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)

The receptor erbB2/neu is a member of the epidermal growth factor receptor (EGFR or erbB) family that also includes erbB3 and erbB4. Amplification of the erbB2/neu gene is found in many cancer types and its overexpression is correlated with a poor prognosis for breast and ovarian cancer patients. Investigation of the biology of erbB2 led to the identification of a family of ligands termed neuregulins which included the neu-differentiation factors, the heregulins, a ligand with acetylcholine-receptor-inducing activity and glial growth factor. Several lines of evidence suggest that heterodimerization of erbB2 with other erbB receptors is required for neuregulin signalling. Here we investigate the developmental role of erbB2 in mammalian development in mice carrying an erbB2 null allele. We find that mutant embryos die before E11, probably as a result of dysfunctions associated with a lack of cardiac trabeculae. Development of cranial neural-crest-derived sensory ganglia was markedly affected. DiI retrograde tracing revealed that the development of motor nerves was also compromised. Our results demonstrate the importance of erbB2 in neural and cardiac development.
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PMID:Requirement for neuregulin receptor erbB2 in neural and cardiac development. 747 64

The topical application of recombinant growth factors such as epidermal growth factor, platelet-derived growth factor-BB homodimer (rPDGF-BB), keratinocyte growth factor (rKGF), and neu differentiation factor has resulted in significant acceleration of healing in several animal models of wound repair. In this study, we established highly reproducible and quantifiable full and deep partial thickness porcine burn models in which burns were escharectomized 4 or 5 days postburn and covered with an occlusive dressing to replicate the standard treatment in human burn patients. We then applied these growth factors to assess their efficacy on several parameters of wound repair: extracellular matrix and granulation tissue production, percent reepithelialization, and new epithelial area. In full thickness burns, only rPDGF-BB and the combination of rPDGF-BB and rKGF induced significant changes in burn repair. rPDGF-BB induced marked extracellular matrix and granulation tissue production (P = 0.013) such that the burn defect was filled within several days of escharectomy, but had no effect on new epithelial area or reepithelialization. The combination of rPDGF-BB and rKGF in full thickness burns resulted in a highly significant increase in extracellular matrix and granulation tissue area (P = 0.0009) and a significant increase in new epithelial area (P = 0.007), but had no effect on reepithelialization. In deep partial thickness burns, rKGF induced the most consistent changes. Daily application of rKGF induced a highly significant increase in new epithelial area (P < 0.0001) but induced only a modest increase in reepithelialization (83.7% rKGF-treated versus 70.2% control; P = 0.016) 12 days postburn. rKGF also doubled the number of fully reepithelialized burns (P = 0.02) at 13 days postburn, at least partially because of marked stimulation of both epidermal and follicular proliferation as assessed by proliferating cell nuclear antigen expression. In situ hybridization for KGFR in porcine burns revealed strong expression of KGFR on hair follicles and basal epidermis, confirming direct rKGF action on follicular as well as epidermal keratinocytes. Although the epithelial proliferation induced by rKGF resulted in marked neoepidermal psoriasiform hyperplasia with exaggerated rete ridges and neoepidermal and follicular maturation as assessed by expression of cytokeratin 10, a marker of keratinocyte terminal differentiation was not delayed and appeared to be accelerated in some rKGF-treated burns. Recombinant epidermal growth factor induced a trend toward increased new epithelial area in deep partial thickness burns, but had no effect on reepithelialization. The recombinant neu differentiation factor-alpha 2 isoform had no significant biological effects in either full or deep partial thickness burns.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Growth factors in porcine full and partial thickness burn repair. Differing targets and effects of keratinocyte growth factor, platelet-derived growth factor-BB, epidermal growth factor, and neu differentiation factor. 748 90

c-RET is an orphan receptor tyrosine kinase essential for enteric neurogenesis in mice and is involved in several human genetic disorders. RET is also one of the earliest surface markers expressed by postmigratory neural crest cells in the gut. We generated anti-RET monoclonal antibodies to isolate such cells. We find that RET+ cells are antigenically and functionally distinct from neural crest stem cells (NCSCs) characterized previously. Unlike NCSCs, which are RET- and MASH1-, most RET+ cells express MASH1. Moreover, unlike NCSCs, which are multipotent and have high proliferative capacity, many RET+ cells generate only neurons following a limited number of divisions. This behavior is observed even in the presence of glial growth factor, a polypeptide that suppresses neuronal and promotes glial differentiation by NCSCs. These data provide direct evidence for the existence of committed neuronal progenitor cells and support a model of neural crest lineage diversification by progressive restriction of developmental potential.
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PMID:Postmigratory neural crest cells expressing c-RET display restricted developmental and proliferative capacities. 754 33

ErbB-2 and EGFR (epidermal growth factor receptor) are expressed in lung adenocarcinomas and associated with a poor prognosis. Immunocytochemical analysis revealed erbB-2 and EGFR coexperession as a characteristic feature of most lung adenocarcinomas, and at levels of receptor expression present in bronchial epithelial cells. In primary lung tumours and cell lines, erbB-2 detected using Western blot analysis demonstrated low-level phosphotyrosine staining of the 185 kDa band, as compared with breast cancer cell lines. A549 and A427 lung adenocarcinoma cells treated with neu differentiation factor (NDF) showed increased erbB-2 phosphotyrosine staining, but to a much lesser extent than breast cancer cells. The lung cells were examined for expression of the potential autocrine growth factors NDF and transforming growth factor alpha (TGF-alpha) by Northern blot analysis. Both NDF and TFG-alpha mRNA were abundantly expressed in the A549 cells. NDF mRNA was highest during active cell proliferation and decreased in confluent cells or after treatment with the growth-inhibitory steroid dexamethasone. Primary tumours and cell lines expressed EGFR, showing higher basal level phosphotyrosine staining than erbB-2. Treatment with NDF and EGF (epidermal growth factor) stimulated cell growth, and in A549 cells the presence of both factors provided an additive increase in cell growth. The growth stimulus that ligand-activated erbB-2 and EGFR provides to lung adenocarcinoma cells may establish a background of continued cell proliferation over which other critical transforming events may occur.
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PMID:Expression and activation of erbB-2 and epidermal growth factor receptor in lung adenocarcinomas. 759 67

The HER4/erbB-4 gene has been isolated as the fourth member of the human EGFR subfamily of tyrosine kinases and has been reported to encode a receptor for NDF/heregulin. In the present study we determined the chromosomal location of the HER4/erbB-4 gene within the human genome. Using human cDNA probes in fluorescence in situ hybridization (FISH), we mapped the HER4/erbB-4 gene to human chromosome 2q33.3-34. This finding established that also the HER4/erbB-4 gene is located in close vicinity of homeobox and collagen gene loci, as is the case for the related EGFR, erbB-2/neu and erbB-3. Aberrations of this chromosomal region associated with T cell leukemias and lymphomas as well as alveolar rhabdomyosarcomas raise the possibility that HER4/erbB-4 might be activated in these tumour types.
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PMID:Localization of the human HER4/erbB-4 gene to chromosome 2. 770 Jun 49

The family of Neu differentiation factors (NDFs, or heregulins) includes a dozen secreted glycoproteins, whose receptor binding domain displays two variants, alpha and beta, and they bind to two receptor tyrosine kinases, ErbB-3 and ErbB-4. Certain isoforms were reported to induce growth-arrest and differentiation of mammary tumor cells, while other breast cancer cell lines responded mitogenically. The present study addressed the biologic effects of various NDF isoforms on normal EGF-dependent epithelial cells, Balb/MK keratinocytes, that can undergo either proliferation or differentiation. We found that beta isoforms of NDF induced a mitogenic effect, that was significantly smaller than the maximal response to EGF. By contrast with NDF-beta, NDF-alpha isoforms exerted almost no mitogenic effect, but they were sufficient to maintain keratinocytes in culture. Consistent with their higher mitogenic potency, NDF-beta isoforms bound to Balb/MK cells with higher affinity (Kd = 2.2 nM) than alpha isoforms, however both groups shared their receptor, that we identified as ErbB-3. No transcript of ErbB-4 was detectable in the keratinocytes, but these cells express multiple NDF mRNAs and also ErbB-2. We conclude that different isoforms of NDF induce distinct growth regulatory effects on cultured keratinocytes, through direct interaction with ErbB-3.
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PMID:ErbB-3 mediates differential mitogenic effects of NDF/heregulin isoforms on mouse keratinocytes. 773 91

Transmembrane receptor tyrosine kinases that bind to peptide factors transmit essential growth and differentiation signals. A growing list of orphan receptors, of which some are oncogenic, holds the promise that many unknown ligands may be discovered by tracking the corresponding surface molecules. The neu gene (also called erbB-2 and HER-2) encodes such a receptor tyrosine kinase whose oncogenic potential is released in the developing rodent nervous system through a point mutation. Amplification and overexpression of neu are thought to contribute to malignancy of certain human adenocarcinomas. The search for soluble factors that interact with the Neu receptor led to the discovery of a 44 kDa glycoprotein that induces phenotypic differentiation of cultured mammary tumor cells to growth-arrested and milk-producing cells. The Neu differentiation factor (NDF or heregulin), however, also acts as a mitogen for epithelial, Schwann and glial cells. Multiple forms of the factor are produced by alternative splicing and their expression is confined predominantly to the central and to the peripheral nervous systems. One identified neuronal function of this family of polypeptides is to control the formation of neuromuscular junctions, but their physiological role in secretory epithelia is still unknown. Other open questions relate to the transmembrane topology of various precursors, the identity of a putative coreceptor, the possible existence of additional ligands of Neu and the functional significance of the interaction between Neu and at least three highly related receptor tyrosine kinases.
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PMID:Neu and its ligands: from an oncogene to neural factors. 790 91

Neu differentiation factor (NDF/heregulin) is a 44-kDa glycoprotein that interacts with the Neu/ErbB-2 receptor tyrosine kinase to increase its phosphorylation on tyrosine residues. In vitro NDF promotes differentiation of certain mammary tumor cell lines to milk-producing cells. As a first step toward understanding the physiological role of NDF, we performed in situ hybridization analyses to determine mRNA distribution in the mouse embryo and to map the gene to human karyotypes. In 14.5-day-postcoitum mouse embryos, NDF expression is confined predominantly to the central and peripheral nervous system, including the neuroepithelium that lines the lateral ventricles of the brain, the ventral horn of the spinal cord, and the intestinal as well as dorsal root ganglia. Other tissues that contain NDF transcripts are the adrenal gland, liver, and distinct cell layers of the dermis and germinal ridge. In situ hybridization of a 3H-labeled probe to human metaphase spreads localized the NDF gene to the short arm of chromosome 8 at bands p12-p21.
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PMID:Neural expression and chromosomal mapping of Neu differentiation factor to 8p12-p21. 809 34

Neu differentiation factor (NDF, also called heregulin) is a 44-kilodalton glycoprotein that stimulates tyrosine phosphorylation of the Neu/HER-2 receptor and induces phenotypic differentiation of certain mammary cancer cell lines to growth-arrested and milk-producing cells. To determine which molecules participate in the concomitant morphological alterations, we analyzed the expression of several cytoskeletal and surface molecules and found that NDF elevated the expression of the intercellular adhesion molecule 1 (ICAM-1) in cultured AU-565 human adenocarcinoma cells. The levels of both the protein and the mRNA of ICAM-1 were elevated after 3-5 days of treatment with NDF. Elevated expression of ICAM-1 was induced also by gamma-interferon and by the tumor-promoting phorbol ester (PMA), albeit with different kinetics. Down-regulation of protein kinase C or its inhibition by calphostin C partially inhibited the effect of NDF, implying that the induction of ICAM-1 may be mediated by protein kinase C. NDF transcripts were detectable in 3 of 9 human mammary tumors, suggesting that the in vitro effect of the factor may be relevant to breast cancer. By selecting Neu-positive human mammary tumors (n = 39), we found a significant correlation (P < 0.001) between the expression of ICAM-1 and histological features of invasive ductal carcinoma with a prominent carcinoma in situ component. When cultured in vitro the cells of these tumors grew in clusters and formed domelike structures reminiscent of comedo-type carcinoma in situ. In addition, the majority of patients with tumors that coexpressed ICAM-1 and Neu had no lymph node involvement, unlike most Neu-positive but ICAM-1-negative tumors, which metastasized to the lymphatic system. Taken together, our observations suggest that the induction of ICAM-1 by NDF may affect the morphology, differentiation state, and metastasis of Neu-expressing mammary tumor cells.
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PMID:Neu differentiation factor (heregulin) induces expression of intercellular adhesion molecule 1: implications for mammary tumors. 810 45

Our objective was to evaluate the effects of substituting feather meal (FM) for soybean meal (SBM) on ruminal fiber fermentation, lamb gain, blood metabolite profiles, and wool growth. A SBM supplement was formulated, and FM replaced either 33% (33FM), 66% (66FM), or 100% (FMS) of the SBM protein. Four ruminally cannulated wethers were used in a 4 x 4 Latin square design to study in situ ruminal digestion. Wethers were limit-fed barley straw and fed the supplements once daily. Ruminal NH3 N concentrations reflected a sampling time x protein source interaction (P < .01). Within sampling times, ruminal NH3 N concentrations decreased linearly (P < .05) as FM replaced soybean meal. Cubic (0 h; P < .10) and quadratic (24 h; P < .05) responses also were noted for ruminal NH3 N concentration. Substitution of FM for SBM had no effect (P > .10) on rate and extent of straw NDF disappearance. A 56-d feeding trial was conducted using 28 wether lambs (n = 7 per treatment; initial BW 32.3 kg). Wethers were individually fed chopped barley straw and one of the four supplements described previously. Linear increases (P < .05) in BW gain and serum total protein concentration were observed as FM replaced SBM. Wool fiber diameter and sulfur content did not differ (P > .10) among treatments. These data suggest that FM can be substituted for SBM in protein supplements fed to sheep consuming low-quality roughages at a maintenance level of ME intake.
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PMID:Effects of substituting feather meal for soybean meal on ruminal fiber fermentation and lamb and wool growth. 815 38


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