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)

Recent publications dealing with the pathology of squamous carcinomas of the head and neck have been critically reviewed with particular reference to potential prognostic factors and improved methods for identifying nodal metastases. The topics covered include cytophotometry and proliferative patterns, molecular biology (EGFR and p53 genes), cell adhesion molecules (E cadherin), and combined radiologic and pathologic approaches to detect small volume metastases in cervical lymph nodes.
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PMID:Pathology of squamous carcinomas of the head and neck. 849 10

Pagliaccio (Pag) is a receptor tyrosine kinase of the Eph family that is expressed in Xenopus embryos in a diverse set of localized tissues. Pag is the Xenopus homolog of Hek-8 (human), Sek-1 (mouse), cek8 (chicken), and RTK-1 (zebrafish). We have investigated the function of this protein by injecting RNA encoding an epidermal growth factor receptor-Pag chimera into early Xenopus embryos. Activation of the chimeric receptor results in a kinase-dependent loss of cell-cell adhesion. This dissociation can be reversed by co-injection of RNA encoding C-cadherin, suggesting that one or more cadherins could be the functional targets for Pag activity.
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PMID:Disruption of cell adhesion in Xenopus embryos by Pagliaccio, an Eph-class receptor tyrosine kinase. 890 47

Tumour angiogenesis is an important prognostic factor in non-small cell lung cancer. Recently, EGFR and c-erbB-2 protein was found to regulate cell adhesion and the invasive growth of cancer through its association with the cadherin-catenin complex. The role of c-erbB-2 protein in cell migration has been also reported. In this study we investigate the combined role of tumoral neoangiogenesis and c-erbB-2/EGFR expression in the metastatic behaviour and prognosis of operable non-small cell lung cancer. 107 tumour samples from patients suffering from operable non small cell lung cancer were examined. EGFR and c-erbB-2 were not correlated with each other. C-erbB-2 expression was associated with low angiogenesis, approaching statistical significance in adenocarcinomas (p = 0.08). The absence of expression of both c-erbB-2 and EGFR oncogenes in tumours with high angiogenesis, was most frequently observed in node negative cases (p = 0.04). C-erbB-2 overexpression defined a subgroup of node negative patients with low angiogenesis and prognosis similar to patients with tumours bearing high angiogenesis. These findings support the hypothesis that expression of the erb genes is a mechanism activated in non-small cell lung cancer to enable cancer cell migration. This pathway seems to be activated mainly in tumours with poor vasculature presumably lading to an unfavourable intratumoral nutritional and oxygen ambience.
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PMID:Non-small cell lung cancer: c-erbB-2 overexpression correlates with low angiogenesis and poor prognosis. 904 64

Multiple endocrine neoplasia type 2 (MEN 2) is a cancer syndrome which comprises three related disorders, MEN type 2A (MEN 2A), type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC), MEN 2A is characterized by the association of MTC, a tumour arising from thyroid C-cells, pheochromocytoma and parathyroid hyperplasia. In addition to the thyroid cancer, MEN 2B associates pheochromocytoma, mucosal neuromas, ganglioneuromatosis of the digestive tract and skeletal abnormalities. In FMTC, the MTC is the sole clinical manifestation. MEN 2 is a dominantly inherited neural crest disorder caused by germline mutations of the RET proto-oncogene. The RET gene encodes a receptor tyrosine kinase, which displays a cadherin-like domain and a cysteine rich motif in its extracellular part. Missense mutations at one of five cysteines clustered in the extra-cytoplasmic domain of RET have been identified in the majority of the MEN 2A families and in two-thirds of FMTC. A single point mutation leading to the replacement of a methionine by a threonine within the tyrosine kinase domain has been detected in almost all cases of MEN 2B. We have screened 170 french MEN 2 families and a germline mutations in the RET gene have been identified in 92% of cases. Moreover, we confirmed the significant correlation between the nature, the position of the RET mutations and the clinical phenotype. The accurate identification by DNA testing of individual predisposed to MEN 2 suggests new protocols of treatment. Thyroidectomy as early as 6 years of age in individuals with MEN 2 mutations has been recently advocated by clinicians. We further provide evidence that MEN 2A and MEN 2B mutations convert the RET proto-oncogene in a dominantly-acting transforming gene due to the ligand-independent constitutive activation of the tyrosine kinase. Finally, we have constructed transgenic mice carrying the RET gene carrying a MEN 2A mutation fused to the calcitonin gene related peptide/calcitonin promoter. Animals of three independent transgenic lines developed C-cell hyperplasia and subsequently MTC with a complete penetrance. Taken together, these findings indicate that MEN 2A form of RET is oncogenic in thyroid C-cells, and suggest that these transgenic animals should prove a valuable model for hereditary MTC. Future work should yield insights in the signaling pathways subverted by the RET-MEN 2 proteins.
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PMID:[Neural crest and multiple endocrinopathies]. 907 21

The recent highlighted points in prognostic factors after breast cancer operation include: 1) the emergence of many genetic and biochemical markers, including c-erbB-2, int-2, EGFR, p53, nm23, LOH, E cadherin, s-phase fraction. The prognostic value of these factors is related to their role in cell cycle regulation, invasion/metastasis mechanisms, etc. The agents related to therapeutic effectiveness, namely p-glycoprotein, pS2, and bcl-2 may become important stratification factors when conducting clinical trials. Pathologic factors, like nodal status, however, are the most useful prognostic factors at the moment. Many newly developed prognostic factors should be examined by multivariate analysis and validated prospectively before clinical use.
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PMID:[Recent prognostic factors for breast cancer]. 912 98

Hirschsprung's disease (HSCR) is a common congenital malformation characterized by the absence of intramural ganglion cells of the hindgut. Recently, mutations of the RET tyrosine kinase receptor have been identified in 50 and 15-20% of familial and sporadic HSCR, respectively. These mutations include deletion, insertion, frameshift, nonsense, and missense mutations dispersed throughout the RET coding sequence. To investigate their effects on RET function, seven HSCR missense mutations were introduced into either a 1114-amino acid wild-type RET isoform (RET51) or a constitutively activated form of RET51 (RET-MEN 2A). Here, we report that one mutation affecting the extracytoplasmic cadherin domain (R231H) and two mutations located in the tyrosine kinase domain (K907E, E921K) impaired the biological activity of RET-MEN 2A when tested in Rat1 fibroblasts and pheochromocytoma PC12 cells. However, the mechanisms resulting in RET inactivation differed since the receptor bearing R231H extracellular mutation resulted in an absent RET protein at the cell surface while the E921K mutation located within the catalytic domain abolished its enzymatic activity. In contrast, three mutations mapping into the intracytoplasmic domain neither modified the transforming capacity of RET-MEN 2A nor stimulated the catalytic activity of RET in our ligand-independent system (S767R, P1039L, M1064T). Finally, the C609W HSCR mutation exerts a dual effect on RET since it leads to a decrease of the receptor at the cell surface and converted RET51 into a constitutively activated kinase due to the formation of disulfide-linked homodimers. Taken together, our data show that allelic heterogeneity at the RET locus in HSCR is associated with various molecular mechanisms responsible for RET dysfunction.
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PMID:Various mechanisms cause RET-mediated signaling defects in Hirschsprung's disease. 950 84

Totipotent murine ES cells have an enormous potential for the study of cell specification. Here we demonstrate that ES cells can differentiate to hemopoietic cells through the proximal lateral mesoderm, merely upon culturing in type IV collagen-coated dishes. Separation of the Flk1+ mesoderm from other cell lineages was critical for hemopoietic cell differentiation, whereas formation of the embryoid body was not. Since the two-dimensionally spreading cells can be monitored easily in real time, this culture system will greatly facilitate the study of the mechanisms involved in the cell specification to mesoderm, endothelial, and hemopoietic cells. In the culture of ES cells, however, lineages and stages of differentiating cells can only be defined by their own characteristics. We showed that a combination of monoclonal antibodies against E-cadherin, Flk1/KDR, PDGF receptor(alpha), VE-cadherin, CD45 and Ter119 was sufficient to define most intermediate stages during differentiation of ES cells to blood cells. Using this culture system and surface markers, we determined the following order for blood cell differentiation: ES cell (E-cadherin+Flk1-PDGFRalpha-), proximal lateral mesoderm (E-cadherin-Flk1+VE-cadherin-), progenitor with hemoangiogenic potential (Flk1+VE-cadherin+CD45-), hemopoietic progenitor (CD45+c-Kit+) and mature blood cells (c-Kit-CD45+ or Ter119+), though direct differentiation of blood cells from the Flk1+VE-cadherin- stage cannot be ruled out. Not only the VE-cadherin+CD45- population generated from ES cells but also those directly sorted from the yolk sac of 9.5 dpc embryos have a potential to give rise to hemopoietic cells. Progenitors with hemoangiogenic potential were identified in both the Flk1+VE-cadherin- and Flk1+VE-cadherin+ populations by the single cell deposition experiment. This line of evidence implicates Flk1+VE-cadherin+ cells as a diverging point of hemopoietic and endothelial cell lineages.
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PMID:Progressive lineage analysis by cell sorting and culture identifies FLK1+VE-cadherin+ cells at a diverging point of endothelial and hemopoietic lineages. 952 12

Interendothelial junctions play an important role in the regulation of endothelial functions, such as vasculogenesis, angiogenesis, and vascular permeability. In this paper we show that vascular endothelial growth factor (VEGF), a potent inducer of new blood vessels and vascular permeability in vivo, stimulated the migration of endothelial cells after artificial monolayer wounding and induced an increase in paracellular permeability of human umbilical vein endothelial cells (HUVECs). Furthermore, VEGF increased phosphotyrosine labeling at cell-cell contacts. Biochemical analyses revealed a strong induction of VEGF-receptor-2 (flk-1/KDR) tyrosine-autophosphorylation by VEGF which was maximal after 5 minutes and was followed by receptor downregulation. 15 minutes to 1 hour after VEGF stimulation the endothelial adherens junction components VE-cadherin, beta-catenin, plakoglobin, and p120 were maximally phosphorylated on tyrosine, while alpha-catenin was not modified. PECAM-1/CD31, another cell-cell junctional adhesive molecule, was tyrosine phosphorylated with similar kinetics in response to VEGF. In contrast, activation of VEGF-receptor-1 (Flt-1) by its specific ligand placenta growth factor (PlGF) had no effect on the tyrosine phosphorylation of cadherins and catenins. Despite the rapid and transient receptor activation and the subsequent tyrosine phosphorylation of adherens junction proteins the cadherin complex remained stable and associated with junctions. Our results demonstrate that the endothelial adherens junction is a downstream target of VEGFR-2 signaling and suggest that tyrosine phosphorylation of its components may be involved in the the loosening of cell-cell contacts in established vessels to modulate transendothelial permeability and to allow sprouting and cell migration during angiogenesis.
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PMID:Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells. 962 48

LPS directly disrupts EC barrier function in vitro and in vivo. This barrier dysfunction has been reported to occur in EC derived from both the macro- and microvasculature of varying species, including humans. Unlike other EC responses, LPS-induced loss of endothelial barrier function is protein-synthesis independent. In fact, protein synthesis inhibition enhances the LPS effect. The lipid A moiety is responsible for LPS-induced activation of the non-CD14-bearing EC, and agents that bind to and neutralize this highly conserved portion of the LPS molecule can crossprotect against EC barrier dysfunction elicited by LPS derived from diverse species of Gram-negative bacteria. Although the presentation of LPS to CD14-bearing cells such as macrophages and monocytes has been well characterized, far less is known about the interactions of LPS with the non-CD14-bearing EC. An EC receptor involved in LPS binding and cellular activation has yet to be identified. The presence of the accessory molecules, LBP and sCD14, are prerequisite to LPS-induced activation of EC at clinically relevant LPS concentrations. As with monocytes and macrophages, the CD14 dependence of LPS-induced endothelial barrier dysfunction can be overcome with high concentrations of LPS. In the absence of LBP and sCD14, a 200,000-fold increase in LPS concentration is required to elicit the same increments in EC monolayer permeability relative to when these accessory molecules are present. Within 30 minutes after LPS exposure, PTK activation is observed. PTK inhibition blocks LPS-induced EC actin depolymerization and endothelial barrier dysfunction which are seen only after a > or = 2-hour stimulus-to-response lag time. Furthermore this LPS-induced actin depolymerization is a prerequisite to opening up the paracellular pathway and loss of monolayer integrity. Interestingly LPS-induced increments in transendothelial 14C-BSA flux and EC detachment parallel caspase-mediated cleavage of ZA and FA proteins that participate in cell-cell and cell-matrix adhesion. The cleavage of the ZA components, beta- and gamma-catenin, does not affect their ability to bind the transmembrane protein, cadherin, or the actin-binding protein, alpha-catenin, suggesting that the linkage of the ZA to the actin cytoskeleton remains intact. LPS-induced cleavage of the FA protein, FAK, leads to dissociation of its catalytic domain from paxillin substrate and decreased paxillin phosphotyrosine content. Caspase inhibition protects against LPS-provoked apoptosis, cleavage of adherens junction proteins, paxillin dephosphorylation, cell-shape changes, and EC detachment. In contrast it fails to block LPS-induced increments in transendothelial 14C-BSA flux. PTK inhibition, which does protect against increased transendothelial 14C-BSA flux, does not block LPS-induced proteolytic cleavage events and only partially inhibits EC detachment. These findings suggest that the EC detachment and endothelial barrier dysfunction elicited by LPS are mediated through distinct pathways (Fig. 6). Much of the work to date has focused on LPS interactions with mCD14-bearing cells, such as monocytes and macrophages, which are central to the inflammatory response elicited by endotoxin. EC, which line the vasculature, are one of the first host tissue barriers to encounter circulating LPS. Because damage to the endothelium is known to contribute to the development of multiorgan failure, including ARDS, understanding LPS-induced EC dysfunction in the setting of Gram-negative septicemia has clear pathophysiologic implications. (ABSTRACT TRUNCATED)
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PMID:Direct effects of endotoxin on the endothelium: barrier function and injury. 1053 83

Expression of the brain natriuretic peptide (BNP) gene in cultured neonatal rat ventricular myocytes is activated by mechanical strain in vitro. We explored the role of cell-matrix contacts in initiating the strain-dependent increment in human BNP (hBNP) promoter activity. Coating the culture surface with fibronectin effected a dose-dependent increase in basal hBNP luciferase activity and amplification of the response to strain. Preincubation of myocytes with an RGD peptide (GRGDSP) or with soluble fibronectin, each of which would be predicted to compete for cell-matrix interactions, resulted in a dose-dependent reduction in strain-dependent hBNP promoter activity. A functionally inert RGE peptide (GRGESP) was without effect. Using fluorescence-activated cell sorting, we demonstrated the presence of beta(1), beta(3), and alpha(v)beta(5) integrins in myocytes as well as non-myocytes and alpha1 only in non-myocytes in our cultures. Inclusion of antibodies directed against beta(1), beta(3), or alpha(v)beta(5), but not alpha(1), alpha(2), or cadherin, was effective in blocking the BNP promoter response to mechanical strain. These same antibodies (anti-beta(3), -beta(1), and -alpha(v)beta(5)) had a similar inhibitory effect on strain-stimulated ERK, p38 MAPK, and, to a lesser extent, JNK activities in these cells. Cotransfection with chimeric integrin receptors capable of acting as dominant-negative inhibitors of integrin function demonstrated suppression of strain-dependent BNP promoter activity when vectors encoding beta(1) or beta(3), but not beta(5), alpha(5), or a carboxyl-terminal deletion mutant of beta(3) (beta(3)B), were employed. These studies underscore the importance of cell-matrix interactions in controlling cardiac gene expression and suggest a potentially important role for these interactions in signaling responses to mechanical stimuli within the myocardium.
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PMID:Integrin dependence of brain natriuretic peptide gene promoter activation by mechanical strain. 1076 70


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