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 repertoire of cytokine and cytokine receptor mRNA expressed by unstimulated human thymocytes and thymic stromal cells was explored by a quantitative polymerase chain reaction (PCR) using sequence specific internal standards. Of the 18 cytokines tested we found a considerable overlap in the expression of cytokines by human thymocytes and by thymic stromal cells; both cell types express the mRNA for interleukin-1 beta(IL-1, IL-6, IL-7 and tumour necrosis factor-alpha (TNF-alpha). However, there are substantial differences in the levels of cytokine mRNA expressed in these two types of cells as revealed by the quantitative PCR assay. Stromal cells express considerably higher levels of IL-1 beta and IL-6 than thymocytes (14- and 27-fold respectively). In addition, a number of cytokines such as lymphotoxin and interferon-gamma (IFN-gamma), are expressed exclusively in thymocytes whereas others such as stem cell factor (SCF), IL-1 receptor antagonist-2 (IRAP-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are produced only in stromal cells. There is a complete overlap in the expression of a group of cytokine receptors tested in thymocytes and thymic stromal cells; these include IL-1R, IL-2R, IL-6R, IL-7R, TNFR and stem cell growth factor receptor (c-KIT). The expression of specific cytokines by thymic stromal cells and the parallel expression of their receptors on thymocytes under physiological conditions, support the hypothesis that these cytokines participate in paracrine interactions between these two cell populations during thymocyte differentiation.
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PMID:Expression of cytokines and their receptors by human thymocytes and thymic stromal cells. 133 59

The capacity of staphylococcal enterotoxins to stimulate all T cells bearing certain TCR variable region alleles has generated a great deal of interest. This stimulation appears to involve specific binding of the toxin to class II molecules and subsequent stimulation of the T cell via the TCR V beta elements. Recent studies from our laboratory have focused on the ability of staphylococcal enterotoxins to directly activate purified lymph node T cells and a panel of T cell clones and hybridomas. A T cell costimulation assay was performed to assess cellular activation requirements and cytokine receptor expression. Activation of highly purified lymph node T cells by staphylococcal enterotoxin B (SEB) required costimulatory signals which could be provided by IL-1, IL-2, IL-4, or IL-6, whereas SEB alone demonstrated no significant proliferative response. Using a panel of TH1 and TH2 cell clones and T cell hybridomas possessing various responsive and nonresponsive V beta alleles, it was possible to demonstrate that SEA and SEB costimulate T cells via the TCR complex. Additionally, enterotoxin-pretreated T cells demonstrated a significant proliferative response upon exposure to class II-bearing accessory cells, suggesting that these toxins bind directly to T cells. Highly purified T cells cultured with both SEB and IL-1 exhibit significantly increased levels of IL-2 receptor, whereas cells cultured with SEB or IL-1 alone demonstrated low levels of this receptor. These results do not exclude an association of the staphylococcal enterotoxins with class II molecules in a manner which results in a high avidity binding to the TCR required for transduction of the appropriate activation signals. In the absence of class II molecules, however, these superantigens can still bind to T cells, and the activation signal is delivered in the presence of cytokines that trigger T cell growth and lymphokine production.
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PMID:Direct activation of murine T cells by staphylococcal enterotoxins. 154 63

Recombinant human tumor necrosis factor (TNF) alpha decreased the expression of ERBB2 mRNA by stimulating p55 TNF receptors of pancreatic tumor cells. This decrease contrasts with an increase in epidermal growth factor receptor (EGFR) mRNA. Both effects were selectively achieved by TNF-alpha or -beta, whereas interferon alpha or gamma or transforming growth factor beta showed no such effects. The inverse regulatory effects of TNF on ERBB2 and EGFR mRNA levels were evoked by different signaling pathways of p55 TNF receptors. The TNF-mediated ERBB2 mRNA decrease was followed by a reduction in protein. Four of five pancreatic tumor cell lines exhibited this down-regulation. This decrease of ERBB2 is a singular example of a modulation of this growth factor receptor by TNF. Overexpression of ERBB2 has been reported to cause resistance to TNF and other cytotoxic cytokines. In our study we show that the TNF-mediated down-regulation of ERBB2 in pancreatic tumor cells is accompanied by an increase in growth inhibition at low doses of TNF. The simultaneous alteration of the ERBB2/EGFR balance by TNF represents a striking model of cytokine receptor transregulation in the growth control of malignant pancreatic epithelial cells.
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PMID:Inverse regulation of human ERBB2 and epidermal growth factor receptors by tumor necrosis factor alpha. 810 69

The growth of cells in vitro and in vivo is regulated by several environmental signals among which growth factors (cytokines) figure prominently. FLT3 is a novel cytokine receptor with intrinsic ligand-stimulated (FLT3 ligand, FL) tyrosine kinase activity. Here, using a specific anti-FLT3 monoclonal antibody (McAb) and flow cytometry we determined the expression pattern of the receptor protein in 55 human leukemia-lymphoma cell lines and in 20 primary samples from patients with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). FLT3 receptor surface expression was found predominantly in pre-B cell, myeloid and monocytic cell lines and in pre-B-ALL and AML cells, FL was overexpressed in baby hamster kidney cells producing a recombinant protein that was functional in receptor binding and signaling. Incubation with FL induced 3H-thymidine uptake-measured proliferation in some myeloid cell lines and in 2/9 AML cases. The strongest proliferative response was seen in the two growth factor-dependent myeloid leukemia cell lines MUTZ-2 and OCI-AML-5. Long-term substitution of the commonly used cytokines with FL sustained the continuous proliferation of these two cell lines suggesting that also upon permanent activation FLT2 can function as a mitogenic signaling molecule. Despite the high density of FLT3 receptor expression on cultured and fresh pre-B-ALL cells, no proliferation could be stimulated in any of these specimens. Incubation with the anti-FLT3 McAb had agonistic proliferative effects in MUTZ-2 and OCI-AML-5; and anti-FL reagent blocked FL-stimulated proliferation. To summarize, we demonstrated that FL is effective in inducing proliferation of leukemic myeloid cells and that protein expression does not necessarily indicate an FL-responsive cell. While the present data clearly demonstrate that FL might play a proliferative role in leukemogenesis, further studies are needed to clarify whether the signals provided by FL:FLT3 interaction are confined to a proliferation-inducing function or whether maturational progression could also be elicited in certain cells.
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PMID:Effects of FLT3 ligand on human leukemia cells. I. Proliferative response of myeloid leukemia cells. 863 35

The Jak family of tyrosine kinases and the Stat family of transcription factors have been implicated in transducing signals from the hematopoietic growth factor receptors. To explore the role played by a member of the Jak family, Jak2, in hematopoietic cell growth signaling, we constructed a chimeric cDNA coding for the Jak2 tyrosine kinase domain linked to the extracellular and transmembrane regions of the epidermal growth factor (EGF) receptor (EGFR) and expressed the chimera in an interleukin (IL)-3-dependent cell line, 32D. When deprived of IL-3, EGF prevented apoptosis of the transfected cells, induced dose-dependent proliferation, and supported long-term growth. EGF stimulation of the transfectants induced dose-dependent tyrosine phosphorylation of the EGFR/Jak2 chimera and Stat5, which correlated with the EGF dose dependence of cell proliferation. On the other hand, EGF did not induce tyrosine phosphorylation of other factors implicated in cytokine receptor signaling, including the IL-3 receptor beta subunit, Jak kinases, Stat proteins other than Stat5, Shc, Syp, and mitogen-activated protein kinases. These results suggest that the activation of Jak2 may be sufficient for transducing a growth signal in hematopoietic cells by activating the Stat5 pathway or previously unidentified signaling pathways. In addition, because EGF induces homodimerization of the EGFR to activate its tyrosine kinase activity, the present study, which shows EGF-dependent activation of the EGFR/Jak2 chimera, implies that Jak2 may also become activated by homodimerization.
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PMID:An epidermal growth factor receptor/Jak2 tyrosine kinase domain chimera induces tyrosine phosphorylation of Stat5 and transduces a growth signal in hematopoietic cells. 870 38

The c-fes proto-oncogene encodes a non-receptor tyrosine kinase (Fes) that has been implicated in cytokine receptor signal transduction and myeloid differentiation. Previous work from our laboratory has shown that Fes autophosphorylates via an intermolecular mechanism more commonly associated with growth factor receptor tyrosine kinases. Analysis of the Fes amino acid sequence with the COILS algorithm indicates that the N-terminal region of the protein has a very high probability of forming coiled-coil structures often associated with oligomeric proteins. These findings suggest that oligomerization may be a prerequisite for trans-autophosphorylation and activation of Fes. To establish whether the active form of Fes is oligomeric, we performed gel-filtration experiments with recombinant Fes and found that it eluted as a single symmetrical peak of approximately 500 kDa. No evidence of the monomeric, 93-kDa form of the protein was observed. Deletion of the unique N-terminal domain (amino acids 1-450, including the coiled-coil homology region) completely abolished the formation of oligomers. Furthermore, co-precipitation assays demonstrated that an immobilized glutathione S-transferase fusion protein containing the Fes N-terminal region bound to full-length Fes but not to a mutant lacking the N-terminal region. Similarly, a recombinant Fes N-terminal domain protein was readily cross-linked in vitro, whereas the SH2 and kinase domains were refractory to cross-linking. Incubation of wild-type Fes with a kinase-inactive Fes mutant or with the isolated N-terminal region suppressed Fes autophosphorylation in vitro, suggesting that oligomerization may be essential for autophosphorylation of full-length Fes. The presence of an oligomerization function in the Fes family of tyrosine kinases suggests a novel mechanism for non-receptor protein-tyrosine kinase regulation.
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PMID:Oligomerization of the Fes tyrosine kinase. Evidence for a coiled-coil domain in the unique N-terminal region. 921 95

Interleukin-6 (IL-6) is a cytokine that was initially recognized as a regulator of immune and inflammatory responses, but it also regulates the growth of many tumour cells, including prostrate carcinoma. Overexpression of the growth-factor receptors ErbB2/neu and ErbB3 has been implicated in the neoplastic transformation of prostate carcinoma. Here we show that treatment of the prostate cancer cell line LNCaP with IL-6 induces tyrosine phosphorylation of ErbB2 and ErbB3, but not ErbB1/EGFR. We also show that ErbB2 forms a complex with the gp130 subunit of the IL-6 receptor in an IL-6-dependent manner. This association is important because the inhibition of ErbB2 activity results in abrogation of IL-6-induced MAPK activation. Thus ErbB2 is a critical component of IL-6 signalling through the MAP kinase pathway. These data show how a cytokine receptor can diversify its signalling pathways by engaging with a growth-factor receptor kinase.
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PMID:Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells. 959 Jun 94

The cloning of receptor targets procedure, used so far to identify proteins associated with tyrosine kinase receptors was modified to clone SH2 proteins able to bind to the growth hormone receptor (GHR). The cytoplasmic region of GHR, a member of the cytokine receptor superfamily does not contain tyrosine kinase activity. It was thus phosphorylated in bacteria by the Elk tyrosine kinase and radiolabeled to screen a mouse expression library. With this probe, we identified Shc and the p85 subunit of phosphatidylinositol 3-kinase as direct targets of the receptor. The other proteins identified, Csk, Shb, Grb4, and Grb10 are new potential transducers for cytokine receptors. We show in Huh-7 hepatoma cells that Grb10 and GHR associate under GH stimulation. Co-transfections in 293 cells further show that Grb10 interacts with both the GHR and Jak2. Functional tests demonstrate that Grb10 inhibits transcription of two reporter genes containing, respectively, the serum response element of c-fos and the GH response element 2 of the Spi2.1 gene, whereas it has no effect on a reporter gene containing only Stat5 binding elements. Our results suggest that Grb10 is a new target for a member of the cytokine receptor family that down-regulates some GH signaling pathways downstream of Jak2 and independently of Stat5.
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PMID:Grb10 identified as a potential regulator of growth hormone (GH) signaling by cloning of GH receptor target proteins. 963 36

Gab1 has structural similarities with Drosophila DOS (daughter of sevenless), which is a substrate of the protein tyrosine phosphatase Corkscrew. Both Gab1 and DOS have a pleckstrin homology domain and tyrosine residues, potential binding sites for various SH2 domain-containing adapter molecules when they are phosphorylated. We found that Gab1 was tyrosine phosphorylated in response to various cytokines, such as interleukin-6 (IL-6), IL-3, alpha interferon (IFN-alpha), and IFN-gamma. Upon the stimulation of IL-6 or IL-3, Gab1 was found to form a complex with phosphatidylinositol (PI)-3 kinase and SHP-2, a homolog of Corkscrew. Mutational analysis of gp130, the common subunit of IL-6 family cytokine receptors, revealed that neither tyrosine residues of gp130 nor its carboxy terminus was required for tyrosine phosphorylation of Gab1. Expression of Gab1 enhanced gp130-dependent mitogen-activated protein (MAP) kinase ERK2 activation. A mutation of tyrosine 759, the SHP-2 binding site of gp130, abrogated the interactions of Gab1 with SHP-2 and PI-3 kinase as well as ERK2 activation. Furthermore, ERK2 activation was inhibited by a dominant negative p85 PI-3 kinase, wortmannin, or a dominant negative Ras. These observations suggest that Gab1 acts as an adapter molecule in transmitting signals to ERK MAP kinase for the cytokine receptor gp130 and that SHP-2, PI-3 kinase, and Ras are involved in Gab1-mediated ERK activation.
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PMID:Gab1 acts as an adapter molecule linking the cytokine receptor gp130 to ERK mitogen-activated protein kinase. 963 95

The propagation of pluripotent mouse embryonic stem (ES) cells depends on signals transduced through the cytokine receptor subunit gp130. Signalling molecules activated downstream of gp130 in ES cells include STAT3, the protein tyrosine phosphatase SHP-2, and the mitogen-activated protein kinases, ERK1 and ERK2. A chimaeric receptor in which tyrosine 118 in the gp130 cytoplasmic domain was mutated did not engage SHP-2 and failed to activate ERKs. However, this receptor did support ES cell self-renewal. In fact, stem cell colonies formed at 100-fold lower concentrations of cytokine than the unmodified receptor. Moreover, altered ES cell morphology and growth were observed at high cytokine concentrations. These indications of deregulated signalling in the absence of tyrosine 118 were substantiated by sustained activation of STAT3. Confirmation that ERK activation is not required for self-renewal was obtained by propagation of pluripotent ES cells in the presence of the MEK inhibitor PD098059. In fact, the growth of undifferentiated ES cells was enhanced by culture in PD098059. Thus activation of ERKs appears actively to impair self-renewal. These data imply that the self-renewal signal from gp130 is a finely tuned balance of positive and negative effectors.
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PMID:Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells. 1036 25


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