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)

HER2 (also known as Neu, ErbB2) is a member of the epidermal growth factor receptor (EGFR; also known as ErbB) family of receptor tyrosine kinases, which in humans includes HER1 (EGFR, ERBB1), HER2, HER3 (ERBB3) and HER4 (ERBB4). ErbB receptors are essential mediators of cell proliferation and differentiation in the developing embryo and in adult tissues, and their inappropriate activation is associated with the development and severity of many cancers. Overexpression of HER2 is found in 20-30% of human breast cancers, and correlates with more aggressive tumours and a poorer prognosis. Anticancer therapies targeting ErbB receptors have shown promise, and a monoclonal antibody against HER2, Herceptin (also known as trastuzumab), is currently in use as a treatment for breast cancer. Here we report crystal structures of the entire extracellular regions of rat HER2 at 2.4 A and human HER2 complexed with the Herceptin antigen-binding fragment (Fab) at 2.5 A. These structures reveal a fixed conformation for HER2 that resembles a ligand-activated state, and show HER2 poised to interact with other ErbB receptors in the absence of direct ligand binding. Herceptin binds to the juxtamembrane region of HER2, identifying this site as a target for anticancer therapies.
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PMID:Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. 1261 Jun 29

The rapidly growing knowledge of molecular mechanisms will change the daily routine of clinicians in the near future. Regarding urothelial bladder carcinoma, one may expect that molecular diagnostics will identify patients susceptible to disease development by screening their genotype. Furthermore, in addition to histopathologic findings, prognostic markers will be used for disease management. In an ongoing multicenter trial, the decision on whether or not to treat patients with adjuvant chemotherapy after cystectomy is based on their p53 status. In the near future, cytostatic medications are expected to be chosen according to genetic profiles of the tumor or patient. New medications, which target tumor-specific alterations of cell-signaling cascades in bladder or other cancers, prominently inhibitors of the ERBB membrane receptor family, are currently under clinical investigation and will undoubtedly form an important part of therapeutic oncologic regimens. In conclusion, evaluation of gene profiles of tumors and patients will gain importance for clinicians.
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PMID:[Perspectives for molecular diagnostics exemplified by urothelial bladder carcinoma]. 1275 Aug

The 8p11-21 region is a frequent target of alterations in breast cancer and other carcinomas. We surveyed 34 breast tumor cell lines and 9 pancreatic cancer cell lines for alterations of this region by use of multicolor fluorescence in situ hybridization (M-FISH) and BAC-specific FISH. We describe a recurrent chromosome translocation breakpoint that targets the NRG1 gene on 8p12. NRG1 encodes growth factors of the neuregulin/heregulin-1 family that are ligands for tyrosine kinase receptors of the ERBB family. Breakpoints within the NRG1 gene were found in four of the breast tumor cell lines: ZR-75-1, in a dic(8;11); HCC1937, in a t(8;10)(p12;p12.1); SUM-52, in an hsr(8)(p12); UACC-812, in a t(3;8); and in two of the pancreatic cancer cell lines: PaTu I, in a der(8)t(4;8); and SUIT-2, in a del(8)(p). Mapping by two-color FISH showed that the breaks were scattered over 1.1 Mb within the NRG1 gene. It is already known that the MDA-MB-175 breast tumor cell line has a dic(8;11), with a breakpoint in NRG1 that fuses NRG1 to the DOC4 gene on 11q13. Thus, we have found a total of seven breakpoints, in two types of cancer cell lines, that target the NRG1 gene. This suggests that the NRG1 locus is a recurring target of translocations in carcinomas. PCR analysis of reverse-transcribed cell line RNAs revealed an extensive complexity of the NRG1 transcripts but failed to detect a consistent pattern of mRNA isoforms in the cell lines with NRG1 breakpoint.
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PMID:A recurrent chromosome translocation breakpoint in breast and pancreatic cancer cell lines targets the neuregulin/NRG1 gene. 1280 Jan 45

The ErbB-driven autocrine growth pathway has been implicated in the development and progression of most common human epithelial malignancies; its blockade is therefore a promising therapeutic strategy, and several candidate drugs are currently undergoing clinical trials. Paradoxically, little is known of the expression pattern of these 4 genes in human tumors, and the clinical significance of the 2 most recently discovered ERBB genes, ERBB3 and ERBB4, is unclear. We used a real-time quantitative RT-PCR assay to quantify ERBB family mRNA copy numbers in a large series of breast tumors from patients with known long-term outcome. ERBB gene expression varied widely, by more than 2 orders of magnitude for ERBB1 and ERBB3, more than 3 orders for ERBB2 and more than 4 orders for ERBB4. We found a positive correlation between ERBB3 and ERBB4 mRNA levels, and a negative correlation between the expression of these 2 latter genes and that of ERBB1. Compared to normal breast tissue, ERBB1 was underexpressed (82.3% of tumors), ERBB2 (16.9%) and ERBB3 (46.2%) were overexpressed and ERBB4 was both underexpressed (24.6%) and overexpressed (29.2%). Links were also found between ERBB status on the one hand and Scarff-Bloom-Richardson (SBR) histopathological grade and estrogen receptor alpha (ERa) status on the other hand. Relapse-free survival (RFS) was shorter among patients with ERBB3-overexpressing tumors (p=0.0092) and longer among those with ERBB4-underexpressing tumors (p=0.0085) relative to patients with normal expression of the respective genes; in contrast, RFS was not significantly influenced by ERBB1 or ERBB2 mRNA status. Only ERBB4 status retained prognostic significance in Cox multivariate regression analysis (p=0.015). Our results point to the involvement of several ErbB-specific ligands (amphiregulin and neuregulin 1) and enzymes or adaptor molecules (PI3K, Src, Shc and Grb7) in the ErbB pathway dysregulation associated with breast cancer. These findings reveal a complex expression pattern of ERBB gene family members in breast tumors and suggest that it is this pattern of expression, rather than the expression of individual family members, that should be taken into account when evaluating antitumoral drugs designed to target these receptors.
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PMID:Prognostic value of ERBB family mRNA expression in breast carcinomas. 1286 37

Ionizing radiation induces in autocrine growth-regulated carcinoma and malignant glioma cells powerful cytoprotective responses that confer relative resistance to consecutive radiation exposures. Understanding the mechanisms of these responses should provide new molecular targets for tumor radiosensitization. ERBB and other receptor Tyr kinases have been identified as immediate early response gene products that are activated by radiation within minutes, as by their physiological growth factor ligands, and induce secondary stimulation of cytoplasmic protein kinase cascades. The simultaneous activation of all receptor Tyr kinases and nonreceptor Tyr kinases leads to complex cytoprotective responses including increased cell proliferation, reduced apoptosis and enhanced DNA repair. Since these responses contribute to cellular radioresistance, ERBB1, the most extensively studied ERBB receptor, is examined as a target for tumor cell radiosensitization. The three methods of ERBB1 inhibition include blockade of growth factor binding by monoclonal antibody against the ligand-binding domain, inhibition of the receptor Tyr kinase-mediating receptor activation, and overexpression of a dominant-negative epidermal growth factor receptor-CD533 that lacks the COOH-terminal 533 amino acids and forms nonfunctional heterodimeric complexes with wild-type receptors. All the three approaches enhance radiation toxicity in vitro and in vivo. The different mechanisms of inhibition have contributed to the understanding of cellular responses to radiation, vary in relative effectiveness and pose different challenges for translation.
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PMID:ERBB receptor tyrosine kinases and cellular radiation responses. 1294 92

The ERBB family of type 1 receptor tyrosine kinases and their ligands have crucial functions during mammopoiesis, but the signaling networks that ultimately regulate ERBB activity in the breast have remained elusive. Here, we show that mice with Cre-lox mediated deletions of both Erbb4 alleles within the developing mammary gland (Erbb4(Flox/Flox)Wap-Cre) fail to accumulate lobuloalveoli or successfully engage lactation at parturition owing, in part, to impaired epithelial proliferation. Analysis of the mammary differentiation factor STAT5 by immunohistochemistry and western blot revealed a complete ablation of STAT5 activation in Erbb4(Flox/Flox)Wap-Cre mammary epithelium at parturition. Consistent with disrupted STAT5 function, Erbb4(Flox/Flox)Wap-Cre mammary glands at parturition failed to express the mammary epithelial differentiation marker NPT2B. Defects in epithelial functional differentiation at parturition were accompanied by a profound reduction in expression of the STAT5-regulated milk genes casein beta and whey acidic protein. We propose that ERBB4 functions as an essential mediator of STAT5 signaling, and that loss of STAT5 activity contributes to the impaired functional differentiation of mammary glands observed in mice containing conditional Erbb4 deletions.
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PMID:Impaired differentiation and lactational failure of Erbb4-deficient mammary glands identify ERBB4 as an obligate mediator of STAT5. 1295 15

Previously, we demonstrated that deoxycholic acid (DCA)-induced ERK1/2 and AKT signaling in primary hepatocytes is a protective response. In the present study, we examined the regulation of the phosphatidylinositol 3 (PI3) kinase/AKT/glycogen synthase (kinase) 3 (GSK3)/glycogen synthase (GS) pathway by bile acids. In primary hepatocytes, DCA activated ERBB1 (the epidermal growth factor receptor), ERBB2, and the insulin receptor, but not the insulin-like growth factor 1 (IGF-1) receptor. DCA-induced activation of the insulin receptor correlated with enhanced phosphorylation of insulin receptor substrate 1, effects that were both blocked by the insulin receptor inhibitor AG1024 and by expression of the dominant negative IGF-1 receptor (K1003R), which inhibited in trans. Expression of the dominant negative IGF-1 receptor (K1003R) also abolished DCA-induced AKT activation. Bile acid-induced activation of AKT and phosphorylation of GSK3 were blunted by the ERBB1 inhibitor AG1478 and abolished by AG1024. Bile acids caused activation of GS to a similar level induced by insulin (50 nM); both were blocked by inhibition of insulin receptor function and the PI3 kinase/AKT/GSK3 pathway. In conclusion, these findings suggest that bile acids and insulin may cooperate to regulate glucose storage in hepatocytes.
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PMID:Bile acids enhance the activity of the insulin receptor and glycogen synthase in primary rodent hepatocytes. 1476 98

We examined the impact of purified bacterially synthesized GST-MDA-7 (IL-24) and ionizing radiation on the proliferation and survival of nonestablished human glioblastoma multiforme (GBM) cells. Glioma cell types expressing mutated PTEN and p53 molecules, activated ERBB1VIII, overexpressing wild type ERBB1 or without receptor overexpression were selected. In MTT assays, GST-MDA-7 caused a dose-dependent reduction in the proliferation of nonestablished glioma cells; however only at higher concentrations did GST-MDA-7 reduce cell viability. The anti-proliferative and cytotoxic effects of GST-MDA-7 were enhanced by radiation in a greater than additive fashion that correlated with JNK1/2/3 activation. The reduction in cell growth and enhancement in cell killing by the combination of GST-MDA-7 and radiation were blocked by an ROS scavenger, N-acetyl cysteine (NAC), a JNK1/2/3 inhibitor SP600125, a pan-caspase inhibitor (zVAD) and by an inhibitor of caspase 9 (LEHD), but not by an inhibitor of caspase 8 (IETD). Low concentrations of either GST-MDA-7 or radiation reduced clonogenic survival, however colony formation ability was significantly further decreased when the two treatments were combined, which was also blocked by inhibition of caspase 9 function. In general agreement with activation of the intrinsic caspase pathway, cell death correlated with reduced BCL-XL expression and with increased levels of the pro-apoptotic proteins BAD and BAX. Inhibition of caspase 9 after combination treatment blunted neither JNK1/2/3 activation nor the enhanced expression of BAD and BAX, but did block caspase 3 cleavage, reduced expression of BCL-XL and inhibition of ERK1/2 activity. In contrast, incubation with NAC blocked JNK1/2/3 activation and cell killing, but not the increases in BAD and BAX expression. These findings argue that after combination treatment JNK1/2/3 activation is a primary pro-apoptotic event and loss of BCL-XL expression and ERK1/2 activity are secondary caspase-dependent processes. This data also argues that GST- MDA-7 induces two parallel pro-apoptotic pathways via ROS-dependent and -independent mechanisms. Infection of primary human astrocytes with a recombinant adenovirus to express MDA-7, Ad.mda-7, but not infection with either Ad.cmv or Ad.mda-7SP- lacking MDA-7 secretion, resulted in the suppression of GBM cell colony formation in soft agar overlay assays, an effect that was enhanced in a greater than additive fashion by radiation. Collectively, our findings demonstrate that MDA-7 reduces proliferation and enhances the radiosensitivity of nonestablished human GBM cells in vitro, and when grown in 3 dimensions, and that sensitization occurs independently of basal EGFR/ERK1/2/AKT activity or the functions of PTEN and p53.
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PMID:MDA-7 regulates cell growth and radiosensitivity in vitro of primary (non-established) human glioma cells. 1532 89

Previous studies have demonstrated in hepatocytes that deoxycholic acid (DCA) promotes inactivation of protein tyrosine phosphatases (PTPases) and activation of ERBB1 and the extracellular-regulated kinase (ERK) 1/2 pathway. The present studies have determined the biochemical mechanism(s) through which these events occur. DCA and taurodeoxycholic acid (TDCA) (100 micromol/L) caused activation of ERBB1, insulin receptor, and the ERK1/2 and AKT pathways in primary rodent hepatocytes. DCA- and TDCA-induced receptor and signaling pathway activations were blocked by the reactive oxygen species (ROS) scavengers N-acetyl cysteine (NAC) and Trolox (TX), as well as by cyclosporin A (CsA) and bongkrekic acid (BKA). DCA activated the ERK1/2 pathway in HuH7 human hepatoma cells that was blocked by the incubation of cells with an ERBB1 inhibitor, NAC, TX, CsA, or BKA. DCA did not activate the ERK1/2 pathway in mitochondria-defective HuH7 Rho 0 cells. In HuH7 cells and primary hepatocytes, DCA enhanced the production of ROS, an effect that was abolished in Rho 0 cells and by prior incubation of cells with CsA or BKA. In hepatocytes and HuH7 cells, DCA inhibited PTPase activity. Incubation of hepatocytes with either CsA or BKA prevented DCA-induced inhibition of PTPase activity. Loss of mitochondrial function in Rho 0 cells also abolished the inhibitory effects of DCA on PTPase activity. In conclusion, DCA and TDCA cause ROS generation in hepatocytes that is dependent on metabolically active mitochondria. The generation of ROS is essential for PTPase inactivation, receptor tyrosine kinase activation, and enhanced signaling down the ERK1/2 and AKT pathways.
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PMID:Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes. 1538 21

As a single agent the ERBB1 inhibitor, gefitinib (Iressa; ZD1839) showed minimal activity against a panel of 10 pediatric tumor xenografts that do not express the ERBB1 receptor. However, combined with irinotecan (CPT-11), significantly greater than additive activity was observed in four of eight models (P < 0.05), and the combination showed enhanced activity against three additional tumor lines. Breast cancer resistance protein (ABCG2), a transporter that confers resistance to SN-38 (the active metabolite of irinotecan), was readily detected in six of nine xenograft models examined by immunohistochemistry. In vitro gefitinib potently reversed resistance to SN-38 only in a cell line that overexpressed functional ABCG2. However, overexpression of ABCG2 did not decrease accumulation nor increase the rate of efflux of [(14)C]gefitinib. On the basis of these results and the distribution of Abcg2 in mouse tissues, we assessed the ability of gefitinib to modulate irinotecan pharmacokinetics. Oral gefitinib coadministration resulted in no change in clearance of intravenously administered irinotecan. However, gefitinib treatment dramatically increased the oral bioavailability of irinotecan after simultaneous oral administration. It is concluded that gefitinib may modulate SN-38 activity at the cellular level to reverse tumor resistance mediated by ABCG2 through inhibiting drug efflux and may be used potentially in humans to modulate the oral bioavailability of a poorly absorbed camptothecin such as irinotecan.
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PMID:Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice. 1549 75


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