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)

In 1985, Stein et al demonstrated the expression of the lymphoid activation antigen CD30/Ki by neoplastic cells. Fifteen years after the first description, anaplastic large-cell lymphomas (ALCL) are now thought to be a heterogeneous group in terms of their clinical, morphologic, phenotypic, cytogenetic, and molecular biology features. However, on the basis of a specific genetic anomaly and expression of a chimeric nucleophosmin anaplastic lymphoma kinase (NPM-ALK) protein and its variants, a distinct clinicopathologic entity defined as "ALK-positive lymphoma" or "ALKoma" can be recognized. Based on molecular and clinical criteria, 3 entities of primary ALCL can be identified: primary systemic ALK positive, primary systemic ALK negative, and primary cutaneous ALCL. This review focuses on advances in the knowledge of primary systemic ALCL biology and discusses therapeutic approaches based on ALK expression. The presence of this protein appears to be an important prognostic factor and, combined with an age-adjusted International Prognostic Index, could allow researchers to design more specific clinical trials aimed at finding new, more efficacious and less toxic treatments.
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PMID:Primary systemic anaplastic large-cell lymphoma (CD30+): advances in biology and current therapeutic approaches. 1170 67

Activation of focal adhesion kinase (FAK), overexpressed in several human cancers, induces survival, proliferation and motility of cells in culture, but its functional importance in human tumor growth in vivo has not been elucidated. I explored the role of FAK in regulating tumorigenicity of human carcinoma cells, HEp3. These cells overexpress urokinase receptor (uPAR) which, by activating alpha5beta1 integrin, initiates an intracellular signal through FAK and Src leading to ERK activation and tumorigenicity in vivo. Down regulation of uPAR in these cells led to an approximately 3-5-fold reduction in FAK phosphorylation and association with Src and dormancy in vivo. Both FAK phosphorylation and ability to grow in vivo were restored by re-expression of uPAR. The FAK signaling pathway in T-HEp3 cells, measured by FAK phosphorylation, GTP-loaded Ras and ERK activation, was inhibited by transient or stable transfection of FAK related non-kinase (FRNK), known to have a dominant negative function, but not by a FRNK mutant version (S1034-FRNK). Most importantly, while vector- and mutant-S1034-FRNK transfected cells inoculated onto chicken embryo CAMs formed progressively growing tumors, the HA-FRNK-expressing T-HEp3 cells did not proliferate in vivo and remained dormant for at least 6 weeks. Both cell types had similar rate of apoptosis in vivo and the p38(SAPK) or PI3K-Akt signaling pathways were unaffected by FRNK. FRNK induced dormancy could be reverted by expression of an active-R4F-Mek1 mutant. These results show that active FAK is an important mediator of uPAR-regulated tumorigenicity of HEp3 cells and that interruption of FAK mitogenic signaling either through down-regulation of uPAR or by expression of FRNK can force human carcinoma cells into dormancy.
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PMID:Inhibition of FAK signaling activated by urokinase receptor induces dormancy in human carcinoma cells in vivo. 1197 Nov 86

In order to identify metastasis-associated and promoting genes of pancreatic carcinoma we investigated the transcriptional profile of rat pancreatic carcinoma cell lines BSp73-AS (non-metastatic) and BSp73-ASML (highly metastatic) with Affymetrix GeneChip Array technology. We analyzed the expression profile of 7000 genes. Two hundred and ten genes (3%) were up-regulated and 247 genes (3.5%) were down-regulated in the metastatic cell line based on a fold change of expression of at least 3 and a change factor quality of > or = 2. In order to classify the de-regulated genes we defined the following categories: proteases and protease-related genes, cytokines, receptor tyrosine kinases, other transmembrane proteins/receptors, transcription, cell cycle/apoptosis, signaling, adhesion/extracellular matrix, metabolism, detoxification, protein modification, trafficking, immune response and other genes. We identified de-regulated AP1, FRA-1 and c-myc-mediated transcription in cell line BSp73-ASML. Up-regulation of transmembrane tyrosine kinase receptors c-met, IGFR1, IGFR2 and EGFR family-related ligands such as HB-EGF, TGFa, amphiregulin and neuregulin as well as c-met ligand HGF point to a possible role of this system in metastasis. We identified 56 non-tyrosine kinase transmembrane receptors as new target candidates for inhibition of metastasis, four of them representing already validated targets. In addition, we identified MMP9, uPA, uPAR, cyclin D1 and S100A4 (mts1) as possible contributors of the metastatic phenotype.
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PMID:Identification of rat pancreatic carcinoma genes associated with lymphogenous metastasis. 1217 79

The urokinase-type plasminogen activator (uPA) is able to cleave its cell surface receptor (uPAR) anchored to the cell membrane through a glycophosphatidylinositol tail. The cleavage leads to the formation of cell surface truncated forms, devoid of the N-terminal domain 1 (D1) and unmasks or disrupts, depending on the cleavage site, a sequence in the D1-D2 linker region (residues 88-92), which in the soluble form is a potent chemoattractant for monocyte-like cells. To investigate the possible role(s) of the cleaved forms of cell surface glycophosphatidylinositol-anchored uPAR, uPAR-negative human embrional kidney 293 cells were transfected with the cDNA of intact uPAR (uPAR-293) or with cDNAs corresponding to the truncated forms of uPAR exposing (D2D3-293) or lacking (D2D3wc-293) the peptide 88-92 (P88-92). Cell adhesion assays and co-immunoprecipitation experiments indicated that the removal of D1, independently of the presence of P88-92, abolished the lateral interaction of uPAR with integrins and its capability to regulate integrin adhesive functions. The expression of intact uPAR induced also a moderate increase in 293 cell proliferation, which was accompanied by the activation of ERK. Also this effect was abolished by D1 removal, independently of the presence of P88-92. The expression of intact and truncated uPARs regulated cell directional migration toward uPA, the specific uPAR ligand, and toward fMLP, a bacterial chemotactic peptide. In fact, the uPA-dependent cell migration required the expression of intact uPAR, including D1, whereas the fMLP-dependent cell migration required the expression of a P88-92 containing uPAR and was independent of the presence of D1. Together these observations indicate that uPA-mediated uPAR cleavage and D1 removal, occurring on the cell surface of several cell types, can play a fundamental role in the regulation of multiple uPAR functions.
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PMID:The cleavage of the urokinase receptor regulates its multiple functions. 1229 5

After dissemination from a primary tumor, cancer cells may resume growth, leading to overt metastasis, or enter a state of protracted dormancy. However, mechanisms that determine their fate, or markers that predict it, are mostly unavailable. We previously showed that in HEp3 human head and neck carcinoma, the extracellular signal-regulated kinase (ERK)(MAPK)/p38(SAPK) activity ratio predicts whether the cells will proliferate or enter a state of dormancy in vivo. The proliferative balance of high ERK/p38 ratio was induced by high urokinase (uPA) receptor (uPAR) expression, which activated alpha5beta1-integrin and epidermal growth factor receptor. This signaling pathway was additionally enhanced by uPA binding to uPAR and fibronectin binding to alpha5beta1-integrin. We tested whether the ERK/p38 balance is predictive of in vivo behavior in other cancer cell types and whether altering the balance will shift their phenotype between proliferation and dormancy. ERK and p38 activities were determined using either phospho-specific monoclonal antibodies or a trans-reporting system where GAL4-Elk and GAL4-CHOP trans-activation of luciferase gene served as reporters for ERK and p38 activities, respectively. We show that in breast, prostate, melanoma, and fibrosarcoma cell lines, the level of active phospho-ERK and the ERK/p38 activity ratio predict for the in vivo behavior in approximately 90% of the cell lines tested. Modulation of ERK/p38 activity ratio by multiple pharmacological and genetic interventions confirms that high ERK/p38 ratio favors tumor growth, whereas high p38/ERK ratio induces tumor growth arrest (dormancy) in vivo and that ERK is negatively regulated by p38. A melanoma cell line appeared to have developed an escape mechanism to avoid the growth inhibitory effect of high p38 activity. Mechanistic analysis implicated high uPAR expression and its interaction with and activation of alpha5beta1-integrin as determinants of the in vivo growth promoting high ERK/p38 ratio in several cell lines. The small GTPase, Cdc42, was implicated in activation of p38 and growth arrest. These results suggest that even cells that originate in advanced cancers retain a degree of dependence on surface receptors and matrix for their proliferative signals in vivo and provide a therapeutic opportunity to change their phenotype from tumorigenic to dormant.
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PMID:ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). 1267 Sep 23

Increased expression and/or activity of c-Met, the receptor protein tyrosine kinase for hepatocyte growth factor/scatter factor, occurs commonly during colon tumor progression. To examine potential roles for c-Met in promoting metastasis, we compared the colon tumor cell line KM12C with low metastatic potential to the isogenic variants KM,12L4 and KM12SM with high metastatic potential. KM12C cells express c-Met with low levels of tyrosine phosphorylation in the absence of HGF. The high metastatic cells express a c-Met that is constitutively tyrosine phosphorylated, they have increased colony formation, and are minimally responsive to HGF relative to the parental cells. Tyrosine-phosphorylated beta-catenin was constitutively associated with c-Met in the more metastatic cells, but was inducible only after HGF addition in the less metastatic cells. Functions mediated by beta-catenin, including cell-cell adhesion and migration, and activation of the tcf (T-cell factor) family of transcription factors, were also elevated in the more metastatic KM12SM and L4 cells. Furthermore, analysis of the known tcf transcriptional target genes, cyclin D1, c-Myc, and uPAR, demonstrated increased expression in the high metastatic cells, correlating with the levels of tcf activity. Collectively, these results suggest that endogenous activation of c-Met in highly metastatic KM12SM CRC cells results in increased survival and growth under anchorage independent conditions, increased in vitro migration, and elevated levels of tcf target genes. Thus, beta-catenin association with activated c-Met may contribute to a more aggressive liver metastatic phenotype of these cells.
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PMID:Activation of c-Met in colorectal carcinoma cells leads to constitutive association of tyrosine-phosphorylated beta-catenin. 1285 16

We describe two signaling events downstream of ERK-MAP kinase contributing to cell motility in colon carcinoma cells. The Fos family member Fra-1 is expressed in an ERK-dependent manner. Silencing of Fra-1 expression with short interfering RNAs leads to losses of cell polarization, motility, and invasiveness in vitro. These effects of ablating Fra-1 are a consequence of activation of a RhoA-ROCK pathway by beta1-integrin, leading to an increase in the amount of stress fibers and stabilization of focal adhesions. We propose that Fra-1 promotes cell motility by inactivating beta1-integrin and keeping RhoA activity low. This depression of RhoA activity is necessary to permit a second ERK-dependent signaling event via uPAR, the receptor for urokinase-type plasminogen activator, to activate Rac and to drive motility through polarized lamellipodia extension.
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PMID:ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility. 1289 14

The urokinase-type plasminogen activator receptor (uPAR) is released from human cancers and is readily detected in blood. In animal models, soluble uPAR (SuPAR) antagonizes cancer progression; however, the mechanism by which SuPAR functions in vivo remains unclear. It is generally thought that SuPAR scavenges uPA and prevents its interaction with membrane-anchored uPAR. In this study, we demonstrate a novel molecular mechanism by which SuPAR may inhibit cancer progression. We show that SuPAR has the potential to directly and in a uPA-independent manner block the signaling activity of membrane-anchored uPAR. Whether SuPAR inhibits signaling is cell type-specific, depending on the state of the endogenous uPA-uPAR signaling system. In uPAR-deficient cells that lack endogenous uPAR signaling, including uPAR-/-murine embryonic fibroblasts and human embryonal kidney 293 cells, SuPAR functions as a partial signaling agonist that activates ERK/mitogen-activated protein kinase. By contrast, in cells with potent autocrine uPA-uPAR signaling systems, including MDA-MB 231 breast cancer cells and low density lipoprotein receptor-related protein-1-deficient murine embryonic fibroblasts, SuPAR substantially decreases ERK activation. The mechanism probably involves competitive displacement of membrane-anchored uPAR-uPA complex from signaling adaptor proteins. As a result of its effects on cell signaling, SuPAR blocks cell growth and inhibits cellular invasion of Matrigel. Cleavage of SuPAR by proteinases increases its signaling agonist activity and reverses its inhibitory effects on growth and invasion. Thus, proteolytic cleavage represents a molecular switch that neutralizes the anticancer activity of SuPAR.
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PMID:Soluble urokinase-type plasminogen activator receptor inhibits cancer cell growth and invasion by direct urokinase-independent effects on cell signaling. 1296 22

VEGF-A is a major angiogenesis and permeability factor. Its cellular effects, which can be used as targets in anti-angiogenesis therapy, have mainly been studied in vitro using endothelial cell cultures. The purpose of the present study was to further characterize these effects in vivo in vascular endothelial cells and pericytes, in an experimental monkey model of VEGF-A-induced iris neovascularization. Two cynomolgus monkeys (Macaca fascicularis) received four injections of 0.5 microg VEGF-A in the vitreous of one eye and PBS in the other eye. After sacrifice at day 9, eyes were enucleated and iris samples were snap-frozen for immunohistochemistry (IHC) and stained with a panel of antibodies recognizing endothelial and pericyte determinants related to angiogenesis and permeability. After VEGF-A treatment, the pre-existing iris vasculature showed increased permeability, hypertrophy, and activation, as demonstrated by increased staining of CD31, PAL-E, tPA, uPA, uPAR, Glut-1, and alphavbeta3 and alphavbeta5 integrins, VEGF receptors VEGFR-1, -2 and -3, and Tie-2 in endothelial cells, and of NG2 proteoglycan, uPA, uPAR, integrins and VEGFR-1 in pericytes. Vascular sprouts at the anterior surface of the iris were positive for the same antigens except for tPA, Glut-1, and Tie-2, which were notably absent. Moreover, in these sprouts VEGFR-2 and VEGFR-3 expression was very high in endothelial cells, whereas many pericytes were present that were positive for PDGFR-beta, VEGFR-1, and NG2 proteoglycan and negative for alpha-SMA. In conclusion, proteins that play a role in angiogenesis are upregulated in both pre-existing and newly formed iris vasculature after treatment with VEGF-A. VEGF-A induces hypertrophy and loss of barrier function in pre-existing vessels, and induces angiogenic sprouting, characterized by marked expression of VEGFR-3 and lack of expression of tPA and Tie-2 in endothelial cells, and lack of alpha-SMA in pericytes. Our in vivo study indicates a role for alpha-SMA-negative pericytes in early stages of angiogenesis. Therefore, our findings shed new light on the temporal and spatial role of several proteins in the angiogenic cascade in vivo.
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PMID:In vivo angiogenic phenotype of endothelial cells and pericytes induced by vascular endothelial growth factor-A. 1468 16

We established the novel sublines HPC-1H5, HPC-3H4, HPC-4H4, and Panc-1H5, which have a high potential of liver metastasis, and HPC-1P5a, HPC-3P4a, HPC-4P4a, and Panc-1P5a, which have a high potential of peritoneal dissemination, derived from low metastatic HPC-1, HPC-3, HPC-4, and Panc-1cell lines, respectively. To clarify the molecular mechanisms of cancer metastasis and of the different levels of gene expression in a variety of metastatic potentials in pancreatic cancer, we performed a broad analysis of differential gene expression analysis between parental cell lines and metastatic sublines. In comparison with the parental cell lines, 65 and 36 genes were overexpressed and underexpressed in highly liver-metastatic sublines. On the other hand, 43 and 45 genes were overexpressed and underexpressed in highly peritoneal-metastatic sublines. uPAR and Serin protease were overexpressed, and E2A and IGF1R were underexpressed in both metastatic sublines. Hierarchical clustering analysis revealed 22 genes classifying liver, peritoneal metastatic sublines and low-metastatic parental cell lines. These genes might be targeted genes separating those two major metastatic forms after surgery. A greater number of cell line samples and more genes will have to be utilized in future studies in order to understand the involvement of genes in cancer metastasis more thoroughly. However, these results will help to clarify the molecular mechanisms of pancreatic cancer metastasis.
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PMID:Profiling analysis of differential gene expression between hematogenous and peritoneal metastatic sublines of human pancreatic cancer using a DNA chip. 1559 44


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