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)

The ligand-binding domain of the epidermal growth factor (EGF) receptor is separated from the cytoplasmic protein tyrosine kinase domain by a predicted single transmembrane segment. Antipeptide antibodies prepared against the outer portion of the predicted transmembrane segment confirmed this area was exposed only when cells were treated with permeabilizing agents. To investigate structural requirements for signal transduction by the transmembrane domain, three types of mutant EGF receptor were prepared. The first type was designed to shorten the transmembrane domain, the second to place proline substitutions within this domain, and the third to make amino acid substitutions analogous to those present in the transforming c-erbB2/neu oncoprotein. Mutant human receptors were expressed in null recipient mouse B82L and Chinese hamster ovary cells. All receptors bound EGF and exhibited EGF-stimulated protein tyrosine kinase activity in vivo as assayed using a 125I-labeled monoclonal anti-phosphotyrosine antibody. EGF stimulated growth of cells expressing each mutant receptor with similar dose-response characteristics. In contrast to other growth factor receptors, the transmembrane domain of the EGF receptor is tolerant to a variety of changes which neither mimic EGF action by constitutive activation nor interfere with ligand-induced signal transduction.
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PMID:Structural analysis of the transmembrane domain of the epidermal growth factor receptor. 200 11

Leflunomide has been shown to be very effective in preventing and curing several autoimmune animal diseases. Further, this agent is as effective as cyclosporin A in preventing the rejection of skin and kidney transplants in rats. Preliminary results from patients suffering from severe cases of rheumatoid arthritis demonstrated that clinical and immunological parameters could be improved with leflunomide therapy. Mode of action studies revealed that this substance antagonizes the proliferation inducing activity of several cytokines and is cytostatic for certain cell types. In this light, we could show that tyrosine phosphorylation of the RR-SRC peptide substrate and the autophosphorylation of the epidermal growth factor (EGF) receptor were, dose dependently, inhibited by leflunomide. EGF activates the intrinsic tyrosine kinase of its receptor, which stimulates the phosphorylation of a variety of peptides, the amino acid residue in all cases is tyrosine. These results indicate that much of leflunomide's activity could be due to the inhibition of tyrosine-kinase(s), which is an important general mechanism for the proliferation of various cell types. Thus, leflunomide, which is effective against autoimmune diseases and reactions leading to graft rejection, would seem to have a mode of action separating it from known immunosuppressive drugs.
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PMID:Leflunomide (HWA 486), a novel immunomodulating compound for the treatment of autoimmune disorders and reactions leading to transplantation rejection. 205 54

Although signaling by the epidermal growth factor (EGF) receptor is thought to be dependent on receptor tyrosine kinase activity, it is clear that mitogen-activated protein (MAP) kinase can be activated by receptors lacking kinase activity. Since analysis of the signaling pathways used by kinase-defective receptors could reveal otherwise masked capabilities, we examined in detail the tyrosine phosphorylations and enzymes of the MAP kinase pathway induced by kinase-defective EGF receptors. Following EGF stimulation of B82L cells expressing a kinase-defective EGF receptor mutant (K721M), we found that ERK2 and ERK1 MAP kinases, as well as MEK1 and MEK2 were all activated, and SHC became prominently tyrosine-phosphorylated. By contrast, kinase-defective receptors failed to induce detectable phosphorylations of GAP (GTPase-activating protein), p62, JAK1, or p91STAT1, all of which were robustly phosphorylated by wild-type receptors. These data demonstrate that kinase-defective receptors induce several protein tyrosine phosphorylations, but that these represent only a subset of those seen with wild-type receptors. This suggests that kinase-defective receptors activate a heterologous tyrosine kinase with a specificity different from the EGF receptor. We found that kinase-defective receptors induced ErbB2/c-Neu enzymatic activation and ErbB2/c-Neu binding to SHC at a level even greater than that induced by wild-type receptors. Thus, heterodimerization with and activation of endogenous ErbB2/c-Neu is a possible mechanism by which kinase-defective receptors stimulate the MAP kinase pathway.
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PMID:An incomplete program of cellular tyrosine phosphorylations induced by kinase-defective epidermal growth factor receptors. 753 32

The family of protein kinases includes many oncogenes and growth factor receptors, many of which have been linked to the pathogenesis and progression of cancer. Protein tyrosine kinases such as HER-2/c-erbB-2 and the epidermal growth factor receptor (EGFR) have been linked specifically to breast cancer, and perturbations of HER-2 affect response to chemotherapy. We have reviewed the biology of protein kinases in human breast cancer, as well as their translational applications to breast cancer patients. We have studied the spectrum of protein kinases expressed in human breast cancer cells and have identified four protein kinases with potentially important functions in breast cancer: rak (src-related), TK5 (which we now designate JAK3), the focal adhesion kinase (FAK), and STK1 (human M015/CAK). We describe the potential significance of these genes in breast cancer, as well as our methodology for identifying and characterizing novel genes in breast cancer.
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PMID:Protein kinases in human breast cancer. 761 97

Previous studies have implicated ADP-ribosylation in the mechanism of TNF cytotoxicity. In short-term 51Cr-release assays with several mouse and human tumor cell lines, the inhibitors aminobenzamide (ABA) and nicotinamide (NA) of ADP-ribosylation sensitized HER-2/neu-nonoverexpressing cells (CaOV-3 and MCF-7) but not HER-2/neu-overexpressing cells (SKOV-3 and SKBR-3) to TNF. However, both inhibitors alone or in combination with either TNF and/or actinomycin D (AD) caused similar effects on ADP-ribosylation rates of CaOV-3 and SKOV-3 cells after 4 h of treatment. This result suggests that ADP-ribosylation may not be involved in sensitizing these human tumor cells to TNF. Both ABA and NA decreased the TNF sensitivity of L929 cells and either increased or decreased TNF sensitivity of EMT-6 cells in the absence or presence of actinomycin D, respectively. Again, there was no correlation between ADP-ribosylation and TNF cytotoxicity in these mouse cell lines. Thus, modulation of TNF sensitivity by these inhibitors might be linked to a compromised repair mechanism distinct from the effects on ADP-ribosylation alone.
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PMID:TNF cytotoxicity: effects of HER-2/neu expression and inhibitors of ADP-ribosylation. 791 50

We have examined the function of the epidermal growth factor (EGF) receptor, c-Src and focal adhesion kinase (FAK) in the progression of colon cancer using an in vitro progression model. A non-tumorigenic cell line was derived from a premalignant colonic adenoma (PC/AA) from which a clonogenic variant was established (AA/C1). Following sequential treatment with sodium butyrate and the carcinogen N-methyl-N'-nitro-N-nitro-soguanidine an anchorage-independent line was isolated which, with time in culture, became tumorigenic when injected into athymic nude mice (AA/C1/SB10). We have shown that both EGF receptor and FAK protein levels were elevated in the carcinoma cells as compared to the adenoma cells, while the expression and activity of c-Src were unaltered during the adenoma to carcinoma transition. EGF induced the movement of the carcinoma cells into a reconstituted basement membrane which was not seen with the premalignant adenoma cells. This increased motility was accompanied by an EGF-induced increase in c-Src kinase activity, relocalisation of c-Src to the cell periphery and phosphorylation of FAK in the carcinoma cells but not in the adenoma cells. This suggests that c-Src plays a role in the biological behaviour of colonic carcinoma cells induced by migratory factors such as EGF, perhaps acting in conjunction with FAK to regulate focal adhesion turnover and tumour cell motility. Furthermore, although c-Src has been implicated in colonic tumour progression, we demonstrate here that in the adenoma to carcinoma in vitro model c-Src is not the driving force for this progression but co-operates with other molecules in carcinoma development.
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PMID:A role for epidermal growth factor receptor, c-Src and focal adhesion kinase in an in vitro model for the progression of colon cancer. 901 14

The role of the cytoplasmic regions of interleukin-12 receptors (IL-12R) beta1 and beta2 in stimulating proliferation was examined. The transmembrane and cytoplasmic regions of IL-12Rbeta1 or IL-12Rbeta2 were fused to the extracellular domain of the epidermal growth factor (EGF) receptor, yielding chimeric receptors E12R1 and E12R2, respectively. These chimeras were stably transfected into BaF3 cells, a factor-dependent murine pro-B cell line. Only E12R2 or E12R1+E12R2 transfectants were capable of EGF-dependent proliferation. EGF-dependent phosphorylation of E12R2, JAK2, Tyk2, and STAT3 was observed. JAK2 was phosphorylated in E12R1-, E12R2-, and E12R1+E12R2-expressing cells. However, direct associations were detectable only between E12R2 and JAK2. Tyk2 phosphorylation was observed only in cells expressing E12R1 or E12R1+E12R2. In parallel with this activation pattern, direct interactions only between Tyk2 and E12R1 were demonstrable. Phosphorylation of STAT3 was observed in cells expressing E12R1, E12R2, and E12R1+E12R2. The expression levels of STAT4 protein in BaF3 cells are undetectable by the methods employed here; therefore, STAT4 phosphorylation was not observed. Taken together, the data indicate that differential interactions take place between the cytoplasmic regions of the two IL-12R subunits and JAK2/Tyk2 and that the cytoplasmic region of IL-12Rbeta2 alone is capable of delivering a proliferative signal.
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PMID:Differential associations between the cytoplasmic regions of the interleukin-12 receptor subunits beta1 and beta2 and JAK kinases. 903 32

The corneal epithelium, like other stratifying epithelium, does not present a well formed junctional complex as compared to that of simple epithelia. However, the resistance barrier of the corneal epithelium is to a great extent generated by zonula occludens (ZO, tight junction), which are formed between the cells of the apical-most strata. The tight junction provides a continuous seal around the apical aspect of adjoining epithelial cells, thereby preventing the free passage of molecules between adjacent epithelial cells (paracellular pathway). We have examined rabbit corneal epithelia with monoclonal antibody against the tight junction associated protein ZO1. With this antibody, we resolved two distinct patterns of ZO1 expression, one being the lateral boundary of the apical cell, which appeared as a true zonula around these cells. The second pattern of expression for ZO1 was at a set of punctate spots that correspond to the connection of the most apical portion of the basal corneal epithelial cells, with the above wing cells. En face, confocal analyses revealed that these areas consisted of 5-6 distinct spots per basal cell at or near the contact points with the immediate wing cells above. ImmunoEM revealed that the mid-epithelial accumulations of ZO1 were not tight junctions, but rather a form of adherens junction. The expression of ZO1 in the mid-epithelial level of the cornea is neither correlated with the presence of tight junction, nor with the established barrier functions. Interestingly, these junctions in the corneal epithelium also contain paxillin, a focal adhesion associated phosphoprotein which is a target of pp125 focal adhesion kinase, erbB-2 kinase and p21Obcr/abl oncogene. We postulated that the ZO1/paxillin adherens junction within stratified epithelium, such as the corneal epithelium, may function to reinforce attachments at the level of the basal cell to wing cell junction and be regulated by reversible phosphorylation. We speculate that the regulated phosphorylation of tyrosine residues on paxillin may perform a critical role in controlling epithelial cell-cell interactions as it does in cell-matrix adhesion.
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PMID:ZO1 in corneal epithelium: association to the zonula occludens and adherens junctions. 909 16

Interleukin-6 (IL-6) is an important B-cell growth and differentiation factor. IL-6 treatment of the human lymphoblastoid cell line, SKW6.4, leads to increased IgM production. We have previously shown that IL-6 induces activation of JAK1 and JAK2 in human B cell lines. A chimeric IL-6 receptor, comprised of the intracellular tail of the IL-6 receptor subunit gp130 fused to the extracellular domain of the epidermal growth factor (EGF) receptor, was stably transfected into SKW6.4 cells. EGF treatment induced IgM production in cells transfected with an intact gp130 cytoplasmic tail, but not in untransfected cells or cells transfected with a cytoplasmic tail lacking all four signal transducers and activators of transcription (Stat) binding sites. Moreover, EGF treatment induced Stat3 phosphorylation in cells transfected with the intact chimeric EGF-gp130 receptor along with induction of DNA-mobility shift of a classical interferon-gamma-activated site. To define further the relation between Stat3 activation and enhanced IgM production, we determined the effect of chimeric gp130 on the transcriptional activation of a genetic element linked to immunoglobulin production, namely the immunoglobulin heavy chain enhancer (IgH-enhancer). Parental as well as transfected SKW6.4 cells were transiently transfected with an IgH-enhancer-luciferase construct. The transcriptional activity of the IgH-luciferase construct was induced upon ligation of the full-length chimeric receptor but not by truncated gp130 receptors. Moreover, the gp130-induced activity of this reporter gene was abrogated by Stat3EE, a mutant Stat3 incapable of binding DNA. These results indicate that IL-6-induced B-cell differentiation, as measured by IgM production, may be controlled by Stat3 proteins.
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PMID:Involvement of Stat3 in interleukin-6-induced IgM production in a human B-cell line. 915 40

The epidermal growth factor (EGF) receptor is well known as a mediator of mitogenic signaling and its tyrosine kinase activity has been suggested as a viable target in cancer chemotherapy. To explore the consequences of abolishing the kinase activity of this receptor, we have utilized a potent and specific inhibitor of the enzyme, PD 153035, to sustain a long-term suppression of its activity. This compound inhibits EGF receptor autophosphorylation in cells with an IC50 in the low nanomolar range and does not block PDGF or FGF receptor kinase until concentrations are greater than 10 microM. [1] Human epidermoid carcinoma A431 cells were grown in the presence of PD 153035 and were passed weekly until cells grew in the presence of 1 microM inhibitor. These cells, referred to as A431R, showed a remarkable change in morphology, becoming flattened and spread out. A comparison of the sensitivity of EGF receptor autophosphorylation to PD 153035 between A431 and A431R showed a similar dose response, indicating that the cells had not developed any defect in the kinase which might make it resistant to the inhibitor. Likewise, EGF receptor autophosphorylation in response to exogenously added EGF, as well as receptor internalization, was similar between the two cell lines. Furthermore, analysis of A431R cells by flow cytometry showed no significant change in DNA content or percentage of cells in any one phase of the cell cycle compared to the parent line. 125I-labeled EGF/receptor binding studies showed that receptor number in the A431R cells was equivalent to that of the parent line; however, the Scatchard plot was linear, in contrast to the typical biphasic plot obtained with the parent cells, implying a loss of high-affinity receptors. Cytoskeletal preparations from both cell lines indicated that the A431R had fourfold less EGF receptor associated with the cytoskeleton than A431. This was accompanied by a remarkable increase in polymerized actin stress fibers throughout the A431R cells, which most likely accounts for their flattened morphology. The A431R cells also exhibited a twofold increase in the expression of focal adhesion kinase, which is consistent with a greater contact area for their cell surface and increase in focal adhesions. Finally, although the A431R cells have a doubling time of 24 h, similar to that of the parent line, these cells stop growing as the monolayer approaches confluence, reminiscent of the contact inhibition seen in nontransformed cells. These data indicate that long-term suppression of the EGF receptor tyrosine kinase activity in A431 human epidermoid carcinoma results in certain cellular properties which are more consistent with a differentiated and nontransformed phenotype.
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PMID:Cytoskeletal and morphological changes associated with the specific suppression of the epidermal growth factor receptor tyrosine kinase activity in A431 human epidermoid carcinoma. 919


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