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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of ErbB-2/HER2 is associated with aggressive human malignancies, and therapeutic strategies targeting the oncoprotein are currently in different stages of clinical application. Tyrosine kinase inhibitors (TKIs) that block the nucleotide-binding site of the kinase are especially effective against tumors. Here we report an unexpected activity of TKIs: along with inhibition of tyrosine phosphorylation, they enhance ubiquitylation and accelerate endocytosis and subsequent intracellular destruction of ErbB-2 molecules. Especially potent is an irreversible TKI (CI-1033) that alkylates a cysteine specific to ErbB receptors. The degradative pathway stimulated by TKIs appears to be chaperone mediated, and is common to the heat shock protein 90 (Hsp90) antagonist geldanamycin and a stress-induced mechanism. In agreement with this conclusion, CI-1033 and geldanamycin additively inhibit tumor cell growth. Based upon a model for drug-induced degradation of ErbB-2, we propose a general strategy for selective destruction of oncoproteins by targeting their interaction with molecular chaperones.
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PMID:Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy. 1200 93

The expression of tissue factor (TF) by monocytes that have transmigrated across the endothelium to sites of extravascular inflammation acts both to focus and amplify the inflammatory response. Because clustering of the integrins responsible for endothelial adhesion and transmigration induces tyrosine phosphorylation and activation of the mitogen-activated protein (MAP) kinases, we postulated that transmigration might lead to monocyte activation and TF production. Monocytes were migrated across TNFalpha-primed ECV304 cells grown on fibronectin-coated Transwell chambers in response to FMLP (10(-8) M). After transmigration, monocytes showed a time-dependent increase in surface TF expression and biological procoagulant activity. TF expression was dependent on monocyte adhesion to ECV304 cells. Specifically, TF was not induced by FMLP treatment of suspended monocytes, by migration across fibronectin alone, or by soluble factors induced during migration, whereas monocyte-ECV304 adhesion was sufficient to stimulate TF. Antibodies against CD29 (beta1 integrin), but not against CD18 (beta2 integrin) or CD31 (PECAM-1), inhibited TF expression. Monocyte adhesion to ECV304 cells induced tyrosine phosphorylation of cellular proteins and specifically of the ERK and p38 MAP kinases. Tyrosine kinase inhibition with genistein (10 microg/mL) blocked transmigration, whereas selective ERK inhibition with PD98059 (50 microM) or p38 inhibition with SB203580 (20 microM) did not. However, both ERK and p38 inhibition dose dependently abolished TF expression. These studies suggest that an extravascular focus of infection or inflammation can promote both intravascular thrombosis and extravascular fibrin deposition during the process of adhesion and transmigration across the endothelial barrier. The selective inhibition of the mitogen-activated protein kinases may offer a novel therapeutic means of modulating this inflammatory sequence.
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PMID:Monocyte adhesion and transmigration induce tissue factor expression: role of the mitogen-activated protein kinases. 1209 34

The varying efficacy and toxicity of traditional cancer therapies has driven the development of novel target-based agents. Members of the HER (Human Epidermal Receptor) family, in particular epidermal growth factor receptor (HER1/EGFR), are attractive therapeutic targets because they are overexpressed and/or dysregulated in many solid tumors. Activation of HER1/EGFR mediated through ligand binding triggers a network of signaling processes that promote tumor cell proliferation, migration, adhesion, and angiogenesis, and decrease apoptosis. Therefore, inhibiting HER1/EGFR activity could effectively block downstream signaling events and, consequently, tumorigenesis. Various approaches are being investigated to target members of the HER family, particularly HER1/EGFR and HER2. At the forefront are monoclonal antibodies and small molecules that inhibit the receptor tyrosine kinase activity. Monoclonal antibodies have been developed that act against HER1/EGFR and HER2. Monoclonal antibodies block ligand binding and prevent ligand-induced activation. Tyrosine kinase inhibitors block receptor phosphorylation, preventing downstream signal transduction. Several HER1/EGFR-targeted agents are advanced in clinical development and attention is focused on optimizing their clinical use. While this process may prove challenging, it promises to be beneficial.
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PMID:Targeting HER1/EGFR: a molecular approach to cancer therapy. 1284 Jul 96

We, and others, have demonstrated an in utero origin for translocations associated with childhood leukemia, with latency periods in some cases exceeding 10 years. The mechanism of generation of most of the translocations is thought to be aberrant repair following abortive apoptosis, rather than V(D)J recombination or exposure to topoisomerase II inhibitors. Folate supplementation may prevent some of the chromosome breakage leading to translocation formation. Translocations t(8;21) and t(12;21) have been shown to occur in the normal population (before birth) at a frequency that is 100-fold greater than the risk of developing the corresponding leukemia. In most instances, additional genetic changes are required for progression to leukemia. Tyrosine kinase receptor (RTK) mutations, which give cells a survival/proliferative advantage, are proposed to act cooperatively with fusion genes, leading to transformation. However, translocations and cooperating RTK mutations have not been identified for all leukemia subtypes, particularly in acute myeloid leukemia. The core binding transcriptional pathway is frequently targeted by translocation in utero. We propose that this pathway is highly sensitive during fetal hematopoiesis and may be targeted by mechanisms other than translocation. For each leukemia subtype it is important to characterize the corresponding leukemic stem cell, which is thought to be the initial target for translocation. This would help to elucidate the molecular pathways involved in the progression from preleukemic clone harboring a translocation to fully disseminated leukemia.
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PMID:Prenatal origin of chromosomal translocations in acute childhood leukemia: implications and future directions. 1505 23

Activating mutations of FLT3 (FMS-Like Tyrosine kinase-3) are the most common molecular abnormality in acute myeloid leukemia (AML). Their presence is associated with a worse prognosis, and the recognition of this has led to the development of several new small molecule FLT3 tyrosine kinase inhibitors. In this review, we summarize these developments and compare and contrast these novel agents both with regards to the assays used to characterize them as well as to their clinical potential.
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PMID:Small molecule FLT3 tyrosine kinase inhibitors. 1507 34

Myeloid leukaemias are frequently associated with translocations and mutations of tyrosine kinase genes. The products of these oncogenes, including BCR-ABL, TEL-PDGFR, Flt3 and c-Kit, have elevated tyrosine kinase activity and transform haematopoietic cells, mainly by augmentation of proliferation and enhanced viability. Activated ABL kinases are associated with chronic myeloid leukaemia. Mutations in platelet-derived growth factor receptor beta are associated with chronic myelomonocytic leukaemia. Flt3 or c-Kit cooperate with other types of oncogenes to create fully transformed acute leukaemias. Elevated activity of these tyrosine kinases is crucial for transformation, thus making the kinase domain an ideal target for therapeutic intervention. Tyrosine kinase inhibitors for various kinases are currently being evaluated in clinical trials and are potentially useful therapeutic agents in myeloid leukaemias. Here, the authors review the signalling activities, mechanism of transformation and therapeutic targeting of several tyrosine kinase oncogenes important in myeloid leukaemias.
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PMID:Targeting mutated tyrosine kinases in the therapy of myeloid leukaemias. 1516 29

Activation of the KIT receptor tyrosine kinase contributes to the pathogenesis of several human diseases, but the mechanisms regulating KIT signaling have not been fully characterized. Here, we show that stem cell factor (SCF), the ligand for KIT, induces the interaction between KIT and Cbl proteins and their mutual degradation. Upon SCF stimulation, KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. We propose a negative feedback loop controlling the SCF-KIT signaling pathway, in which SCF activates KIT. The activated KIT in turn induces phosphorylation and activation of Cbl proteins. The Cbl proteins then bind and direct the degradation of activated KIT, leading to down-regulation of KIT signaling.
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PMID:Regulation of stem cell factor receptor signaling by Cbl family proteins (Cbl-b/c-Cbl). 1531 62

Tyrosine kinase receptors of the EGFR family play a significant role in vital cellular processes and in various cancers. EGFR members are unique among kinases, as the regulatory elements of their kinase domains are constitutively ready for catalysis. Nevertheless, the receptors are not constantly active. This apparent paradox has prompted us to seek mechanisms of regulation in EGFR's cytoplasmic domain that do not involve conformational changes of the kinase domain. Our computational analyses, based on the three-dimensional structure of EGFR's kinase domain suggest that direct contact between the kinase and a segment from the C-terminal regulatory domains inhibits enzymatic activity. EGFR activation would then involve temporal dissociation of this stable complex, for example, via ligand-induced contact formation between the extracellular domains, leading to the reorientation of the transmembrane and intracellular domains. The model provides an explanation at the molecular level for the effects of several cancer-causing EGFR mutations.
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PMID:A putative mechanism for downregulation of the catalytic activity of the EGF receptor via direct contact between its kinase and C-terminal domains. 1557 39

Frizzled-1 (FZD1), FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9 and FZD10 are seven-transmembrane-type WNT receptors with extracellular Frizzled (Fz) domain. ROR1, ROR2 and MUSK are receptor-type tyrosine kinases with extracellular Fz domain, while MFRP is type II transmembrane protein with extracellular Fz domain. ROR1, ROR2, MUSK and MFRP are predicted to transduce or regulate WNT signaling. Here, we identified and characterized rat Ror1 and Ror2 genes by using bioinformatics. Rat Ror1 gene was located within AC108320.4, AC098031.5 and AC129856.4 genome sequences, while rat Ror2 gene was located within AC139870.3 and AC123431.4 genome sequences. Exon-intron structure was conserved between rat Ror1 and Ror2 genes, consisting of nine exons. Rat Ror1 mRNA was expressed in fetal ventricle, while rat Ror2 mRNA was expressed in cerebral cortex, hypothalamus, dorsolateral prostate, and chondrosarcoma. Rat Ror1 (937 aa) and Ror2 (943 aa) showed 56.5% total-amino-acid identity. Rat Ror1 and Ror2 were type I transmembrane proteins with extracellular Immunoglobulin-like (Ig), Fz, Kringle (KR) domains, and cytoplasmic Juxta-membrane (JM), Tyrosine kinase (TK), and Ror homology C-terminal (RORHC) domains. Casein kinase Iepsilon-binding RORHC domain was conserved among vertebrate Ror1 and Ror2 homologs, but not in Drosophila Ror. Thr 582 within TK domain was conserved among mammalian Ror family members, and was predicted as Casein kinase I phosphorylation site. This is the first report on rat Ror1 and Ror2 genes as well as on molecular evolution of Ror1 and Ror2 homologs.
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PMID:Identification and characterization of rat Ror1 and Ror2 genes in silico. 1570 50

Most women with epithelial ovarian cancer are diagnosed with advanced disease. Despite surgery and initial tumor reduction by standard chemotherapy, the tumors frequently recur and the patients eventually die of their disease. New drugs that inhibit tyrosine kinase receptors (TKRs) are being investigated for treatment and this study was undertaken to determine the expression and mutational state for 3 TKRs (c-kit, platelet-derived growth factor receptor [PDGFR] alpha, and PDGFR beta) in ovarian cancer. Tissue arrays containing 84 epithelial ovarian tumors were studied by immunohistochemistry with antibodies specific for c-kit, PDGFR alpha, and PDGFR beta. Immunoreactivity was detected in 78% of the tumor to at least one TKR. PDGFR alpha was expressed in the largest percentage of ovarian tumors (58%) whereas 29% expressed PDGFR beta. Two commercial antibodies against c-kit were studied and 33% of the tumors stained with one but only 6% were interpreted as positive with the second antibody. Activation of TKRs may occur through mutations but, by sequence analysis, no mutations were detected in 6 ovarian tumors with elevated immunoreactivity for each of the TKRs (c-kit, PDGFR alpha, and PDGFR beta). Tyrosine kinase receptors could also be activated through autocrine or paracrine stimulation of receptor by its ligand. Of 43 (35%) tumors tested for both c-kit receptor and its ligand (stem cell factor), 15 expressed both proteins indicating the possibility that this autocrine stimulation feedback loop is a factor in the growth of some ovarian cancers. This study demonstrates that PDGFR alpha, PDGFR beta, and c-kit are expressed in a high percentage of epithelial ovarian cancers suggesting that tyrosine kinase inhibitors may be useful in the treatment of these tumors.
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PMID:Expression and mutational analysis of tyrosine kinase receptors c-kit, PDGFRalpha, and PDGFRbeta in ovarian cancers. 1579 68


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