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)

Signals transmitted from mesenchyme to epithelia or vice versa constitute the basis of reciprocal epithelial-mesenchymal interactions. As a first step toward understanding epithelial-mesenchymal interactions on the ocular surface where the transit amplifying cell-containing corneal epithelium is anatomically separated from the stem cell-containing limbal epithelium, we sought to characterize the expression patterns of cytokines and their receptors by primary epithelial and early-passaged fibroblast cultures of human cornea and limbus. Northern hybridization with oligonucleotide and cDNA probes to a total of 25 cytokines and 12 of their receptors revealed that the positively expressed cytokines could be divided into the following four patterns. Type I: TGF-alpha, IL-1 beta, and PDGF-B were expressed exclusively by epithelial cells but their respective receptors EGFR and IL-1R were predominantly and PDGFR-beta was exclusively expressed by fibroblasts. Type II: IGF-I, TGF-beta 1, -beta 2, LIF, and bFGF, and their receptors were expressed by both epithelial cells and fibroblasts. FGFR-1 (flg) and FGFR-2 (bek) were expressed more by fibroblasts and bFGF was expressed more by corneal than limbal epithelial cells. Type III: keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF) were expressed exclusively by fibroblasts and their respective receptors, KGFR and c-met, were predominantly expressed by epithelial cells. Combined with RT-PCR, the quantity of KGF and KGFR transcripts was highest in limbal fibroblasts and epithelial cells, respectively. In contrast, the quantity of HGF and HGFR (c-met) transcripts was highest in corneal fibroblasts and epithelial cells, respectively. Type IV: M-CSF and IL-8 were expressed by fibroblasts and/or epithelial cells but their receptors were not expressed by epithelial cells nor fibroblasts, but by immune or inflammatory cells. In addition to these potential paracrine actions, autocrine actions mediated by TGF-alpha/EGFR, IL-1 beta/IL1-R, and bFGF/FGFR-1 were more expressed by corneal than limbal epithelial cells. Immunofluorescence staining on human corneoscleral cryosections confirmed that EGFR and bFGF were not expressed by the limbal basal epithelium, but expressed strongly by the corneal epithelium, a pattern consistent with Northern hybridization. These results indicate that ocular surface epithelial cells and fibroblasts can express a myriad of cytokines, among which the first three patterns constitute the network of potential epithelial-mesenchymal cytokine dialogues. The difference of certain cytokine expression between corneal and limbal regions suggests that this network participates in normal epithelial growth and differentiation, and plays an important role in wound healing.
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PMID:Three patterns of cytokine expression potentially involved in epithelial-fibroblast interactions of human ocular surface. 789 1

Src homology/collagen (SHC) proteins are thought to participate in signaling through both receptor tyrosine kinases, such as the insulin receptor and the EGF (epidermal growth factor) receptor, and cytoplasmic tyrosine kinases, such as v-src and v-fps. Here we approached the insulin-induced and the insulin-like-growth-factor-I-induced (IGF-I-induced) phosphorylation of SHC proteins, and the possible role of these proteins in insulin and IGF-I signaling. First, we showed that SHC proteins are phosphorylated on tyrosine residues upon insulin and IGF-I treatment of fibroblasts transfected with a SHC cDNA construct. More important, ligand-activated insulin and IGF-I receptors phosphorylate SHC proteins in vitro, indicating that SHC proteins could be direct substrates for insulin and IGF-I receptors. Further, insulin or IGF-I treatment of SHC-transfected fibroblasts leads to immunoprecipitation of SHC proteins with insulin-receptor substrate 1 (IRS-1). We next looked at the possible effect of SHC proteins on biological responses in SHC-transfected fibroblasts. We found that the expression of exogenous SHC proteins results in an increased basal MEK (MAPK/ERK-activating kinase) activity. Further, neither the basal nor the insulin-induced or IGF-I-induced PtdIns-3-kinase activity were modified by expression of exogenous SHC proteins. These results illustrate that SHC proteins are implicated in the MAP (mitogen-activated protein)-kinase pathway, but not in that of PtdIns-3-kinase. Finally, we show that SHC-transfected cells, unlike control cells, are able to advance into the early phases of the cell cycle, and are more sensitive to the growth-promoting effect of insulin. In conclusion, SHC proteins are substrates for insulin and IGF-I receptors, and would appear to function as early post-receptor signaling components.
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PMID:Involvement of Src-homology/collagen (SHC) proteins in signaling through the insulin receptor and the insulin-like-growth-factor-I-receptor. 803 92

IGF-I has been reported to increase hematopoietic progenitor cell cloning efficiency. To investigate this phenomenon, we studied the IGF-I responsiveness of human marrow cells expressing IGF-I receptor (IGF-IR), a direct strategy not used previously. IGF-IR+ and control CD34+ marrow cells were isolated using immunoaffinity methods. Then, the cells were cloned in methylcellulose containing variable amounts of serum- and lineage-appropriate growth factors supplemented with recombinant human IGF-I. In contrast to CD34+ cells, IGF-IR+ cells never gave rise to CFU-Blast, CFU-Mix, CFU-GM, BFU-E, or CFU-E. To substantiate the suggestion that CD34+ and IGF-IR+ cells were distinct populations, we used reverse transcription PCR to detect IGF-I, EpO, and KIT receptor mRNAs in these cells. The mRNA phenotype of CD34+ cells was EpO (+), KIT (+), and IGF-IR (-), while IGF-IR+ cells were IGF-IR (+), EpO (-), and KIT (-). These results suggested that IGF-IR is either not expressed or expressed at low levels on normal hematopoietic progenitor cells. Functional significance of the latter possibility was tested by exposing CD34+ cells to IGF-IR antisense oligodeoxynucleotides. Colony formation was unaffected by oligodeoxynucleotide disruption of IGF-IR, suggesting that, even if expressed at low level, the receptor's functional significance was doubtful. Nevertheless, when cultured in the presence of IGF-I, IGF-IR+ cells elaborated an activity with mild BFU-E stimulatory effects. Accordingly, if IGF-I plays a role in hematopoietic colony formation, it is probably and results from stimulation of IGF-IR-positive ancillary cells to secrete growth factors. Studies carried out with human leukemia cells yielded similar results.
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PMID:A reappraisal of the role of insulin-like growth factor I in the regulation of human hematopoiesis. 804 Feb 73

The insulin receptor-related receptor (IRR) has recently been identified as a member of the insulin receptor tyrosine kinase family; however, its endogenous ligand and biological function are still unknown. In contrast to the very widespread pattern of expression of the homologous insulin and IGF-I receptors, IRR demonstrates a very restricted cellular distribution. Using in situ hybridization and immunohistochemistry, we now show that the expression of this receptor is selectively concentrated in a subset of neurons where its appearance is closely associated with that of the NGF receptor TRK. IRR and TRK demonstrate synchronized patterns of coexpression in neural crest-derived sensory and sympathetic neurons and in non-neural crest basal forebrain and striatal neurons. Both appear early in the embryonic development of dorsal root and trigeminal neurons and somewhat later, near the time of birth, in sympathetic neurons. Expression of both IRR and TRK appears perinatally in basal forebrain neurons, reaching maximal levels about postnatal day 20. This association is highly selective, since TRK mRNA is not detected anywhere in the developing nervous system in the absence of coordinate IRR expression, and the same is true for IRR expression with respect to TRK. In the adult rat, the majority of TRK-positive sensory neurons still express IRR mRNA, and coexpression in sympathetic and forebrain neurons continues without evidence of diminution. These findings are consistent with a functional linkage of the IRR and TRK receptors in NGF-sensitive neurons.
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PMID:Selective coexpression of insulin receptor-related receptor (IRR) and TRK in NGF-sensitive neurons. 804 42

We investigated the growth-regulatory mechanism of 2 esophageal squamous-cancer cell lines, TE2-NS and TE3-OS cells, both of which can grow stably in protein-free conditions in vitro. Protein-free conditioned media from TE2-NS and TE3-OS cells stimulated the growth of these cells. Exogenous epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), insulin-like growth factor (IGF)-I and -II enhanced cell proliferation by 2.2- to 3.8-fold in protein-free conditions, as compared with an untreated control. Receptor-binding assays showed that both TE2-NS and TE3-OS cells possessed a single class of high-affinity binding sites for IGF-I and 2 classes of binding sites for TGF-alpha, as confirmed on the cell membrane by immunochemistry. These results suggest that EGF, TGF-alpha and IGFs are candidates for the autocrine growth factor in cancer cells. The addition of inhibitory monoclonal antibodies against TGF-alpha and EGFR, but not those against either EGF or IGF-IR, significantly inhibited growth of the cells. Immunocytochemical staining and ELISA of the conditioned media both confirmed the production of TGF-alpha protein, but not EGF protein, in these cell lines. The data for a protein-free culture system strongly suggested that TGF-alpha, but not EGF or IGF, is biologically important as an autocrine growth factor in the growth of these cell lines in vitro.
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PMID:Growth-regulatory mechanism of two human esophageal-cancer cell lines in protein-free conditions. 837 19

Growth factor receptors may be transactivated not only by homologous receptors, but also by heterologous receptors. We have investigated this possibility, using for this purpose R-/EGFR cells, which are mouse embryo cells devoid of IGF-I receptors, but overexpressing the EGF receptor. At variance with mouse embryo cells with a wild-type number of IGF-I receptors and overexpressing the EGF receptor, R-/EGFR cells cannot grow in EGF only, nor can they form colonies in soft agar. However, if a wild type human IGF-I receptor is stably transfected into R-/EGFR cells, growth in EGF and colony formation in soft agar are restored. To determine a possible interaction between the two receptors, we transfected into R-/EGFR cells a number of IGF-I receptor mutants with different impaired functions. The only IGF-I receptor that cannot reverse the growth phenotype of R-/EGFR cells is a receptor with a point mutation at the ATP-binding site. All other mutant receptors, even when incapable of responding to IGF-I with a mitogenic signal, made R-/EGFR cells fully capable of responding with growth to EGF stimulation. IGF-I receptor mutants that are mitogenic but not transforming made R-/EGFR cells grow in EGF only, but were incapable of inducing the transformed phenotype. The mutant IGF-I receptors are activated (tyrosyl phosphorylation of IRS-I) in response to EGF. These experiments indicate that certain IGF-I receptor mutants with loss of function can be reactivated intracellularly by an overexpressed EGF receptor and confirm that the C-terminus of the IGF-IR is required for its transforming activity.
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PMID:Intracellular transactivation of the insulin-like growth factor I receptor by an epidermal growth factor receptor. 860 18

Little is known about the factors and the mechanisms involved in preosteoclast emigration from the vasculature. In this study, an in vitro model of bone endothelial lining was mimicked by culturing bone endothelial (BBE) cells at confluence on a 3-microm pore polycarbonate membranes. Preosteoclastic (FLG 29.1) cells were then added on top of the BBE cell monolayer and 10 nM insulin-like growth factor-1 (IGF-I) was added below the supporting membrane. Scanning and transmission electron microscopy were used to evaluate the chemotactic responses of preosteoclastic FLG 29.1 cells towards the IGF-I generated gradient. IGF-I potently stimulated chemotaxis in the FLG 29.1 cells, as shown by the migration of the preosteoclastic cells across the underlying BBE and through the intercellular junctions between adjacent endothelial cells. Subsequently, FLG 29.1 cells penetrated the pores of the supporting membrane and reached the lower face of the membrane. Thus, IGF-I, which is abundantly present in the bone tissue microenvironment, may play a paracrine role in the recruitment of the circulating preosteoclasts from the vascular compartment into the bone tissue. This in vitro model, which mimicks the in vivo phenomenon of preosteoclast extravasation, should prove useful in elucidating the molecular mechanisms that underlie this process.
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PMID:Insulin-like growth factor-I stimulates in vitro migration of preosteoclasts across bone endothelial cells. 904 77

R- cells are 3T3-like fibroblasts generated from mouse embryos nullizygous for a targeted disruption of the genes encoding the type 1 insulin-like growth factor (IGF) receptor (IGF1R). These cells fail to proliferate in serum-free medium supplemented with purified growth factors, in contrast to their wild-type counterparts. However, when R- cells overexpress the insulin receptor from a stably integrated plasmid, R-/IR cells, they become capable of growing in serum-free medium supplemented solely with insulin or IGF-II, but not with IGF-I. Moreover, the introduction into R-/IR cells of an additional plasmid expressing IGF-II causes these cells to proliferate in serum-free medium without growth factor supplementation. From these results, we conclude that IGF-II can stimulate cell proliferation not only through its cognate IGF1R but also through the insulin receptor.
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PMID:Insulin-like growth factor II stimulates cell proliferation through the insulin receptor. 910 54

Insulin, insulin-like growth factor-I (Igf-I), and insulin-like growth factor-II (Igf-II) are known to enhance growth in mouse preimplantation embryos. The addition of insulin, Igf-I, and Igf-II to mouse embryos in culture results in an increase in protein synthesis, cell number, and the proportion of embryos developing to the blastocyst stage. To study the role of the insulin-like growth factors in early human development, the timing of gene expression of insulin, IGF1, IGF2, and their receptors was analysed. Reverse transcription polymerase chain reaction (RT-PCR) was used to examine the presence of transcripts in preimplantation embryos. Following reverse transcription, strategically designed nested primers were used for amplification from cDNA. Transcripts for all three receptors (insulin receptor, IGF1R, IGF2R) were present in human oocytes and preimplantation embryos. However, of the ligands, only IGF2 transcripts were detected. This is consistent with expressed patterns seen in the mouse. As in the human, mouse Igf2 is the only ligand in the family expressed and has been shown to have an autocrine effect on preimplantation development. It has previously been shown that insulin and Igf-I are produced by the mouse maternal reproductive tract and have a paracrine effect on the preimplantation embryo. We speculate that a similar relationship exists in the human and that preimplantation development may be regulated by IGFs from both embryonic (IGF-II) and maternal (insulin and IGF-I) sources.
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PMID:Expression of mRNA for the insulin-like growth factors and their receptors in human preimplantation embryos. 913 13

Genetic analyses of dwarfing phenotypes resulting from targeted mutagenesis of the genes encoding the insulin-like growth factors (IGF-I and IGF-II) and their cognate type 1 IGF receptor (IGF1R) have demonstrated that this signaling system is a major determinant of mouse embryonic growth. Of the two IGF ligands, IGF-I interacts exclusively with IGF1R, whereas IGF-II recognizes an additional receptor (XR), because the growth retardation of embryos lacking both IGR1R and IGF-II (30% of normal birthweight) is more severe than that manifested in either class of single Igf1r or Igf2 null mutants (45 and 60% of normal, respectively). To determine whether XR is the insulin receptor (IR), we examined embryos nullizygous for both Igf1r and Insr. While the growth of embryos lacking solely IR is affected very mildly and only at the end of gestation, concomitant absence of IGF1R results in a severe growth-deficiency phenotype (30% of normal size at birth) that is first detected at Embryonic Day 13.5 and is also characterized by transient edema, curly tail, generalized organ hypoplasia, including the muscles, developmental delays in ossification, and thin epidermis. The Igf1r/Insr double nullizygotes are phenotypically indistinguishable from double mutants lacking IGF1R and IGF-II and from other double and triple mutants in which all of the IGF ligand/receptor interactions have been eliminated. Therefore, these results provide genetic evidence that the growth-promoting function of IGF-II during mouse embryogenesis is mediated in part by signaling through the insulin receptor.
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PMID:Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic development. 928 35


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