we discussed intracellular costimulation signals that regulate T cell proliferation, cell cycle progression, cytokine production, survival, and memory development. In general, the pathway of phosphoinositide-3 kinase (PI3K)/protein kinase B (PKB, also known as Akt)/nuclear factor kappaB (NF-kappaB) might be central to many costimulatory effects. Through these pathways, costimulation controls T-cell expansion and proliferation by maintenance of survivin and aurora B expression, and sustains long-term T-cell survival and memory development by regulating the expression of bcl-2 family members.
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PMID:Intracellular signals of T cell costimulation. 1876 11

High-resolution binding profiles were elucidated for anti-GM1 IgM autoantibodies from two patients with a progressive form of paraproteinemic polyneuropathy. Antibody-ligand interaction was characterized by generating STD-NMR signals in target ganglio-oligosaccharides added directly to patient sera, without the requirement of antibody fractionation. Both immunoglobulins were found to have similar binding modalities, with interaction confined to two distinct spatially separated regions of GM1: the terminal betaGal(1-3)betaGalNAc disaccharide unit and the sialic acid residue. We describe a unique and powerful biophysical technique applied to define the molecular interaction between autoimmune disease-causing antibodies and their ganglioside targets.
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PMID:STD-NMR used to elucidate the fine binding specificity of pathogenic anti-ganglioside antibodies directly in patient serum. 1910 26

Antiretroviral therapy (ART) inhibits HIV replication, allowing recovery of CD4+ T cell numbers and the restoration of immune function; its introduction has led to improved outcomes for individuals with HIV infection. However, it has been observed that some individuals responding to ART experience a clinical deterioration with symptoms and signs of an inflammatory illness. Immune reconstitution inflammatory syndrome (IRIS) results from pathological immune responses occurring during immune reconstitution. IRIS is best considered a group of disorders with a wide range of clinical manifestations, incorporating disease resulting from pathological inflammation to pathogens, immune-mediated inflammatory disease and autoimmune disease. Clinical effects range from a mild, self-limiting illness to severe morbidity and mortality. Clinicians working in the field of HIV medicine can expect to encounter individuals with IRIS. In this review, we discuss definitions, describe clinical presentations, summarize research relating to pathogenesis and identify risk factors, preventive and management strategies.
Int J STD AIDS 2009 Apr
PMID:Immune reconstitution inflammatory syndrome. 1930 62

Genetic variation was first shown to be important in systemic lupus erythematosus (SLE or lupus) in the 1970s with associations in the human leukocyte antigen region. Almost four decades later, and with the help of increasingly powerful genetic approaches, more than 25 genes are now known to contribute to the mechanisms that predispose individuals to lupus. Over half of these loci have been discovered in the past 2 years, underscoring the extraordinary success of genome-wide association approaches in SLE. Well-established risk factors include alleles in the major histocompatibility complex region (multiple genes), IRF5, ITGAM, STAT4, BLK, BANK1, PDCD1, PTPN22, TNFSF4, TNFAIP3, SPP1, some of the Fcgamma receptors, and deficiencies in several complement components, including C1q, C4 and C2. As reviewed here, many susceptibility genes fall into key pathways that are consistent with previous studies implicating immune complexes, host immune signal transduction and interferon pathways in the pathogenesis of SLE. Other loci have no known function or apparent immunological role and have the potential to reveal novel disease mechanisms. Certainly, as our understanding of the genetic etiology of SLE continues to mature, important new opportunities will emerge for developing more effective diagnostic and clinical management tools for this complex autoimmune disease.
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PMID:Recent insights into the genetic basis of systemic lupus erythematosus. 1944 Jan 99

Janus kinase 3 (JAK3) is a cytoplasmic tyrosine kinase associated with the common gamma chain that is activated by multiple T-cell growth factors including IL-2, -4, -9, -15, and -21. From the recent reports, genetic absence or ablation of JAK3 is associated with defective T-cell immunity that results in severe combined immunodeficiency (SCID) and pharmacological inhibition has prolonged allograft survival in some models of organ transplantation. This review would provide an overview of some patents along with the role of JAK3 in the immune system and efficacy of JAK3 inhibitors in experimental allograft rejection and autoimmune disease.
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PMID:JAK3 inhibitors in organ transplantation and autoimmune disease. 1983 95

Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33x10(-11), OR = 1.29; WDFY4: rs7097397, P = 8.15x10(-12), OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3'-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.
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PMID:Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. 2016 77

Inhibiting signal transduction induced by inflammatory cytokines offers a new approach for the treatment of autoimmune diseases such as rheumatoid arthritis. Kinase inhibitors have shown promising oral disease-modifying antirheumatic drug potential with efficacy similar to anti-TNF biologics. Direct and indirect inhibition of the JAKs, with small molecule inhibitors like CP-690,550 and INCB018424 or neutralizing Abs, such as the anti-IL6 receptor Ab tocilizumab, have demonstrated rapid and sustained improvement in clinical measures of disease, consistent with their respective preclinical experiments. Therefore, it is of interest to identify optimized JAK inhibitors with unique profiles to maximize therapeutic opportunities. INCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM). INCB028050 inhibits intracellular signaling of multiple proinflammatory cytokines including IL-6 and IL-23 at concentrations <50 nM. Significant efficacy, as assessed by improvements in clinical, histologic and radiographic signs of disease, was achieved in the rat adjuvant arthritis model with doses of INCB028050 providing partial and/or periodic inhibition of JAK1/JAK2 and no inhibition of JAK3. Diminution of inflammatory Th1 and Th17 associated cytokine mRNA levels was observed in the draining lymph nodes of treated rats. INCB028050 was also effective in multiple murine models of arthritis, with no evidence of suppression of humoral immunity or adverse hematologic effects. These data suggest that fractional inhibition of JAK1 and JAK2 is sufficient for significant activity in autoimmune disease models. Clinical evaluation of INCB028050 in RA is ongoing.
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PMID:Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. 2036 76

Autoimmune diseases are characterised by lymphoproliferation in target tissues with B and T lymphocytes often arranged in pseudofollicles, mimicking the structure of peripheral lymph nodes. Target organ tissue damage produces the clinical phenotype which may be diverse ranging from autoimmune endocrinopathies to malabsorption (coeliac disease) to structural damage within bones and joints (rheumatoid arthritis). Recently, B cell depletion has been shown to be effective in many autoimmune conditions suggesting a common pathological origin for these conditions which might be triggered by an autoimmune B cell that has escaped deletion. We postulate that a mutation in a transcription factor early in B cell development might allow persistence and foster proliferation of a clone of autoimmune B cells, capable of producing autoantibodies. A similar common mutation within the JAK2 tyrosine kinase gene has recently been described associated with the myeloproliferative disorders which are also characterised by diverse clinical disease phenotypes. There is considerable evidence that autoimmune diseases could be indolent lymphoproliferative disorders of B-cell origin, extending the forbidden clone hypothesis first proposed in the 1950s.
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PMID:B cell lymphoproliferation and organ-directed self-recognition to explain autoimmunity: back to the past. 2040 69


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