Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cell adhesion molecules (CAMs) NCAM, N-cadherin, and L1 are homophilic binding molecules that stimulate axonal growth. We have postulated that the above CAMs can stimulate this response by activating the fibroblast growth factor receptor (FGFR) in neurons. In the present study, we demonstrate that activation of NCAM and L1 can lead to phosphorylation of the FGFR. Both this and the neurite outgrowth response stimulated by all three of the above CAMs are lost when a kinase-deleted, dominant negative form of FGFR1 is expressed in PC12 cells. In addition, we have generated transgenic mice that express the dominant negative FGFR under control of the neuron-specific enolase (NSE) promoter. We show that cerebellar neurons isolated from these mice have also lost their ability to respond to NCAM, N-cadherin, and L1. A peptide inhibitor of phospholipase C gamma (PLCgamma) that inhibits neurite outgrowth stimulated by FGF also inhibited neurite outgrowth stimulated by the CAMs. Thus, we conclude that activation of the FGFR is both necessary and sufficient to account for the ability of the above CAMs to stimulate axonal growth, and that PLCgamma is a key downstream effector of this response.
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PMID:Expression of a dominant negative FGF receptor inhibits axonal growth and FGF receptor phosphorylation stimulated by CAMs. 905 94

Pattern formation of the limb muscles involves a network between intrinsic programs of gene expression in myogenic precursor cells and extrinsic signals derived from the surrounding tissue. The cells at the lateral edge of the somite are specified to the precursors of the hypaxial muscles by intercelluler interaction with the dorsal ectoderm and the lateral mesoderm. At the level of the limb bud, these premyogenic cells expressing c-MET and Pax-3 are induced to invade into the limb bud by HGF/SF and unknown chemotactic signal(s) exerted by the limb mesenchyme. It is likely that N-cadherin and some extracellular matrixes are involved in this phenomena. In the limb bud, myogenic cells proliferate under influence of the limb ectoderm and congregate into the premuscle masses. BMPs expressed in limb ectoderm may maintain the proliferative phase of the myogenic cells by inhibition of the myogenic differentiation. Recently, detailed analysis of expression of Hox genes in the chick limb musculature suggests that Hoxa-11 and Hoxa-13 autonomously regulate the pattern formation of the limb muscles. Hoxa-11 is induced in the myogenic cells by an interaction with the limb mesenchyme as soon as they invade into the limb. It is possible that Hoxa-11 may confer a limb-specific property on these myogenic cells. After the formations of muscle masses, Hoxa-11 and Hoxa-13 are expressed in the muscle masses in region-specific manner along the anteroposterior and proximodistal axes under the control of the limb mesenchyme and the polarizing signal(s). They are candidates for intrinsic regulator of myogenic cells that control 1) the splitting processes of the muscle masses and 2) the specification of each muscle.
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PMID:[Molecular mechanism of limb muscle patterning]. 999 Feb 4

Hirschsprung's disease (HD) is characterised by the absence of ganglion cells and the presence of hypertrophic nerve trunks in the distal bowel. It has been suggested that aganglionosis may be caused by failure of differentiation as a result of microenvironmental change after neuronal migration has occurred. Recently, it was reported that cell-adhesion molecules (CAMs) and fibroblast growth factors (FGFs) stimulate neurite outgrowth through activation of FGF receptors (FGFRs) in neurons. The aim of this study was to investigate the expression of CAMs FGFs, and FGFRs in ganglionic (NG) and aganglionic (AG) segments of HD in order to understand the role of CAM-FGF signalling in the pathogenesis of HD. Specimens from NG and AG segments of bowel from 11 patients with HD were obtained at the time of definitive pull-through operation, snap-frozen in OCT compound, and stored at -70 degrees C. Aganglionosis was confirmed by Haematoxylin and eosin staining and acetylcholinesterase histochemistry; 8-micron cryosections were immunostained using the standard streptavidinbiotin-immunoperoxidase method. The following antibodies were used as the first antibody; FGF2 and FGF7 for FGFs, FGFR1 and FGFR2 for FGFRs, NCAM, L1CAM, and N-cadherin for CAMs. FGF2, FGF7, and FGFR2 were expressed in neuronal tissue of NG segments as well as in hypertrophic nerves of AG segments. There was a lack of FGFRI expression in neuronal tissue of both NG and AG bowel. Immunoreactivity with all three CAMs was detected in ganglion cells in NG bowel and in hypertrophic nerve trunks in AG bowel. In contrast the numbers of CAM-positive nerve fibres in muscle layers were markedly decreased in AG bowel compared to NG bowel. The markedly decreased expression of CAMs on nerve fibres within the muscle of AG bowel suggests that CAM-FGF signalling is altered in HD, resulting in failure of enteric neuroblast migration.
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PMID:Cell-adhesion molecules and fibroblast growth factor signalling in Hirschsprung's disease. 1140 66

Over-expression of alpha7 nicotinic acetylcholine receptor (alpha7nAChR) in PC12 cells, independent of agonistic stimulation, induces marked neurite outgrowth and high capacity for migration and adherence (differentiation-like transformation), and increases tolerance against cell damage. In the present study, we investigated the effects of alpha7nAChR over-expression and nicotine on ERK phosphorylation and N-cadherin expression by comparing 3 groups of cells: PC12 cells transfected with alpha7 subunit cDNA (alpha7pCMV cells); untransfected PC12 cells exposed to 50 microM nicotine (PC12 cells+nicotine); and PC12 cells transfected with vector only (pCMV cells). alpha7 subunit protein was detected in alpha7pCMV cells at 24 to 72 h after transfection. alpha7pCMV cells exhibited sustained expression of phospho-ERKs (p42 and p44) at 24 to 72 h after transfection, and differentiation-like transformation at 72 h after transfection. PC12 cells+nicotine exhibited transient expression of phospho-ERKs at 48 h after addition of nicotine, but did not exhibit differentiation-like transformation. Neither ERK phosphorylation nor differentiation-like transformation was observed in pCMV cells. Expression of surface N-cadherin increased at 72 h after transfection on alpha7pCMV cells, but did not increase on PC12 cells+nicotine or pCMV cells. These findings suggest that, in PC12 cells, over-expression of alpha7nAChR induces sustained activation of ERK, which probably promotes N-cadherin expression and differentiation-like transformation.
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PMID:Over-expression of alpha7 nicotinic acetylcholine receptor induces sustained ERK phosphorylation and N-cadherin expression in PC12 cells. 1239 68

The intracellular signaling events causing tumor cells to become metastatic are not well understood. N-cadherin and FGF-2 synergistically increase migration, invasion, and secretion of extracellular proteases in breast tumor cells. Here, we define a metastatic signaling cascade activated by N-cadherin and FGF-2. In the presence of N-cadherin, FGF-2 caused sustained activation of the MAPK-ERK pathway, leading to MMP-9 gene transcription and cellular invasion. N-cadherin prevented the FGF receptor (FGFR) from undergoing ligand-induced internalization, resulting in increased FGFR-1 stability. Association of FGFR-1 with N-cadherin was mediated by the first two Ig-like domains of FGFR-1. These results suggest that protection of the FGFR-1 from ligand-induced downregulation by N-cadherin enhances receptor signaling and provides a mechanism by which tumor cells can acquire metastatic properties.
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PMID:A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. 1239 94

A common glycan alteration in transformed cells and human tumors is the highly elevated levels of N-linked beta(1,6)glycans caused by increased transcription of N-acetylglucosaminyltransferase V (GnT-V). Here, we define the involvement of GnT-V in modulation of homotypic cell-cell adhesion in human fibrosarcoma HT1080 and mouse NIH3T3 cells. Increased GnT-V expression resulted in a significant decrease in the rates of calcium-dependent cell-cell adhesion. Reduced cell-cell adhesion was blocked by function-blocking antibody against N-cadherin and abrogated by pre-treatment of cells with swainsonine, demonstrating the involvement of N-cadherin in the cell-cell adhesion and that changes in N-linked beta(1,6)glycan expression are responsible for the reduction in rates of adhesion, although this reduction could be mediated by the altered N-linked glycosylation of glycoproteins other than N-cadherin. Overexpression of GnT-V had no effect on the levels of cell surface expression of N-cadherin; however, it did cause a marked enhancement of both beta(1,6) branching and poly-N-acetyllactosamine expression on N-cadherin. GnT-V overexpression resulted in decreased N-cadherin clustering on the cell surface induced by anti-N-cadherin antibody and affected the outside-in signal transduction pathway of ERK mediated by N-cadherin. Overexpression of GnT-V sensitized stimulation of tyrosine phosphorylation of catenins by growth factors and expression of v-src, which is consistent with its reduction of cell-cell adhesion. In vitro, GnT-V-overexpressing cells showed increased motility concomitant with increased phosphorylation of catenins. Moreover, GnT-V-deficient embryo fibroblasts from GnT-V homozygous null mice (GnT-V(-/-)) express N-cadherin and showed significantly increased levels of N-cadherin-based cell-cell adhesion compared with those from GnT-V(+/-) mice. These levels of adhesion were inhibited significantly by transient expression of GnT-V, confirming the hypothesis that levels of GnT-V can regulate cadherin-associated homotypic cell-cell adhesion. Aberrant N-linked beta(1,6) branching that occurs during oncogenesis can, therefore, lessen cell-cell adhesion, contributing to increased cellular motility and invasiveness.
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PMID:N-acetylglucosaminyltransferase V expression levels regulate cadherin-associated homotypic cell-cell adhesion and intracellular signaling pathways. 1456 52

We derived the transcriptional profiles of four invasive and four noninvasive mammary carcinoma cell lines by Affymetrix GeneChip((R)) Technology with the profile of human mammary epithelial cells as a reference. We focused on the identification of genes which are upregulated in the invasive cell lines based on the following threshold levels: -fold change of 2 or higher in at least three or more cell lines. According to the scoring criteria as described above, we identified 18 transmembrane receptors, 18 secreted proteins and 5 kinases. Several of the genes described have already been put into context with respect to invasion of mammary carcinoma. We therefore focused on deregulated genes for which such an association has not been described before: transmembrane receptor tyrosine kinase DDR2, transmembrane receptors PMP22 and EMP3 and cell adhesion molecule N-cadherin. Making use of real-time PCR, consistently increased steady-state levels of mRNAs for these genes were found in an extended panel of invasive and noninvasive mammary cancer cell lines.
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PMID:Identification of genes associated with the invasive status of human mammary carcinoma cell lines by transcriptional profiling. 1465 13

Mammary small cell carcinoma (SmCC) is a very rare neoplasm with a poor prognosis compared with other invasive carcinomas. We studied the histological and immunohistochemical profiles of two cases of mammary SmCC, and compared them with those of five cases of carcinoma with endocrine features (CEF) and five cases of invasive ductal carcinoma (IDC), to elucidate the correct diagnosis of mammary SmCC. Immunohistochemical analysis was performed with antibodies against cytokeratins (CKAE1/AE3, CK34betaE12, CKCAM5.2, CK7, CK8, CK19, CK20), epithelial membrane antigen (EMA), vimentin, CD10, neural cell adhesion molecule (NCAM; CD56), neuron-specific enolase (NSE), chromogranin A, S-100 protein, carcino-embryonic antigen (CEA), E-cadherin, N-cadherin, thyroid transcription factor-1 (TTF-1), p53, estrogen (ER), progesterone (PR), HER2/neu, bcl-2, synaptophysin, calcitonin and Leu7. SmCCs were diffusely and strongly positive for NCAM in comparison with CEFs and IDCs. SmCCs were negative for vimentin, whereas CEFs and IDCs were positive. Neuro-endocrine carcinomas, including SmCCs and CEFs, were diffusely and strongly positive for NSE, compared with IDCs. Moreover, neuroendocrine carcinomas were negative for CK34betaE12, CK20 and CD10, whereas IDCs were positive. Our study suggests that NCAM and vimentin are useful markers for the diagnosis of mammary SmCC. CK34betaE12, NSE, CD10, CK20 and chromogranin A appear to be useful for differentiating neuroendocrine carcinoma from IDCs.
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PMID:Comparative study of primary mammary small cell carcinoma, carcinoma with endocrine features and invasive ductal carcinoma. 1501 Aug 80

We previously identified pituitary tumor-derived fibroblast growth factor receptor 4 (ptd-FGFR4), an alternatively transcribed N-terminally truncated cytoplasmic receptor isoform. Unlike wild-type FGFR4, ptd-FGFR4 facilitates cell transformation and results in pituitary tumor formation in transgenic mice. To investigate differences in the tumorigenic properties of FGFR4 and ptd-FGFR4, we examined their abilities to modulate cell adhesiveness. Introduction of ptd-FGFR4 into GH4 pituitary cells or NIH 3T3 fibroblasts resulted in significant reduction in cell adhesion to a collagen IV matrix compared with FGFR4- or empty vector-transfected cells. This adhesive difference was evident in the absence or presence of FGF stimulation. Furthermore, treatment with beta1-integrin neutralizing antibody markedly reduced adhesiveness in FGFR4-transfected cells but had little effect on the depressed adhesiveness of ptd-FGFR4-transfected cells. Unlike wild-type FGFR4, ptd-FGFR4 does not associate with neural cell-adhesion molecule (NCAM). Cells expressing FGFR4 demonstrate membranous N-cadherin with a noninvasive growth pattern identical to control GH4 cells when injected into immunodeficient mice. In contrast, ptd-FGFR4-expressing cells develop invasive tumors in vivo with marked loss of N-cadherin that localizes to the cytoplasm. Consistent with these changes, beta-catenin expression was diminished and its interaction with N-cadherin was disrupted in the presence of ptd-FGFR4, but both were intact in the presence of wild-type FGFR4. These data highlight the importance of membrane-anchored FGFR4 in assembling a multiprotein FGFR4 complex with NCAM and N-cadherin playing pivotal functions in maintaining normal cell adhesion. Disruption of distinct NCAM/N-cadherin proadhesive complexes by a tumor-derived FGFR4 isoform provides a novel mechanism beyond ligand independence that explains the pathobiology of proliferative and infiltrative but nonmetastatic neoplasms.
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PMID:Pituitary tumor-derived fibroblast growth factor receptor 4 isoform disrupts neural cell-adhesion molecule/N-cadherin signaling to diminish cell adhesiveness: a mechanism underlying pituitary neoplasia. 1523 74

We describe an autopsy case of a 65-year-old man with prostate cancer accompanied by multiple endocrine neoplasia 2A (MEN 2A), including malignant pheochromocytomas, thyroid medullary carcinomas and parathyroid hyperplasia. Metastatic lesions from the prostate primary were identified using immunohistochemistry for prostate specific antigen within both primary and metastatic pheochromocytomas in the liver. To investigate the affinity of prostate cancer for pheochromocytoma cells, immunohistochemistry was carried out using a number of antibodies and both tumors were positive for N-cadherin. Interestingly, pheochromocytomas, thyroid medullary carcinomas and prostate cancer were all positive for the anti-RET antibody. The immunohistochemical results suggest that the cell affinity may, in part, result from cell-cell adhesion via N-cadherin. Although prostate cancer is rarely associated with MEN, RET activation may have participated in the tumorigenesis of this case.
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PMID:Autopsy case of prostate cancer with multiple endocrine neoplasia 2A. 1559 14


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