Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have identified the 170 kDa epidermal growth factor (EGF) receptor in crude membrane fractions isolated from Ehrlich ascites tumor cells by its EGF-dependent phosphorylation with [gamma-32P]ATP. An apparent affinity constant for the ligand of 40-50 nM, based on the extent of its EGF-dependent phosphorylation, was calculated. [125I]EGF binds to the 170 kDa receptor and Scatchard plot analysis shows high affinity and low affinity Kds of 1.7 nM and 24 nM, respectively, in whole cells, and 0.2-0.8 nM and 39-116 nM, respectively, in isolated non-phosphorylated membrane fractions. We have estimated the presence of 48 x 10(3) high affinity and 275 x 10(3) low affinity EGF binding sites per tumor cell. Phosphoamino acid analysis shows EGF-dependent phosphorylation of tyrosine and serine residues. A polyclonal antibody to a human EGF receptor/c-erbB-2 product common cytoplasmic domain epitope immunoprecipitates a 45 kDa phosphopolypeptide from the tumor membrane fractions and from whole cell lysates. Phosphoamino acid analysis of the immunoprecipitated 45 kDa phosphopolypeptide shows the presence of phosphoserine. The immunoprecipitated 45 kDa polypeptide is able to undergo EGF-independent phosphorylation, although no significant protein kinase activity towards exogenous substrates is detected.
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PMID:Characterization of the epidermal growth factor receptor from Ehrlich ascites tumor cells. 806 May 39

In murine keratinocytes, Ca(++)-induced terminal differentiation is accompanied by a rapid and sustained increase of inositol phosphates and diacylglycerol. Based on Western blotting analysis, basal keratinocytes cultured in 0.05 mM Ca++ medium express phospholipase C (PLC)-gamma 1 predominantly and no detectable PLC-beta 1. Differentiating keratinocytes cultured in 1.4 mM Ca++ express two- to threefold more PLC-gamma 1 protein and PLC-delta 1, but no detectable PLC-beta 1. Although the amount of PLC-gamma 1 and -delta 1 protein increased, PLC-gamma 1 and -delta 1 mRNA decreased in differentiating cells. Thus the sustained rise of PLC activity induced by Ca++ in differentiating keratinocytes may be associated with higher amounts of both PLC-gamma 1 and -delta 1 in maturing cells, determined by a posttranscriptional mechanism. Tyrosine phosphate content in PLC-gamma 1 was low in basal cells and did not change in cells exposed to 1.4 mM Ca++. However, genistein inhibited the increase in PLC activity induced by 1.4 mM Ca++. In contrast, transforming growth factor (TGF)alpha, which stimulates both PLC activity and growth in basal keratinocytes, increased tyrosine phosphorylation of PLC-gamma 1. These results suggest that tyrosine phosphorylation of PLC-gamma 1 by the epidermal growth factor (EGF) receptor is linked to stimulated proliferation, whereas stimulation of PLC activity by Ca++ is linked to keratinocyte differentiation and involves the action of a tyrosine kinase but not tyrosine phosphorylation of PLC-gamma 1. Based on studies using the intracellular free Ca++ chelator BAPTA, a rise in intracellular free Ca++ was not required for stimulation of PLC activity by raising extracellular Ca++. Phorbol esters inhibited PLC stimulation by 1.4 mM Ca++ medium and increased serine phosphorylation of PLC-gamma 1. Exogenous phosphatidylinositol-specific and phosphatidylcholine-specific bacterial PLC also inhibited endogenous inositol phosphate formation and increased endogenous diacylglycerol (DAG). Thus, direct serine phosphorylation of PLC-gamma 1 by protein kinase C is associated with the inhibition of Ca(++)-mediated PLC stimulation. These results show that keratinocytes have multiple mechanisms to regulate PLC activity in response to a specific signal.
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PMID:Keratinocyte differentiation is associated with changes in the expression and regulation of phospholipase C isoenzymes. 822 34

The mechanism(s) by which monoclonal antibodies (mAbs) against the epidermal growth factor (EGF) receptor regulate receptor function have been investigated with NIH3T3/HER14 fibroblasts expressing human EGF receptors. Bivalent 225 mAb or monovalent 225 Fab' inhibited transforming growth factor (TGF)-alpha-induced EGF receptor tyrosine phosphorylation and cell proliferation. Culture of HER14 cells with 225 mAb or 225 Fab' did not activate EGF receptor tyrosine kinase when assayed after lysis of cells in SDS sample buffer. However, when cells were cultured with bivalent 225 mAb, but not with monovalent 225 Fab', and were subsequently lysed and further incubated in Triton X-100 lysis buffer containing proteinase and phosphatase inhibitors, receptor phosphorylation was observed. Phosphorylation was confined to tyrosine residues and was inhibited by addition of genistein after lysis, indicating that it was due to the activation of protein tyrosine kinase. The activity of bivalent 225 mAb was unphysiologic, in contrast with TGF-alpha, in that receptor kinase activation occurred only after cell lysis and with delayed kinetics; serine and threonine phosphorylation did not occur; and down-regulation of EGF receptors was slower. Selective mAb-mediated phosphorylation of tyrosine residues on EGF receptors was sufficient to activate phosphorylation of a SH2 group-bearing substrate, phospholipase C-gamma, indicating that serine/threonine phosphorylation is not required for EGF receptor kinase activity. These studies provide novel insights into the capacity of bivalent mAb to modulate EGF receptor function.
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PMID:Regulation of epidermal growth factor receptor in NIH3T3/HER14 cells by antireceptor monoclonal antibodies. 840 44

The ATDC gene was originally identified by its ability to complement the radiosensitivity defect of an ataxia telangiectasia (AT) fibroblast cell line. Because hypersensitivity to ionizing radiation is an important feature of the AT phenotype, we reasoned that ATDC may function generally in the suppression of radiosensitivity. Previous work in our laboratory focused on radiosensitization mechanisms in human squamous carcinoma (SC) cells, especially A431 cells. To establish a basis for investigating the role of ATDC in radiation-responsive signaling pathways in human SC cells, we characterized ATDC message and protein expressions in A431 cells. ATDC message expression was also compared among human epidermoid cells (A431 cells, HaCaT spontaneously immortalized human keratinocytes and normal human epidermal keratinocytes) and a normal human fibroblast cell line (LM217). We made the following major observations: (i) the relative abundance of ATDC message is substantially higher in the epidermoid cells than in the fibroblast cell line, which has a message level comparable to those reported for other fibroblast lines; (ii) ATDC is constitutively phosphorylated on serine/threonine in A431 cells; (iii) in A431 cells, ATDC is a substrate for the serine/threonine protein kinase C (PKC) but not the epidermal growth factor (EGF) receptor tyrosine kinase; and (iv) EGF decreases ATDC message and protein expressions in A431 cells after a 24-hr exposure. The phosphorylation studies suggest that the ability of ATDC to modulate cellular radiosensitivity may be mediated in part through a PKC signaling pathway.
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PMID:Expression of the ATDC (ataxia telangiectasia group D-complementing) gene in A431 human squamous carcinoma cells. 864 48

We have synthesized a tris-sulfotyrosyl dodecapeptide (3S-peptide-I) that corresponds to the major autophosphorylation domain within the insulin receptor beta-subunit and showed that it potently inhibited insulin receptor dephosphorylation by protein tyrosine phosphatases (PTPases) in vitro. 3S-peptide-I also inhibited tyrosine dephosphorylation of a synthetic peptide by the recombinant PTPase PTP-1B, indicating that 3S-peptide-I interacts directly with PTPase, causing its inactivation. The peptide had no effect on the activity of serine/threonine phosphatases, PP-1 and PP-2A, or alkaline phosphatase. Furthermore, we found that the introduction of a N-stearyl derivative of 3S-peptide-I in CHO/HIRc cells caused a significant increase in insulin-stimulated phosphorylation of the insulin receptor. In contrast, ligand-stimulated phosphorylation of epidermal growth factor (EGF) receptor in CHO cells overexpressing EGF receptors was not affected by the presence of N-stearyl-3S-peptide-I. These data suggest that by inhibiting dephosphorylation of the insulin receptor in intact cells, 3S-peptide-I may specifically enhance insulin signalling.
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PMID:Specific inhibition of insulin receptor dephosphorylation by a synthetic dodecapeptide containing sulfotyrosyl residues as phosphotyrosyl mimetic. 934 28

Eukaryotic cells respond to ionizing radiation with cell cycle arrest, activation of DNA repair mechanisms, and lethality. However, little is known about the molecular mechanisms that constitute these responses. Here we report that ionizing radiation enhances epidermal growth factor (EGF) receptor tyrosine phosphorylation in intact cells as well as in isolated membranes of A431 cells. Phosphoamino acid analysis revealed that ionizing radiation preferentially enhances tyrosine phosphorylation, while EGF enhances the phosphorylation of all three phosphoamino acids (serine, threonine and tyrosine) of the EGF receptor. In addition, radiation reduces the turnover rate of the EGF receptor, while EGF increases the rate of the receptor turnover and down-regulation. Moreover, the confined radiation-induced phosphorylation of tyrosine residues is inhibited by genistein, indicating that this phosphorylation of EGF receptor is due to protein tyrosine kinase activation. These studies provide novel insights into the capacity of radiation to modulate EGF receptor phosphorylation and function. The radiation-induced elevation in the EGF receptor tyrosine phosphorylation and the receptor's slower rate of turnover are discussed in terms of their possible role in cell growth and apoptosis modulation.
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PMID:EGF receptor phosphorylation is affected by ionizing radiation. 936 60

The epidermal growth factor (EGF) receptor purified by calmodulin-affinity chromatography from solubilized rat liver plasma membranes phosphorylates connexin32 in gap junction plaques isolated from the same origin. Phosphorylation of connexin32 was stimulated by EGF and mainly occurs at tyrosine residue(s), although phosphorylation of serine and threonine residues was also detected. The kinetics parameters for the phosphorylation of connexin32 parallel those for the transphosphorylation of the EGF receptor. m-Calpain proteolyzes phosphoconnexin32, and its major 26 kDa proteolytic fragment only contains phosphotyrosine residue(s). Calmodulin binds to connexin32 in the absence of calcium and prevents in great extent its phosphorylation by the EGF receptor tyrosine kinase.
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PMID:The epidermal growth factor receptor tyrosine kinase phosphorylates connexin32. 978 58

Calmodulin (CaM), a major intracellular Ca2+ receptor protein, has been identified and partially characterized in several trypanosomatids. The amino acid sequences of CaM from Trypanosoma cruzi and Trypanosoma brucei are known, while that from Leishmania mexicana is not. CaM from T. cruzi contains 18 amino acid substitutions, as compared with CaM from bovine brain. In addition, CaM from bovine brain contains two tyrosine residues (Tyr-99 and Tyr-138), while CaM from T. cruzi only contains Tyr-138. In the present work we show that a monoclonal antibody developed against the carboxyl-terminal region of bovine brain CaM fails to recognize CaM from both T. cruzi and L. mexicana. CaM from both parasites and from bovine brain were phosphorylated in vitro by a preparation of CaM-binding protein kinases enriched in the epidermal growth factor (EGF) receptor. Phosphoamino acids analysis demonstrated EGF-dependent phosphorylation of tyrosine residues in bovine brain CaM, while only trace amounts of tyrosine phosphorylation were detected in CaM from both trypanosomatids. These results demonstrate that the EGF receptor tyrosine kinase targets Tyr-99, but not Tyr-138, as the single major phosphorylatable residue of CaM. On the other hand, and in contrast to bovine brain CaM, there is a significant phosphorylation of serine residues in CaM from trypanosomatids which is activated by the EGF receptor via a protein-serine/threonine kinase cascade.
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PMID:Comparative phosphorylation of calmodulin from trypanosomatids and bovine brain by calmodulin-binding protein kinases. 982 17

It is now clear that astroglial cells actively contribute to both the generation and flow of information within the central nervous system. In the hypothalamus, astrocytes regulate the secretory activity of neuroendocrine neurons. A small subset of these neurons secrete luteinizing hormone-releasing hormone (LHRH), a neuropeptide essential for sexual development and adult reproductive function. Astrocytes stimulate LHRH secretion via cell-cell signaling mechanisms involving growth factors recognized by receptors with either serine/threonine or tyrosine kinase activity. Two members of the epidermal growth factor (EGF) family and their respective tyrosine kinase receptors appear to play key roles in this regulatory process. Transforming growth factor-alpha (TGFalpha) and its distant congeners, the neuregulins (NRGs), are produced in hypothalamic astrocytes. They stimulate LHRH secretion indirectly, via activation of erbB-1/erbB-2 and erbB-4/erbB-2 receptor complexes also located on astrocytes. Activation of these receptors leads to release of prostaglandin E(2) (PGE(2)), which then binds to specific receptors on LHRH neurons to elicit LHRH secretion. Gonadal steroids facilitate this glia-to-neuron communication process by acting at three different steps along the signaling pathway. They (a) increase astrocytic gene expression of at least one of the EGF-related ligands (TGFalpha), (b) increase expression of at least two of the receptors (erbB-4 and erbB-2), and (c) enhance the LHRH response to PGE(2) by up-regulating in LHRH neurons the expression of specific PGE(2) receptor isoforms. Focal overexpression of TGFalpha in either the median eminence or preoptic area of the hypothalamus accelerates puberty. Conversely, blockade of either TGFalpha or NRG hypothalamic actions delays the process. Thus, both TGFalpha and NRGs appear to be physiological components of the central neuroendocrine mechanism controlling the initiation of female puberty. By facilitating growth factor signaling pathways in the hypothalamus, ovarian steroids accelerate the pace and progression of the pubertal process.
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PMID:Glial-neuronal interactions in the neuroendocrine control of mammalian puberty: facilitatory effects of gonadal steroids. 1045 54

Epithelial mucins are large, secreted and cell surface glycoproteins involved in epithelial cell protection, adhesion modulation, and signaling. Using differential display, we have identified two novel mucin cDNAs (dd34 and dd29), hereafter designated MUC11 and MUC12, respectively, that are down-regulated in colorectal cancers. Northern blots demonstrated polydisperse signals characteristic of mucin transcripts in RNA from normal colon that were absent in colorectal cancer. Both cDNAs were mapped by fluorescence in situ hybridization to chromosome band 7q22, the location of the MUC3 mucin gene, thus suggesting that there may be a cluster of mucin genes at this locus. The sequences of both differential display clones were extended by a combination of screening libraries and PCR. The 2.8-kb MUC11 cDNA composite encoded 35 serine/threonine-rich, mucin-like degenerate 28 amino acid tandem repeats. The MUC12 cDNA composite encoded a putative transmembrane mucin containing two extracellular cysteine-rich, EGF-like domains, a coiled-coil region, and a mucin-like domain consisting of 28 amino acid degenerate tandem repeats. Distinct patterns of expression of MUC11, MUC12, and MUC3 mRNAs were observed in a range of normal human tissues. MUC12 mRNA was not expressed in any of six colorectal cancer cell lines examined and was down-regulated or absent in 6 of 15 (40%) tumors compared with matched normal colonic tissue. In contrast, MUC11 showed a different pattern of mRNA expression, with four of these lines showing low levels and the other two lines showing relatively high levels of MUC11 transcripts. Expression of MUC11 was down-regulated in the tumors of 12 of 15 (80%) paired samples. Structural homology of MUC12 with rat, mouse, and human MUC3 and human and rat MUC4/ASGP2 indicate that there is a distinct subfamily of transmembrane mucins with conserved epidermal growth factor domains. The homology of MUC12 with epidermal growth factor-like growth factors and its down-regulation in colorectal cancers, together with known interactions between rat MUC4 and c-erbB-2 growth factor receptors, suggests that MUC12 may be involved in epithelial cell growth regulation.
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PMID:Two novel mucin genes down-regulated in colorectal cancer identified by differential display. 1046 11


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