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)

In this chapter we have described one of the more complex hemopoietic factors, M-CSF. The single-copy M-CSF gene is almost 21 kb in length and is arranged into 10 exons and 9 introns. Expression of the gene at the RNA level is heterogeneous, and several species of M-CSF mRNA have been found in human and murine cells and tissues. In human cells the different mRNAs arise from alternative splicing of the nuclear RNA precursor in both coding and noncoding regions. This results in mRNAs encoding two distinct M-CSF proteins, 256 and 554 amino acids in length. In murine cells only a 552-amino-acid form has been found thus far. All forms of M-CSF have a 32-amino-acid signal peptide and a 23-amino-acid hydrophobic region near the carboxy-terminus, which resembles a transmembrane domain. A large portion of the carboxy-terminal end, including the hydrophobic region, is not found in the mature protein. Thus, the primary translation product of M-CSF is a prepropolypeptide, with processing occurring at both amino- and carboxy-terminal ends. The exact size of the mature protein is still somewhat in doubt, but deletion mutagenesis from the carboxy-terminal end indicates that the protein may be as small as 150 amino acids and still be functional. Site-directed mutagenesis has also shown that the first seven cysteines in the mature molecule are probably necessary for biological activity, whereas the next two cysteine residues are not. In spite of the heavy glycosylation found in the native protein, removal of the N-linked glycosylation signals does not seem to affect activity to any great degree. The M-CSF gene and its receptor, C-FMS, are tightly linked on the long arm of chromosome 5, a unique finding in the ligand/receptor field. This region also contains the genes for GM-CSF, IL-3, ECGF, and the receptor for PDGF. A similar situation may exist on chromosome 11 of the mouse. The close linkage of these factors and receptors is the probable cause for the disorders of hemopoiesis that arise when deletions occur in this area. The preceding discussion has shown how quickly the area of M-CSF molecular biology has advanced in the past 2-3 years. A great deal of effort is now being directed toward expressing M-CSF at high levels in a variety of prokaryotic and eukaryotic systems.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular biology of macrophage colony-stimulating factor. 209 Feb 50

Phospholipase C-gamma (PLC-gamma) and GTPase activating protein (GAP) are substrates of EGF, PDGF and other growth factor receptors. Since either PLC-gamma or GAP also bind to the activated receptors it was suggested that their SH2 domains are mediating this association. We attempted to delineate the specific region of the EGF receptor that is responsible for the binding, utilizing EGF receptor mutants, PLC-gamma, and a bacterially expressed TRP E fusion protein containing the SH2 domains of GAP. As previously shown, tyrosine autophosphorylation of the wild-type receptor wsa crucial in mediating the association and in agreement, a kinase negative EGF receptor could bind PLC-gamma or TRP E GAP SH2, but only when cross tyrosine phosphorylated by an active EGF receptor kinase. The importance of autophosphorylation for association was confirmed by demonstrating that a carboxy-terminal deletion of the EGFR missing four autophosphorylation sites bound these proteins poorly. To study the role of EGF receptor autophosphorylation further, a 203 amino acid EGF receptor fragment was generated with cyanogen bromide that contained all known tyrosine autophosphorylation sites. This fragment bound both TRP E GAP SH2 and PLC-gamma but only when tyrosine phosphorylated. This data localizes a major binding site for SH2 domain containing proteins to the carboxy-terminus of the EGF receptor and points to the importance of tyrosine phosphorylation in mediating this association.
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PMID:The tyrosine phosphorylated carboxyterminus of the EGF receptor is a binding site for GAP and PLC-gamma. 217 51

We have studied mRNA levels for a variety of growth factors in biopsy specimens from malignant, benign and normal breast tissue. We found TGFb mRNA in all breast cancers and neoplastic breast tissues but the level of the TGFb mRNA were found to be higher in breast cancer (P = 0.01). TGFa mRNA was detected in a similar proportion of cancers as in neoplastic breast tissues but the TGFa receptor EGFR mRNA was detected in only 55% of breast cancers but in all non-neoplastic breast tissue tested. The presence of EGFR mRNA was inverted related to oestrogen receptor status and coexpression of TGFa and EGFR was observed in 28% of carcinomas, and significantly more commonly in ER negative tumours (P = 0.01). PDGF a and b chain transcripts coexisted in all normal and malignant breast tissue. Insulin-like growth factor II mRNA was present in all 15 samples of non-malignant breast tissue but in only 11 of 21 (52%) of carcinomas.
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PMID:Growth factor expression in breast tissue. 228 95

We have previously reported that the J774A.1 macrophage-like tumor cell line produces two potent monokines which stimulate the growth of osteoblasts and chondrocytes. These growth factors, which have an affinity for heparin-agarose, have been termed HEP I (a 30 Kd PDGF-like molecule) and HEP II (an approximately 20 Kd molecule), respectively, based on their elution profile. Unlike HEP I, HEP II does not stimulate the growth of fibroblasts. Extensive biological and chromatographic studies disclosed that HEP II appears to be a unique bone cell mitogen unlike any known growth factor, including the FGFs, IL-1s, and TNFs, EGF, IGF-I and -II, TGF-beta, beta 2 microglobulin, G-CSF, CSF-1 and GM-CSF. To characterize more fully the effects of the macrophage-derived monokines on osteoblast growth and function, clones were derived from calvaria explant cultures. Two clones, SDFRC-2.05 and SDFRC-3, were developed and found to exhibit osteoblastic characteristics, including high levels of alkaline phosphatase, synthesis of type I but not type III collagen, and an increased intracellular cAMP production in response to PTH. The SDFRC-3 cells exhibited a polygonal morphology like that of the explant-derived cells while SDFRC-2.05 cells exhibited a more fibroblastic morphology. When tested on the explant cultures and clones, HEP I and HEP II were found to stimulate DNA synthesis and increase protein per culture, but decreased alkaline phosphatase activity. Clone SDFRC-3 was found to be more responsive to HEP II than clone SDFRC-2.05. Both monokines were found to be more potent mitogens for bone cells than TGF-beta. HEP II, but not HEP I or TGF-beta, induced a transformation of bone cells from a polygonal to a fibroblastic morphology, suggesting the induction of migration prior to proliferation. Thus, macrophages may be responsible not only for bone repair but also for ensuring the linkage of bone formation to resorption during physiological remodeling.
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PMID:Monokines produced by macrophages stimulate the growth of osteoblasts. 263 Jan 69

Previous studies have demonstrated that mouse embryonal carcinoma (EC) cells produce at least two growth factors: one related to platelet-derived growth factor (PDGF) and another related to basic fibroblast growth factor (FGFb). Since human EC cell lines are being used with increased frequency, the current study examined whether human EC cells produce growth factors, in particular those produced by mouse EC cells. In this study, it was determined that the human EC cell line NT2/D1 produces a heat-labile heparin-binding growth factor that behaves like FGF in a bioassay. Three additional criteria suggest that this factor is closely related or identical to FGFb. The factor from NT2/D1 EC cells, bovine FGFb and FGFb produced by the human hepatoma cell line SK-HEP-1 elute from heparin at similar salt concentrations. The factor produced by NT2/D1 EC cells exhibits a thermal stability curve that is nearly identical to those for bovine FGFb and FGFb from SK-HEP-1 cells. Lastly, NT2/D1 and SK-HEP-1 cells express transcripts of the same size that hybridize with a cDNA probe for human FGFb. In the course of these studies it was determined that NT2/D1 EC cells also express several transcripts that hybridize with a cDNA probe for the human PDGF A-chain. Thus, our findings suggest that the pattern of growth factor production by human and mouse EC cells is evolutionarily conserved.
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PMID:Production of growth factors related to fibroblast growth factor and platelet-derived growth factor by human embryonal carcinoma cells. 320 87

The importance of PLC activation in cell proliferation is evident from the fact that the hydrolysis of PtdIns(4,5)P2 is one of the early events that follow the interaction of many growth factors and mitogens with their respective receptors. However, the importance of PLC activation is not restricted to proliferation; it is one of the most common transmembrane signaling events elicited by receptors that regulate many other cellular processes, including differentiation, metabolism, secretion, contraction, and sensory perception. It is also clear that cell proliferation signaling does not always require PLC, as indicated by the fact that growth factors such as insulin and CSF-1 do not appear to elicit the hydrolysis of PtdIns(4,5)P2, even though the intracellular domains of their receptors carry a PTK domain and the receptors show topologies very similar to those of the PLC-activating growth factors PDGF, EGF, and FGF. The growth factor-dependent activation of PLC is initiated by the formation of a complex between the receptor PTK and PLC-gamma; the formation of this complex is mediated by a specific interaction between a tyrosine phosphate residue on the intracellular domain of PTK and the SH2 domain of PLC-gamma. The receptor PTK subsequently phosphorylates PLC-gamma, of which two distinct isozymes, PLC-gamma 1 and PLC-gamma 2, have been identified. Proliferation of T cells and B cells in response to the aggregation of their respective cell surface receptors is also accompanied by the activation of PLC-gamma isozymes at an early stage. Unlike growth factor receptors, the T cell and B cell receptors lack intrinsic PTK activity but associate with several non-receptor PTKs of the Src and Syk families. Although the specific kinases are not known, one or more of these enzymes phosphorylate and activate PLC-gamma 1 and PLC-gamma 2. Transduction of growth signals by G protein-coupled receptors such as those for thrombin or bombesin also requires PtdIns(4,5)P2 hydrolysis, which, in this instance, is mediated by PLC-beta isozymes. The PLC-beta subfamily consists of four distinct members: PLC-beta 1, PLC-beta 2, PLC-beta 3, and PLC-beta 4. Agonist interaction with specific G protein-coupled receptors causes the dissociation of Gq proteins into G alpha and G beta gamma subunits and the exchange of GDP bound to G alpha for GTP. The resulting GTP-bound G alpha subunit then activates PLC-beta isoforms by binding to the carboxyl-terminal region of the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phosphoinositide-specific phospholipase C and mitogenic signaling. 749 69

The prostatic growth factors require a membrane specific receptor to which they must bind in order to carry out their biological activities correctly. The aim of this study was to isolate and quantify the epidermal growth factor receptor in prostatic tissue and indirectly determine the growth factors acting on it (EGF, TGF alpha, PDGF, NGF, IGF). From September, 1992 to June, 1993, we studied 55 patients. These were divided into two groups: the first group comprised 49 patients with benign prostatic hyperplasia (BPH) and 6 patients with prostatic carcinoma comprised the second group. Samples of the prostate were obtained following suprapubic (12 cases), TUR (38 cases), radical prostatectomy (1 case) and transrectal biopsy (4 cases). The EGFR was determined by radioimmunoassay (EGFR-RIA, Vienna Lab, Labordiagnostica GmbH). For the overall group of patients, we obtained mean EGFR values of 6.36 +/- 0.59 fmol/mg of protein and a positivity of 96.36% and 100% for BPH and malignant proliferative processes, respectively. The foregoing data show that EGFR was isolated from the tissue we analyzed and has an evident role in the regulation of prostate growth.
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PMID:[Involvement of epidermal growth factor receptor (EGFR) in the etiopathogenesis of prostatic proliferative processes]. 752 95

PDGFs and their receptors expression were examined in a series of 46 meningiomas by using specific monoclonal antibodies. The immunostaining was quantified by an image analyser and the results correlated with clinical and morphological data (histological type and grade). In addition, since the PDGFB chain is encoded by the c-sis proto-oncogene localized on chromosome 22 and because monosomy 22 has been frequently reported in meningiomas, PDGFs and PDGFRs expression have been correlated with cytogenetic analysis performed in 29 cases. The results demonstrate PDGF A and PDGF B expression in most meningioma specimens and co-expression of these growth factors in numerous cells. PDGF A and B immunoreactivity was related to histological grade. PDGFR beta expression was strong in almost all meningiomas whereas PDGFR alpha was low. PDGFR alpha expression was related to tumour location and grade and PDGFR beta to histological subtype only. The cytogenetic analysis was not related to PDGFB chain expression. Taken together these data further confirm PDGF and PDGFR expression in human meningioma; PDGF may exist as an heterodimer (AB) as well as its receptor. The lack of correlation between cytogenetic analysis and PDGF values, the low level of PDGFB in recurrent meningiomas suggests that it is unlikely that the c-sis proto-oncogene plays an important role in the genesis of meningiomas.
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PMID:Platelet-derived growth factor (PDGF) and receptor (PDGFR) expression in human meningiomas: correlations with clinicopathological features and cytogenetic analysis. 753 Dec 97

Because the protein-tyrosine phosphatase (PTP) Syp associates with the tyrosine-phosphorylated platelet-derived growth factor beta receptor (beta PDGFR), the beta PDGFR is a likely Syp substrate. We tested this hypothesis by determining whether recombinant Syp (rSyp) and a control PTP, recombinant PTP1B (rPTP1B), were able to dephosphorylate the beta PDGFR. The beta PDGFR was phosphorylated at multiple tyrosine residues in an in vitro kinase assay and then incubated with increasing concentrations of rSyp or rPTP1B. While the receptor was nearly completely dephosphorylated by high concentrations of rPTP1B, receptor dephosphorylation by rSyp plateaued at approximately 50%. Two-dimensional phosphopeptide maps of the beta PDGFR demonstrated that rSyp displayed a clear preference for certain receptor phosphorylation sites; the most efficiently dephosphorylated sites were phosphotyrosines (Tyr(P)-771 and -751, followed by Tyr(P)740, while Tyr(P)-1021 and Tyr(P)-1009 were very poor substrates. In contrast, rPTP1B displayed no selectivity for the various rPTP1B displayed no selectivity for the various beta PDGFR tyrosine phosphorylation sites and dephosphorylated all of them with comparable efficiency. A Syp construct that lacked the SH2 domains was still able to discriminate between the various receptor phosphorylation sites, although less effectively than full-length Syp. These in vitro studies predicted that Syp can dephosphorylate the receptor in vivo. Indeed, we found that a beta PDGFR mutant (F1009) that associates poorly with Syp, had a much slower in vivo rate of receptor dephosphorylation than the wild type receptor. In addition, the GTPase-activating protein of Ras (GAP) and phosphatidylinositol 3-kinase were less stably associated with the wild type beta PDGFR than with the F1009 receptor. These findings are consistent with the in vitro experiments showign that Syp prefers to dephosphorylate sites on the beta PDGFR, that are important for binding phosphatidylinositol 3-kinase (Tyr(P)-740 and Tyr(P)-751) and GAP (Tyr(P)-771). These studies reveal that Syp is a substrate-selective PTP and that both the catalytic domain and the SH2 domains contribute to Syp's ability to choose substrates. Furthermore, it appears that Syp plays a role in PDGF-dependent intracellular signal relay by selectively dephosphorylating the beta PDGFR and thereby regulating the binding of a distinct group of receptor-associated signal relay enzymes.
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PMID:Identification of a putative Syp substrate, the PDGF beta receptor. 754 75

In recent study we demonstrated expression of the platelet-derived growth factor alpha receptor (PDGFR alpha) in cells of the early oligodendrocyte lineage that were identified as either GD3 ganglioside + oligodendrocyte progenitors or O4 sulfatide+ preoligodendrocytes. We also identified a subpopulation of GD3 immunoreactive cells that did not express mRNA for the PDGF receptor. The distinct large amoeboid morphology of these cells was characteristic of cells in the macrophage lineage rather than in the oligodendrocyte lineage. To determine if the GD3-positive but PDGFR alpha mRNA-negative cells were in the macrophage lineage, we compared the spatial and temporal expression patterns of GD3 ganglioside and ED1, a macrophage-specific antigen. Analysis prenatally indicated that at embryonic day 15, ED1+ and GD3+ cell populations resided in the subpial connective tissue. At embryonic day 21, these two populations were seen in a region extending from the lateral ventricle through the subventricular and intermediate zones. In this study we report that these large, round, GD3 immunoreactive cells have the same cell morphology and anatomical distribution as the ED1 immunoreactive cells. Both cell populations contained pyknotic nuclei within their cytoplasm. Furthermore, the GD3+/PDGFR alpha- cells appear to be involved in clearing cellular debris in regions of gliogenesis. These data suggest that this subpopulation of GD3 immunoreactive cells belongs to the microglia/macrophage lineage.
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PMID:Amoeboid microglia expressing GD3 ganglioside are concentrated in regions of oligodendrogenesis during development of the rat corpus callosum. 755 39


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