Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the USA, the incidence of kidney cancer has increased 43% since 1973. The risk of the disorder is higher in men than in women and increases with age. The von Hippel-Lindau tumour-suppressor gene is inactivated in over 75% of sporadic cases. Metastatic disease is present in 20-30% of patients at diagnosis. Early-stage kidney cancer is treated with a radical nephrectomy, but under certain circumstances a partial nephrectomy may be done. Tumour thrombus into the vena cava or right atrium requires thoracotomy and hypothermic circulatory arrest for successful removal of the tumour, but should not be done if extensive nodal or frank metastatic disease is present. Interleukin-2 is the systemic therapy of choice for metastatic disease at present, with long-term relapse-free survival of 5-8%. Several treatments including anti-angiogenesis drugs, cyclin-dependent kinase inhibitors, and differentiating agents are being actively investigated. Fluorouracil has a 10-15% response rate, and surgical excision of isolated metastases should always be considered. Therapy for metastatic renal cancer remains inadequate, but recent developments in basic and clinical research suggest future improvement.
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PMID:Kidney cancer. 1002 13

Hematopoietic progenitor kinase 1 (HPK1), a mammalian Ste20-related protein kinase, is an upstream activator of c-Jun N-terminal kinase (JNK). In order to further characterize the HPK1-mediated JNK signaling cascade, we searched for HPK1-interacting proteins that could regulate HPK1. We found that HPK1 interacted with Crk and CrkL adaptor proteins in vitro and in vivo and that the proline-rich motifs within HPK1 were involved in the differential interaction of HPK1 with the Crk proteins and Grb2. Crk and CrkL not only activated HPK1 but also synergized with HPK1 in the activation of JNK. The HPK1 mutant (HPK1-PR), which encodes the proline-rich region alone, blocked JNK activation by Crk and CrkL. Dominant-negative mutants of HPK1 downstream effectors, including MEKK1, TAK1, and SEK1, also inhibited Crk-induced JNK activation. These results suggest that the Crk proteins serve as upstream regulators of HPK1. We further observed that the HPK1 mutant HPK1-KD(M46), which encodes the kinase domain with a point mutation at lysine-46, and HPK1-PR blocked interleukin-2 (IL-2) induction in Jurkat T cells, suggesting that HPK1 signaling plays a critical role in IL-2 induction. Interestingly, HPK1 phosphorylated Crk and CrkL, mainly on serine and threonine residues in vitro. Taken together, our findings demonstrate the functional interaction of HPK1 with Crk and CrkL, reveal the downstream pathways of Crk- and CrkL-induced JNK activation, and highlight a potential role of HPK1 in T-cell activation.
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PMID:Interaction of hematopoietic progenitor kinase 1 with adapter proteins Crk and CrkL leads to synergistic activation of c-Jun N-terminal kinase. 989 Oct 69

Costimulation of both the CD3 and CD28 receptors is essential for T cell activation. Induction of adenosine 3',5'-monophosphate (cAMP)-specific phosphodiesterase-7 (PDE7) was found to be a consequence of such costimulation. Increased PDE7 in T cells correlated with decreased cAMP, increased interleukin-2 expression, and increased proliferation. Selectively reducing PDE7 expression with a PDE7 antisense oligonucleotide inhibited T cell proliferation; inhibition was reversed by blocking the cAMP signaling pathways that operate through cAMP-dependent protein kinase (PKA). Thus, PDE7 induction and consequent suppression of PKA activity is required for T cell activation, and inhibition of PDE7 could be an approach to treating T cell-dependent disorders.
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PMID:CD3- and CD28-dependent induction of PDE7 required for T cell activation. 993 69

Although p21ras, raf-1 and MEK have been shown to regulate directly the transcriptional activity of NFAT (nuclear factor of activated T cells) and/or the interleukin-2 (IL-2) promoter, direct evidence that the extracellular signal-regulated protein kinase (ERK) is involved in regulating IL-2 production is still lacking. Here, we demonstrate that transfection of Jurkat cells with a dominant negative mutant of ERK1 (Erk1-K71R) resulted in the suppression of mitogen-stimulated production/secretion of IL-2. This was accompanied by a parallel inhibition of mitogen-stimulated ERK activity. These data provide direct evidence, for the first time, that ERK plays a vital role in regulating the production/secretion of IL-2.
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PMID:Direct evidence that ERK regulates the production/secretion of interleukin-2 in PHA/PMA-stimulated T lymphocytes. 1023 37

NFAT transcription factors play a central role in initiating T-cell activation through the induction of immediate-early T-cell specific genes including interleukin-2 (IL-2). NFAT transcription factors bind to a sequence in the IL-2 enhancer known as the antigen receptor response element 2 (ARRE-2). Multiple proteins exhibiting ARRE-2 binding activity have been isolated, including a heterodimer from stimulated T-cell nuclear extracts consisting of Mr = 90 000 (NF90) and Mr = 45 000 (NF45) subunits. The subunits of this heterodimer have been cloned, and NF90 was found to encode a protein containing two domains that are predicted to form motifs capable of binding to double-stranded RNA. Using in vitro translated polypeptides, we have demonstrated that NF90 specifically binds to double-stranded RNA. Furthermore, NF90 was phosphorylated in a double-stranded RNA-dependent manner likely by the interferon-induced, double-stranded RNA-dependent protein kinase, PKR. The NF90 protein was found to be expressed not only in T-cells, but also in nonimmune HeLa cells. In HeLa cells, the protein was almost exclusively localized to the ribosome salt wash fraction of cell lysates.
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PMID:Nuclear factor-90 of activated T-cells: A double-stranded RNA-binding protein and substrate for the double-stranded RNA-dependent protein kinase, PKR. 1032 Mar 67

T cell stimulation leads to triggering of signals transmitted from the cell membrane to the nucleus through TCR/CD3 proteins. Characterization of these signals largely results from the use of cell lines stimulated with anti-CD3 monoclonal antibodies. These studies have established that activation caused a rapid increase in the formation of GTP-bound Ras, which stimulates the mitogen-activated protein kinase pathway involving the extracellular-regulated kinase-2 (ERK-2) and activates the nuclear factor of activated T cells (NF-AT) that regulates interleukin-2 (IL-2) gene transcription. In the present study, we used human primary T cells, and we investigated the intracellular signals triggered by two different anti-CD3 monoclonal antibodies (UCHT1 and X-35), which both strongly induce cell proliferation. We found that, in contrast to the commonly used UCHT1, X-35 activated IL-2 gene transcription without stimulation of the Raf-1/mitogen-activated ERK kinase-1 (MEK-1)/ERK-2 phosphorylation cascade; we also showed that X-35 stimulation, which triggers an ERK-2-independent pathway, does not involve activation of p21(ras). In addition to demonstrating that activation of p21(ras) and of its Raf-1/MEK-1/ERK-2 effector pathway is not an event obligatorily triggered upon TCR/CD3 ligation, these results provide the first evidence of the existence of a p21(ras)/ERK-2-independent pathway for IL-2 gene transcription in human primary T lymphocytes.
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PMID:Evidence for a p21(ras)/Raf-1/MEK-1/ERK-2-independent pathway in stimulation of IL-2 gene transcription in human primary T lymphocytes. 1046 12

Calcium-stimulated nuclear factor of activated T cells (NFAT) transcription activity at the interleukin-2 promoter is negatively regulated by cyclic AMP (cAMP). This effect of cAMP is mediated, in part, by protein kinase A phosphorylation of NFAT. The mechanism of regulation involves the creation of a phosphorylation-dependent binding site for 14-3-3. Decreased NFAT phosphorylation caused by the calcium-stimulated phosphatase calcineurin, or mutation of the PKA phosphorylation sites, disrupted 14-3-3 binding and increased NFAT transcription activity. In contrast, NFAT phosphorylation caused by cAMP increased 14-3-3 binding and reduced NFAT transcription activity. The regulated interaction between NFAT and 14-3-3 provides a mechanism for the integration of calcium and cAMP signaling pathways.
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PMID:Integration of calcium and cyclic AMP signaling pathways by 14-3-3. 1061 Dec 49

Pyridinyl imidazole inhibitors, particularly SB203580, have been widely used to elucidate the roles of p38 mitogen-activated protein (MAP) kinase (p38/HOG/SAPKII) in a wide array of biological systems. Studies by this group and others have shown that SB203580 can have antiproliferative activity on cytokine-activated lymphocytes. However, we recently reported that the antiproliferative effects of SB203580 were unrelated to p38 MAP kinase activity. This present study now shows that SB203580 can inhibit the key cell cycle event of retinoblastoma protein phosphorylation in interleukin-2-stimulated T cells. Studies on the proximal regulator of this event, the phosphatidylinositol 3-kinase/protein kinase B (PKB)(Akt/Rac) kinase pathway, showed that SB203580 blocked the phosphorylation and activation of PKB by inhibiting the PKB kinase, phosphoinositide-dependent protein kinase 1. The concentrations of SB203580 required to block PKB phosphorylation (IC(50) 3-5 microM) are only approximately 10-fold higher than those required to inhibit p38 MAP kinase (IC(50) 0.3-0.5 microM). These data define a new activity for this drug and would suggest that extreme caution should be taken when interpreting data where SB203580 has been used at concentrations above 1-2 microM.
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PMID:The pyridinyl imidazole inhibitor SB203580 blocks phosphoinositide-dependent protein kinase activity, protein kinase B phosphorylation, and retinoblastoma hyperphosphorylation in interleukin-2-stimulated T cells independently of p38 mitogen-activated protein kinase. 1070 13

We have previously shown that m1 and m2 muscarinic receptors were expressed on human peripheral blood lymphocytes (hPBL) and that pre-stimulation of these receptors enhanced phytohemagglutinin (PHA)-induced interleukin-2 (IL-2) production. Possible intracellular signal pathways of muscarinic receptors to regulate IL-2 production were examined in human T cell line Jurkat cells. Pretreatment of the cells with muscarinic receptor agonist, oxotremorine M (Oxo-M), enhanced IL-2 production induced by phorbol 12-myristate 13-acetate (PMA)/A23187, while Oxo-M by itself did not affect IL-2 production. The enhancement of IL-2 production by Oxo-M was inhibited by 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) an ml/m3 receptor antagonist. When the cells were pretreated with AF-DX116, an m2 antagonist, the IL-2 production enhanced by Oxo-M was further stimulated. Reverse transcription-polymerase chain reaction (RT-PCR) revealed that ml and m2 muscarinic receptors exist on Jurkat cells. The stimulation of ml receptors enhanced the PMA/A23187-induced binding activity to AP-1 consensus sequences in IL-2 promoter and production of c-Fos and c-Jun protein. The stimulation of ml receptors did not modify the DNA binding of NF-kappaB, NF-AT or Oct-1. When ml receptors were stimulated, activities of mitogen-activated protein kinase (MAPK)/extracellular signal regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) were increased, while p38 MAPK was not affected. Incubation with Oxo-M induced a transient increase in [Ca2+]i, which was abolished by pretreatment with 4-DAMP. Treatment with cyclosporin A markedly decreased the PMA/A23187-induced IL-2 promoter activity. This treatment, however, did not affect the enhancement of the promoter activity induced by ml receptor stimulation. The results suggest that transcription factor AP-1 is involved in the ml receptor-mediated enhancement of IL-2 transcript in Jurkat cells, and that pathways via MAPK/ERK and JNK, but not via p38 MAPK, are involved in the ml receptor-mediated enhancement of IL-2 promoter activity.
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PMID:Extracellular signal regulated protein kinase and c-jun N-terminal kinase are involved in ml muscarinic receptor-enhanced interleukin-2 production pathway in Jurkat cells. 1104 Dec 51

In mice, monoclonal antibody (mAb) to the alpha1 integrin abrogate gastro-intestinal damage during graft-versus-host-disease (GVHD), suggesting anti alpha1 mAb as candidates for treatment in humans as well. Our current data show that one such reagent, mAb 1B3.1, when immobilized to plastic wells via rabbit- anti murine (ram) immunoglobulin (Ig) induces a protein kinase-dependent spreading of activated human T cells. Furthermore, it significantly increases the proliferative response, and expression of interleukin-2 (IL-2) receptors (R) and CD69, of resting T cells, expressing minimal integrin on the cell surface, to sub-optimal stimulation by anti-CD3 mAb. We found, in addition, that mAb 1B3.1 a) immuno-precipitates alpha1beta1 integrins from cell-surface iodinated canine epithelial cells b) is highly reactive with canine T cells after their activation and c) inhibits adhesion of canine T cells to collagen IV. Despite the potential ability of the mAb to co-activate T cells in vitro, two dogs that received 4 injections of 0.5-0.3 mg/Kg of mAb 1B3.1 remained healthy, developing only marginal transient lymphopenia. Injection of 0.75mg/Kg in a third dog induced a more marked lymphopenia, and an additional dose of 1.0 mg/Kg 2 weeks later was followed by gastrointestinal hemorrhage. importantly, the lymphopenia was associated with a greater and more persistent decrease of CD8+ than of CD4+ T cells, leading to an increase in the CD4/CD8 ratio 24 hours after the injection. Thus, despite it's co-activating effects in vitro, administration of this mAb in vivo is feasible when appropriately dosed, and may have immuno-modulatory effects.
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PMID:Parenteral administration of an activating monoclonal antibody to the alpha1beta1 integrin in dogs. 1104 60


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