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)

Cytomegalovirus (CMV) colitis is a well recognized complication of advanced HIV disease and is only rarely diagnosed in patients with normal immune function. A case of CMV colitis occurring in early HIV infection is described. Although CMV infection is normally confined to patients with advanced HIV disease, it is possible that a number of contributing factors may have led to clinical disease in this patient. CMV colitis is an important diagnosis to consider in all patients who present with a diarrhoeal illness associated with systemic features, regardless of underlying immunosuppression.
Int J STD AIDS 2000 Nov
PMID:CMV colitis in early HIV infection. 1108 90

Cytokines exert biological functions by activating Janus tyrosine kinases (JAKs), and JAK inhibitors JAB (also referred to as SOCS1 and SSI1) and CIS3 (SOCS3) play an essential role in the negative regulation of cytokine signaling. We have found that transgenic (Tg) mice expressing a mutant JAB (F59D-JAB) exhibited a more potent STAT3 activation and a more severe colitis than did wild-type littermates after treatment with dextran sulfate sodium. We now find that there is a prolonged activation of JAKs and STATs in response to a number of cytokines in T cells from Tg mice with lck promoter-driven F59D-JAB. Overexpression of F59D-JAB also sustained activation of JAK2 in Ba/F3 cells. These data suggested that F59D-JAB up-regulated STAT activity by sustaining JAK activation. To elucidate molecular mechanisms related to F59D-JAB, we analyzed the effects of F59D-JAB on the JAK/STAT pathway using the 293 cell transient expression system. We found that the C-terminal SOCS-box played an essential role in augmenting cytokine signaling by F59D-JAB. The SOCS-box interacted with the Elongin BC complex, and this interaction stabilized JAB. F59D-JAB induced destabilization of wild-type JAB, whereas overexpression of Elongin BC canceled this effect. Levels of endogenous JAB and CIS3 in T cells from F59D-JAB Tg-mouse were lower than in wild-type mice. We propose that F59D-JAB destabilizes wild-type, endogenous JAB and CIS3 by chelating the Elongin BC complex, thereby sustaining JAK activation.
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PMID:A mutant form of JAB/SOCS1 augments the cytokine-induced JAK/STAT pathway by accelerating degradation of wild-type JAB/CIS family proteins through the SOCS-box. 1152 90

We describe the clinical activity of the ABL kinase inhibitor STI571 in a patient with accelerated phase of chronic myeloid leukemia (CML) relapsing after a second allogeneic BMT and with minimal levels of donor chimerism. STI571 resulted in rapid elimination of leukemic cells with ensuing prolonged severe leukopenia and neutropenia complicated by neutropenic fever and colitis. Subsequent hematopoietic recovery was driven by donor derived cells and was associated with grade 3 graft-versus-host disease (GVHD). STI571 induced sustained hematological and cytogenetic remission combined with controllable GvHD, therapeutic goals not achieved by two preceding allogeneic transplants and repeated donor lymphocyte transfusions (DLT).
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PMID:Hematologic and cytogenetic remission by STI571 (Glivec) in a patient relapsing with accelerated phase CML after second allogeneic stem cell transplantation. 1170 99

Substance P (SP) via its neurokinin-1 receptor (NK-1R) regulates several gastrointestinal functions. We previously reported that NK-1R-mediated chloride secretion in the colon involves formation of PG. PGE2 biosynthesis is controlled by cyclooxygenase-1 (COX-1) and COX-2, whose induction involves the STATs. In this study, we examined whether SP stimulates PGE2 production and COX-2 expression in human nontransformed NCM460 colonocytes stably transfected with the human NK-1R (NCM460-NK-1R cells) and identified the pathways involved in this response. SP exposure time and dose dependently induced an early (1-min) phosphorylation of JAK2, STAT3, and STAT5, followed by COX-2 expression and PGE2 production by 2 h. Pharmacologic experiments showed that PGE2 production is dependent on newly synthesized COX-2, but COX-1 protein. Inhibition of protein kinase Ctheta (PKCtheta), but not PKCepsilon and PKCdelta, significantly reduced SP-induced COX-2 up-regulation, and JAK2, STAT3, and STAT5 phosphorylation. Pharmacological blockade of JAK inhibited SP-induced JAK2, STAT3, and STAT5 phosphorylation; COX-2 expression; and PGE2 production. Transient transfection with JAK2 short-interferring RNA reduced COX-2 promoter activity and JAK2 phosphorylation, while RNA interference of STAT isoforms showed that STAT5 predominantly mediates SP-induced COX-2 promoter activity. Site-directed mutation of STAT binding sites on the COX-2 promoter completely abolished COX-2 promoter activity. Lastly, COX-2 expression was elevated in colon of mice during experimental colitis, and this effect was normalized by administration of the NK-1R antagonist CJ-12,255. Our results demonstrate that SP stimulates COX-2 expression and PGE2 production in human colonocytes via activation of the JAK2-STAT3/5 pathway.
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PMID:Substance P stimulates cyclooxygenase-2 and prostaglandin E2 expression through JAK-STAT activation in human colonic epithelial cells. 1658 2

Recent data indicate that the Bone Morphogenetic Protein BMP-7 exhibits mucosal protection against experimental colitis in rats, suggesting that this cytokine exerts direct actions in intestinal epithelial cells during inflammatory bowel diseases and other precancerous lesions of the colon. In this study, we investigated the functional expression of BMP-7 and its receptors in normal human colon crypts, aberrant crypt foci (ACF) in sigmoiditis and colorectal tumors, and their derived cancer cell lines. Transcripts encoding BMP-7 receptors type II (BMPRII, ActRII, ActRIIB) and type I (ALK-2) were clearly detected by RT-PCR in several premalignant and carcinoma cell lines. The cytokine was identified by immunohistochemistry in surface epithelial cells and crypts in the normal colon mucosa, ACF in sigmoiditis, sporadic high grade dysplastic adenoma, and in 9 of 16 colon carcinomas (56.2%). In addition, the conditioned medium collected from the adenoma PC/AA/C1 and carcinoma HCT8/S11 and SW48 cell lines in culture contained significant levels of BMP-7 ranging from 0.17 to 0.38 ng/ml. We found that BMP-7 induced scattering and proinvasive responses (EC50=1 ng/ml) in kidney and colon cancer cell lines through SMAD4 and src -independent pathways and signaling cascades using FAK phosphorylation at Y925 and activation of ERK1/2, Rac1 and JNK. This phosphorylation of FAK on Y925 was also induced by the proinvasive agent EGF. Taken together, our findings suggest that BMP-7 exerts divergent effects in the colon mucosa, one counteracting transient inflammatory situations and the other linked to pejorative functions during chronic ulcerative diseases and the neoplastic progression.
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PMID:Proinvasive activity of BMP-7 through SMAD4/src-independent and ERK/Rac/JNK-dependent signaling pathways in colon cancer cells. 1747 78

Endometriosis (EMS) is a chronic inflammatory disease of multifactorial etiology characterized by implantation and growth of endometrial glands and stroma outside the uterine cavity. EMS is a significant public health issue as it affects 15-20% of women in their reproductive age. Clinical symptoms may include pelvic pain, dysmenorrhea, dyspareunia, pelvic/abdominal masses, and infertility. Symptomatic treatments such as surgical resection and/or hormonal suppression of ovarian function and analgesics are not as effective as desired. Consequently, there is an enormous unmet need to develop effective medical therapy capable of preventing the occurrence and recurrence of EMS without undesirable side-effects. EMS-associated intra-abdominal bleeding episodes, local inflammation, adhesions, and i.p. immunologic dysfunction leads to pelvic nociception and pelvic pain. Increasing evidence supports the involvement of allergic-type inflammation in EMS. Invasion of mast cells, degranulation, and proliferation of interstitial component are observed in endometriotic lesions. Presence of activated and degranulating mast cells within the nerve structures can contribute to the development of pain and hyperalgesia by direct effects on primary nociceptive neurons. Therefore, treatments targeting endometrial mast cells may prove effective in preventing or alleviating EMS-associated symptoms. The Janus kinase 3 (JAK3) is abundantly expressed in mast cells and is required for the full expression of high-affinity IgE receptor-mediated mast cell inflammatory sequelae. JANEX-1/WHI-P131 is a rationally designed novel JAK3 inhibitor with potent anti-inflammatory activity in several cellular and in vivo animal models of inflammation, including mouse models of peritonitis, colitis, cellulitis, sunburn, and airway inflammation with favorable toxicity and pharmacokinetic profile. We hypothesize that JAK3 inhibitors, especially JANEX-1, may prove useful to prevent or alleviate the symptoms of EMS.
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PMID:Targeting mast cells in endometriosis with janus kinase 3 inhibitor, JANEX-1. 1763 Oct 2

We examined the biologic activity of the rationally designed JAK3 inhibitor, JANEX-1, in several cellular and animal models of inflammation. Notably, JANEX-1 exhibited potent anti-inflammatory activity in each of these preclinical models, including mouse models of peritonitis, colitis, cellulitis, and systemic inflammatory response syndrome. Therefore, JANEX-1 may prove useful as a broad-spectrum anti-inflammatory agent. The present study may provide the basis for new and effective treatment as well as prevention programs for inflammatory disorders.
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PMID:Anti-inflammatory activity profile of JANEX-1 in preclinical animal models. 1802 36

Gastrointestinal complications in AIDS patients with diarrhoea are common clinical manifestations, frequently diagnosed by colonoscopy as non-specific colitis. We retrospectively study colon biopsies diagnosed as chronic colitis associated with HIV (CCH). Biopsies were sorted as patients with AIDS (serum CD4 <200 cell/mm3) but without any clear infectious process (n = 12) and patients without HIV infection (n = 24). There are low numbers of CD4+ T lymphocytes in lamina propria of AIDS patients, but CD8+ T populations in this area appear to be similar in all studied groups, regardless of HIV infection or laboratory evidence of a specific agent. We found the clear evidence of CD8+ T cells infiltration in colonic mucosa in HIV patients with microscopic colitis. An imbalance of lymphocyte subpopulations in the colon, both in the lamina propria and epithelium, could result in an intraepithelial CD8 infiltration, involved in the pathogenesis of CCH in AIDS patients.
Int J STD AIDS 2008 Aug
PMID:Chronic colitis associated with HIV infection can be related to intraepithelial infiltration of the colon by CD8+ T lymphocytes. 1866 37

Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4-20 x 10(9)/l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile.
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PMID:Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy. 2765 75

MFG-E8 (milk fat globule-epidermal growth factor 8) deficiency is strongly associated with acquisition of immune-mediated disorders due to the loss of tissue homeostasis. However, comparatively little is known regarding its functions in gastrointestinal tract disorders, in which immune homeostasis is a major concern. Herein, we report altered MFG-E8 expression in inflamed colons during the acute phase of murine experimental colitis and found that treatment with recombinant MFG-E8, but not its arginine-glycine-aspartate mutant counterpart, ameliorated colitis by reducing inflammation and improving disease parameters. To reveal the MFG-E8-mediated antiinflammatory mechanism, we employed an in vitro system, which showed the down-regulation of NF-kappaB in an LPS-dependent manner. Additionally, MFG-E8 altered alpha(v)beta(3) integrin-mediated focal adhesion kinase phosphorylation by impeding the binding of one of its potent ligands osteopontin, which becomes activated during colitis. Taken together, our results indicated that MFG-E8 has a novel therapeutic potential for treatment of colitis.
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PMID:MFG-E8 attenuates intestinal inflammation in murine experimental colitis by modulating osteopontin-dependent alphavbeta3 integrin signaling. 1945 19


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