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)

DNA encoding the insulin receptor-related receptor (IRR), a novel receptor whose predicted primary structure is similar to those of the insulin and insulin-like growth factor I receptors, has been used in Southern blot analysis of DNA from human x mouse somatic cell hybrids to assign the IRR gene (INSRR) to human chromosome 1.
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PMID:Localization of the insulin receptor-related receptor gene to human chromosome 1. 224 81

The insulin-like growth factor I (IGF-1) mediates the actions of pituitary growth hormone in a variety of tissues. Its receptor (IGF1R) displays considerable structural similarity to the insulin receptor. In humans, the IGF1R gene has been mapped near FES, the cellular counterpart of the feline sarcoma virus transforming gene v-fes, at the q25-q26 region of human chromosome 15 (HSA15). Here, we report the mapping of mouse Igf1r to mouse chromosome 7 (MMU7) by somatic cell hybrid analysis. This result, along with the prior assignment of the loci for mitochondrial isocitrate dehydrogenase and FES to human chromosome 15 and mouse chromosome 7, suggest a conserved autosomal synteny group on the distal long arm of HSA15 and in the center of MMU7.
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PMID:Insulin-like growth factor I receptor gene is concordant with c-Fes protooncogene and mouse chromosome 7 in somatic cell hybrids. 254 93

The receptors for insulin and insulin-like growth factor I (IGF-I) are closely related molecules, with an extracellular binding domain and an intracellular tyrosine kinase domain. The interaction of insulin and IGF-I with their respective receptors activates the receptor kinase domain, leading to the biological actions of the hormones. Since insulin generally regulates metabolic events and IGF-I generally regulates growth events, it is believed that structural differences in the tyrosine kinase domains of the two respective receptors may elicit different biological responses via different transmembrane signaling mechanisms. We studied the regulation of glycogen metabolism and amino acid uptake in human cultured HEP-G2 hepatoma cells, which have distinct receptors for both insulin and IGF-I. The receptor specificity of these responses was probed with specific monoclonal antibodies to both the insulin and IGF-I receptors. Stimulation of both [3H]glucose incorporation into glycogen and alpha-[3H]aminoisobutyric acid uptake by insulin was half-maximal at concentrations of 1-5 nmol/L. These effects were blocked by the insulin receptor monoclonal antibody MA-10, but not by the IGF-I receptor antibody alpha IR-3. Stimulation of both functions by IGF-I was half-maximal at concentrations of 1-5 nmol/L, and these effects were inhibited by alpha IR-3, but not by MA-10. These studies indicate that in HEP-G2 cells both insulin and IGF-I, via their own receptors, stimulate the same biological responses.
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PMID:Insulin and insulin-like growth factor I regulate the same biological functions in HEP-G2 cells via their own specific receptors. 283 99

The ring chromosome 15 syndrome is characterized by mild-to-severe growth failure. We evaluated the status of the insulin-like growth factor I receptor (IGF1R) gene, which had previously been assigned to band 15q26 in several patients with de novo ring 15 chromosomes, to investigate a possible correlation between disruption or loss of the IGF1R gene with the severe growth failure phenotype. The presence or absence of the IGF1R gene on the ring 15 chromosomes of five patients was ascertained by in situ hybridization and gene-dosage (Southern) blotting. The location of the breakpoints was determined by typing polymorphic markers from the distal end of the long arm of chromosome 15 in both the probands and their parents. Deletion mapping determined that all breakpoints were distal to D15S100 and that the IGF1R gene is located between D15S107 and D15S87. Three patients who had suffered severe growth failure in early childhood were hemizygous at the IGF1R locus, while one patient with borderline short stature had two copies of the IGF1R gene. The correlation between IGF1R gene dosage and growth retardation demonstrated here in our ring chromosome 15 patients suggests a possible role for heterozygous IGF1R gene mutations or deletions in other cases of unexplained growth failure.
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PMID:Hemizygosity at the insulin-like growth factor I receptor (IGF1R) locus and growth failure in the ring chromosome 15 syndrome. 778 78

A gene encoding a putative third member of the insulin receptor family (called the insulin receptor-related receptor or IRR) was isolated in 1989. However, the naturally occurring protein product encoded by this gene has yet to be described. In the present studies, we have generated four monoclonal antibodies to a recombinantly expressed chimera, which contains the extracellular domain of human IRR. These antibodies were found to specifically recognize the chimeric IRR (and not the insulin or insulin-like growth factor I receptors), and two of the antibodies were capable of acting as partial agonists in the cells expressing the chimeric IRR. These antibodies have therefore been utilized to study the expression and properties of the native receptor. In contrast to the two other members of this receptor family, the endogenous IRR protein had only a very limited expression, being detected only in neuroblastomas. In primary neuroblastomas, the levels of the receptor were highest in samples from stage A tumors (those which are generally more highly differentiated and have higher levels of the nerve growth factor receptor). The endogenous IRR could also be detected in a neuroblastoma cell line (called IMR-5 cells). In these cells, IRR could be shown to be partly present as a hybrid with the insulin and insulin-like growth factor-I receptors but not with the receptor for nerve growth factor. The intrinsic tyrosine kinase activity of this endogenous IRR was activated by the agonist monoclonal antibody to IRR but not by nerve growth factor, insulin-like growth factor I, or insulin. Finally, this monoclonal antibody was found to stimulate mitogen-activated protein kinase activity in these cells. In summary, these studies demonstrate for the first time that the IRR protein is normally expressed, that its levels are highest in neuronal tissues, and that it can form hybrid receptors with the two other members of this receptor family but not with the more distantly related nerve growth factor receptor.
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PMID:Characterization of the endogenous insulin receptor-related receptor in neuroblastomas. 782 25

When wild-type mouse embryo cells are stably transfected with a plasmid constitutively overexpressing the epidermal growth factor (EGF) receptor (EGFR), the resulting cells can grow in serum-free medium supplemented solely with EGF. Supplementation with EGF also induces in these cells the transformed phenotype (growth in soft agar). However, when the same EGFR expression plasmid is introduced and overexpressed in cells derived from littermate embryos in which the insulin-like growth factor I (IGF-I) receptor genes have been disrupted by homologous recombination, the resulting cells are unable to grow or to be transformed by the addition of EGF. Reintroduction into these cells (null for the IGF-I receptor) of a wild-type (but not of a mutant) IGF-I receptor restores EGF-mediated growth and transformation. Our results indicate that at least in mouse embryo fibroblasts, the EGFR requires the presence of a functional IGF-I receptor for its mitogenic and transforming activities.
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PMID:A functional insulin-like growth factor I receptor is required for the mitogenic and transforming activities of the epidermal growth factor receptor. 800 63

Temperature-sensitive mutations in the avian sarcoma virus UR2 oncogene ros, encoding a receptor protein-tyrosine kinase (PTK), were identified. The Ala385-->Gly change mapping within the highly conserved RDLAARN motif in the Ros kinase domain was responsible for the temperature-sensitive phenotype. Based on the sequence homology of all known protein kinases and the crystalline structure of the cAMP-dependent protein kinase, this conserved region probably represents the PTK catalytic loop. The same mutation when introduced into the human insulin and insulin-like growth factor I receptors made these PTKs temperature sensitive in both biological function and kinase activity. Our results support the presumed catalytic role of this highly conserved sequence in PTKs. Due to its highly conserved nature, we predict that the same mutation would probably confer temperature sensitivity on other PTKs.
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PMID:Ala-->Gly mutation in the putative catalytic loop confers temperature sensitivity on Ros, insulin receptor, and insulin-like growth factor I receptor protein-tyrosine kinases. 827 85

The tyrosines in the cytoplasmic domain of an oncogenic human insulin-like growth factor I receptor (gag-IGFR) were systematically mutated to phenylalanines to investigate the role of those tyrosines in the enzymatic and biological function of the gag-IGFR. Our results indicate that tyrosines 1131, 1135, 1136, and 1221 are important for the receptor protein-tyrosine kinase (PTK) activity. However, mutation of Tyr-1136 only slightly affects the kinase activity but dramatically reduces the transforming ability and overall substrate phosphorylation, in particular, annexin II, which is strongly phosphorylated by the gag-IGFR but not by the Phe-1136 mutant. Single mutation of either Tyr-943 or Tyr-950 resulted in significantly reduced phosphorylation of the receptor but not on its PTK activity or transforming ability. Tyr-950 together with its surrounding sequence is involved in mediating the interaction between the gag-IGFR and insulin receptor substrate 1. Our data also suggest that Tyr-1316 is involved in phosphorylation of phospholipase C-gamma, which is, however, not important for cell transforming activity. Overall, our study has identified several tyrosine residues of IGFR important for its PTK activity and substrate interaction. The transforming potential of the gag-IGFR correlates well with its ability to phosphorylate overall cellular substrates and to activate phosphatidylinositol 3-kinase via insulin receptor substrate 1.
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PMID:Effect of tyrosine mutations on the kinase activity and transforming potential of an oncogenic human insulin-like growth factor I receptor. 855 May 52

Using a coculture system, we have recently demonstrated that insulin-like growth factor I (IGF-I) is a mediator of preosteoclastic cell migration toward bone-derived endothelial cells. To better characterize the mechanisms of IGF-I action on preosteoclastic cells we evaluated the expression of type I IGFs receptor in the human leukemic cell line, FLG 29.1, which differentiates toward the osteoclastic phenotype following phorbol ester (TPA) treatment. Scatchard analysis of 125I-labeled IGF-I to FLG 29.1 cells revealed the presence of a single high affinity binding site in both untreated and TPA-treated cells with a similar Kd value (0.3 +/- 0.2 nmol/L and 0.4 +/- 0.1 nmol/L, respectively). In untreated cells, IGF-I binding capacity (1.43 +/- 0.41 fmol/10(6) cells) was significantly (p < 0.05) lower than in TPA-treated cells (2.62 +/- 0.87 fmol/10(6) cells). Competition analyses and crosslinking studies revealed the presence of type I IGF receptor both in untreated and TPA-treated cells. Northern analysis demonstrated that mRNA for IGF-I receptor was expressed by both untreated and TPA-treated FLG 29.1 cells. In addition, FLG 29.1 cells released in the conditioned medium IGFBP-2 and IGFBP-4, whose expression was increased by TPA treatment as demonstrated by ligand and immunoblot analyses. The previous observations of chemotactic action of IGF-I on FLG 29.1 cells was confirmed by ultrastructural observations. Indeed, these cells revealed a marked migratory activity in response to nanomolar concentrations of IGF-I. In addition, the IGF-I receptor alpha IR-3 antiserum inhibited the IGF-I-induced FLG 29.1 cell's migratory activity. These findings clearly show that type IIGF receptor is expressed by osteoclast precursors and that IGF-I induces migration of these through the binding to type I IGF receptors. Binding proteins expressed by osteoclast precursors may play an autocrine role in modulating the IGF-I bioeffects.
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PMID:Characterization and function of the receptor for IGF-I in human preosteoclastic cells. 870 83

The effect of increased intracellular cAMP on MCF-7 breast cancer cell growth was examined by treating cells with either forskolin, an activator of adenylate cyclase, or 8-[4-chlorophenylthio]-cAMP (8-CPT-cAMP), a cAMP analog. Compared to cells maintained in control medium, treatment with either 1 or 10 microM forskolin decreased cell growth by 17% and 68%, respectively, whereas treatment with 250 microM 8-CPT-cAMP decreased cell growth by 29%. To determine whether this effect of cAMP on cell growth was mediated by inhibition of the activity of extracellular signal-regulated kinases 1 and 2 (ERK1 and -2), two mitogen-activated protein kinases, the effect of cAMP on growth factor-induced ERK activity in MCF-7 cells was examined. Treatment with either insulin-like growth factor I (IGF-I) or epidermal growth factor (EGF) for 10 min stimulated a 4- to 8-fold increase in ERK1 and -2 activity. This effect of IGF-I and EGF was not inhibited by increased intracellular cAMP generated by pretreatment of the cells with 10 microM forskolin. Similarly, 10 microM forskolin had no effect on IGF-I- or EGF-induced ERK activity in cells treated with growth factor for 30 min. To determine whether cAMP inhibits other growth factor-mediated effects, its effect on the activity of the serum response element (SRE), a DNA promoter element whose activity is regulated by a variety of growth-promoting events, was examined. For these assays, MCF-7 cells were transiently transfected with pTK81-SRE-Luc, a luciferase fusion gene that contains the SRE cloned 5' to a minimal thymidine kinase promoter and the luciferase gene. Treatment with either IGF-I or EGF increased pTK81-SRE-Luc activity in a dose-dependent fashion. Pretreatment of cells with 10 microM forskolin decreased IGF-I- and EGF-stimulated luciferase activity by approximately 75%. An intermediate effect was observed using 1 microM forskolin. When intracellular cAMP levels were increased using 8-CPT-cAMP, similar results were obtained. SRE activity is dependent upon the activation by phosphorylation of a ternary complex factor; included among the ternary complex factors is Elk-1. When MCF-7 cells were cotransfected with a vector that expresses a Gal4/Elk-1 fusion protein and UAS-TK-Luc, a plasmid that contains two Gal4 DNA recognition sites cloned 5' to a thymidine kinase promoter and the luciferase gene, treatment with forskolin partially inhibited the activation of Elk-1 by IGF-I and EGF. These data demonstrate that in MCF-7 breast cancer cells, cAMP has no effect on IGF-I- or EGF-induced ERK activity, but it inhibits growth factor-induced transcription. Taken together with the effects of cAMP on IGF-I- and EGF-induced Elk-1 activation, these data suggest that the effect of cAMP on SRE activity occurs distal to ERK activation, possibly via inhibition of an ERK-independent pathway. Finally, these data indicate that the effect of increased intracellular cAMP on breast cancer growth may be mediated through inhibition of specific growth factor-induced effects, including gene transcription.
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PMID:Growth factor-induced transcription via the serum response element is inhibited by cyclic adenosine 3',5'-monophosphate in MCF-7 breast cancer cells. 916 3


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