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 Drosophila, members of the Frizzled family of tissue-polarity genes encode proteins that appear to function as cell-surface receptors for Wnts. The Frizzled genes belong to the seven transmembrane class of receptors (7TMR) and have on their extracellular region a cysteine-rich domain that has been implicated as the Wnt binding domain. This region has a characteristic spacing of ten cysteines, which has also been identified in FrzB (a secreted antagonist of Wnt signaling) and Smoothened (another 7TMR, which is involved in suppression of the hedgehog pathway). We have identified, using BLAST, sequence similarity between the cysteine-rich domain of Frizzled and several receptor tyrosine kinases, which have roles in development. These include the muscle-specific receptor tyrosine kinase (MuSK), the neuronal specific kinase (NSK2), and ROR1 and ROR2. At present, the ligands for these developmental tyrosine kinases are unknown. Our results suggest that Wnt-like ligands may bind to these developmental tyrosine kinases.
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PMID:Identification of a Frizzled-like cysteine rich domain in the extracellular region of developmental receptor tyrosine kinases. 1008 84

In Drosophila, members of the Frizzled family of tissue-polarity genes encode proteins that appear to function as cell-surface receptors for Wnts. The Frizzled genes belong to the seven transmembrane class of receptors (7TMR) and have on their extracellular region a cysteine-rich domain that has been implicated as the Wnt binding domain. This region has a characteristic spacing of ten cysteines, which has also been identified in FrzB (a secreted antagonist of Wnt signaling) and Smoothened (another 7TMR, which is involved in the hedgehog signalling pathway). We have identified, using BLAST, sequence similarity between the cysteine-rich domain of Frizzled and several receptor tyrosine kinases, which have roles in development. These include the muscle-specific receptor tyrosine kinase (MuSK), the neuronal specific kinase (NSK2), and ROR1 and ROR2. At present, the ligands for these developmental tyrosine kinases are unknown. Our results suggest that Wnt-like ligands may bind to these developmental tyrosine kinases
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PMID:Identification of a Frizzled-like cysteine rich domain in the extracellular region of developmental receptor tyrosine kinases. 968 97

Quantitative complementation tests provide a quick test of the hypothesis that a particular gene contributes to segregating phenotypic variation. A set of wild-type alleles is assayed for variation in their ability to complement the degree of dominance of the quantitative effect of a loss of function allele. Analysis of 15 loci known to be involved in wing patterning in Drosophila melanogaster suggests that the genes decapentaplegic, thickveins, EGFR, argos and hedgehog, each of which are involved in secreted growth factor signaling, may contribute to wing shape variation. The phenotype of one deficiency, Df(2R)Px2, which removes blistered/Plexate, is also highly sensitive to the wild-type genetic background and at intermediate expressivity reveals six ectopic veins. These form in the same locations as a projection of the ancestral pattern of dipteran wing veins on- to the D. melanogaster wing. This atavistic phenotype indicates that the wing vein prepatterning mechanism can be conserved in highly derived species, and implies that homoplasic venation patterns may be produced by derepression of vein primordia.
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PMID:Quantitative developmental genetic analysis reveals that the ancestral dipteran wing vein prepattern is conserved in Drosophila melanogaster. 1115 Dec 98

This study addresses the role of Sonic hedgehog (Shh) in promoting the generation of oligodendrocytes in the mouse telencephalon. We show that in the forebrain, expression of the early oligodendrocyte markers Olig2, plp/dm20 and PDGFR(alpha) corresponds to regions of Shh expression. To directly test if Shh can induce the development of oligodendrocytes within the telencephalon, we use retroviral vectors to ectopically express Shh within the mouse embryonic telencephalon. We find that infections with Shh-expressing retrovirus at embryonic day 9.5, result in ectopic Olig2 and PDGFR(alpha) expression by mid-embryogenesis. By postnatal day 21, cells expressing ectopic Shh overwhelmingly adopt an oligodendrocyte identity. To determine if the loss of telencephalic Shh correspondingly results in the loss of oligodendrocyte production, we studied Nkx2.1 mutant mice in which telencephalic expression of Shh is selectively lost. In accordance with Shh playing a role in oligodendrogenesis, within the medial ganglionic eminence of Nkx2.1 mutants, the early expression of PDGFR(alpha) is absent and the level of Olig2 expression is diminished in this region. In addition, in these same mutants, expression of both Shh and plp/dm20 is lost in the hypothalamus. Notably, in the prospective amygdala region where Shh expression persists in the Nkx2.1 mutant, the presence of plp/dm20 is unperturbed. Further supporting the idea that Shh is required for the in vivo establishment of early oligodendrocyte populations, expression of PDGFR(alpha) can be partially rescued by virally mediated expression of Shh in the Nkx2.1 mutant telencephalon. Interestingly, despite the apparent requirement for Shh for oligodendrocyte specification in vivo, all regions of either wild-type or Nkx2.1 mutant telencephalon are competent to produce oligodendrocytes in vitro. Furthermore, analysis of CNS tissue from Shh null animals definitively shows that, in vitro, Shh is not required for the generation of oligodendrocytes. We propose that oligodendrocyte specification is negatively regulated in vivo and that Shh generates oligodendrocytes by overcoming this inhibition. Furthermore, it appears that a Shh-independent pathway for generating oligodendrocytes exists.
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PMID:Sonic hedgehog contributes to oligodendrocyte specification in the mammalian forebrain. 1117 36

In the vertebrate spinal cord, oligodendrocytes arise from the ventral part of the neuroepithelium, a region also known to generate somatic motoneurons. The emergence of oligodendrocytes, like that of motoneurons, depends on an inductive signal mediated by Sonic hedgehog. We have defined the precise timing of oligodendrocyte progenitor specification in the cervico-brachial spinal cord of the chick embryo. We show that ventral neuroepithelial explants, isolated at various development stages, are unable to generate oligodendrocytes in culture until E5 but become able to do so in an autonomous way from E5.5. This indicates that the induction of oligodendrocyte precursors is a late event that occurs between E5 and E5.5, precisely at the time when the ventral neuroepithelium stops producing somatic motoneurons. Analysis of the spatial restriction of oligodendrocyte progenitors, evidenced by their expression of O4 or PDGFR(&agr;), indicate that they always lie within the most ventral Nkx2.2-expressing domain of the neuroepithelium, and not in the adjacent domain characterized by Pax6 expression from which somatic motoneurons emerge. We then confirm that Shh is necessary between E5 and E5.5 to specify oligodendrocyte precursors but is no longer required beyond this stage to maintain ongoing oligodendrocyte production. Furthermore, Shh is sufficient to induce oligodendrocyte formation from ventral neuroepithelial explants dissected at E5. Newly induced oligodendrocytes expressed Nkx2.2 but not Pax6, correlating with the in vivo observation. Altogether, our results show that, in the chick spinal cord, oligodendrocytes originate from Nkx2.2-expressing progenitors.
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PMID:Distinct sites of origin of oligodendrocytes and somatic motoneurons in the chick spinal cord: oligodendrocytes arise from Nkx2.2-expressing progenitors by a Shh-dependent mechanism. 1126 37

Activation of the hedgehog pathway, through the loss of patched (PTC) or the activation of smoothened (SMO), occurs frequently in basal cell carcinoma (BCC), the most common human cancer. However, the molecular basis of this neoplastic effect is not understood. The downstream molecule Gli1 is known to mediate the biological effect of the pathway and is itself up-regulated in all BCCs. Gli1 can drive the production of BCCs in the mouse when overexpressed in the epidermis. Here we show that Gli1 can activate platelet-derived growth factor receptor alpha (PDGFRalpha) in C3H10T(1/2) cells. Functional up-regulation of PDGFRalpha by Gli1 is accompanied by activation of the ras-ERK pathway, a pathway associated with cell proliferation. The relevance of this mechanism in vivo is supported by a high level expression of PDGFRalpha in BCCs of mice and humans. In the murine BCC cell line ASZ001, in which both copies of the PTC gene are inactivated, DNA synthesis and cell proliferation can be slowed by re-expression of PTC, which down-regulates PDGFRalpha expression, or by downstream inhibition of PDGFRalpha with neutralizing antibodies. Therefore, we conclude that increased expression of PDGFRalpha may be an important mechanism by which mutations in the hedgehog pathway cause BCCs.
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PMID:A role of PDGFRalpha in basal cell carcinoma proliferation. 1148 86

Gain of function mutations in fibroblast growth factor (FGF) receptors cause chondrodysplasia and craniosynostosis syndromes. The ligands interacting with FGF receptors (FGFRs) in developing bone have remained elusive, and the mechanisms by which FGF signaling regulates endochondral, periosteal, and intramembranous bone growth are not known. Here we show that Fgf18 is expressed in the perichondrium and that mice homozygous for a targeted disruption of Fgf18 exhibit a growth plate phenotype similar to that observed in mice lacking Fgfr3 and an ossification defect at sites that express Fgfr2. Mice lacking either Fgf18 or Fgfr3 exhibited expanded zones of proliferating and hypertrophic chondrocytes and increased chondrocyte proliferation, differentiation, and Indian hedgehog signaling. These data suggest that FGF18 acts as a physiological ligand for FGFR3. In addition, mice lacking Fgf18 display delayed ossification and decreased expression of osteogenic markers, phenotypes not seen in mice lacking Fgfr3. These data demonstrate that FGF18 signals through another FGFR to regulate osteoblast growth. Signaling to multiple FGFRs positions FGF18 to coordinate chondrogenesis in the growth plate with osteogenesis in cortical and trabecular bone.
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PMID:Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. 1193 93

To investigate the cellular role of dual specificity Yak1-related kinase (Dyrk) 1, a nuclear localized dual specificity protein kinase, we examined its effect on transcriptional regulation using reporter gene assays. We found that Dyrk1 can substantially enhance Gli1-dependent, but not LEF-1-, c-Jun-, or Elk-dependent, gene transcription. In part, Dyrk1 does this through retaining Gli1 in the nucleus. However, we also demonstrate that Dyrk1 can enhance the transcriptional activity of Gli1-AHA, a nuclear export mutant, suggesting that Dyrk1 may be more directly involved in regulating the transcriptional activity of Gli1. In addition, Dyrk1 acted synergistically with Sonic hedgehog (Shh) to induce gene transcription and differentiation in mouse C3H10T1/2 cells. The failure of Shh to stimulate Dyrk1 kinase activity suggests that Dyrk1 may not be directly regulated by the Shh signaling pathway but functionally interacts with it. Thus, Gli1 transcriptional activity may be subjected to further regulation in the cell nucleus by a pathway distinct from Shh signaling, one mediated by Dyrk1.
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PMID:Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1. 1213 25

Dach1 is a mouse homologue of the Drosophila dachshund gene, which is a key regulator of cell fate determination during eye, leg, and brain development in the fly. We have investigated the expression and growth factor regulation of Dach1 during pre- and postnatal skeletal development in the mouse limb to understand better the function of Dach1. Dach1 was expressed in the distal mesenchyme of the early embryonic mouse limb bud and subsequently became restricted to the tips of digital cartilages. Dach1 protein was localized to postmitotic, prehypertrophic, and early hypertrophic chondrocytes during the initiation of ossification centers, but Dach1 was not expressed in growth plates that exhibited extensive ossification. Dach1 colocalized with Runx2/Cbfa1 in chondrocytes but not in the forming bone collar or primary spongiosa. Dach1 also colocalized with cyclin-dependent kinase inhibitors p27 (Kip1) and p57 (Kip2) in chondrocytes of the growth plate and in the epiphysis before the formation of the secondary ossification center. Because fibroblast growth factors (FGF), bone morphogenetic proteins (BMP), and hedgehog molecules (Hh) regulate skeletal patterning of the limb bud and chondrocyte maturation in developing endochondral bones, we investigated the regulation of Dach1 by these growth and differentiation factors. Expression of Dach1 in 11 days postcoitus mouse limb buds in organ culture was up-regulated by implanting beads soaked in FGF1, 2, 8, or 9 but not FGF10. BMP4-soaked beads down-regulated Dach1 expression, whereas Shh and bovine serum albumin had no effect. Furthermore, FGF4 or 8 could substitute for the apical ectodermal ridge in maintaining Dach1 expression in the limb buds. Immunolocalization of FGFR2 and FGFR3 revealed overlap with Dach1 expression during skeletal patterning and chondrocyte maturation. We conclude that Dach1 is a target gene of FGF signaling during limb skeletal development, and Dach1 may function as an intermediary in the FGF signaling pathway regulating cell proliferation or differentiation.
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PMID:Fibroblast growth factor signaling regulates Dach1 expression during skeletal development. 1220 18

Receptor and non-receptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating gastrointestinal cancer. Imatinib mesilate (STI-571, Gleevec(TM)), an inhibitior of bcr-abl TK, which was primarily designed to treat chronic myeloid leukemia is also an inhibitor of c-kit receptor TK, and is currently the drug of choice for the therapy of metastatic gastrointestinal stromal tumors (GISTs), which frequently express constitutively activated forms of the c-kit-receptor. The epidermal growth factor receptor (EGFR), which is involved in cell proliferation, metastasis and angiogenesis, is another important target. The two main classes of EGFR inhibitors are the TK inhibitors and monoclonal antibodies. Gefitinib (ZD1839, Iressa(TM)) has been on trial for esophageal and colorectal cancer (CRC) and erlotinib (OSI-774, Tarceva(TM)) on trial for esophageal, colorectal, hepatocellular, and biliary carcinoma. In addition, erlotinib has been evaluated in a Phase III study for the treatment of pancreatic cancer. Cetuximab (IMC-C225, Erbitux(TM)), a monoclonal EGFR antibody, has been FDA approved for the therapy of irinotecan resistant colorectal cancer and has been tested for pancreatic cancer. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are critical regulators of tumor angiogenesis. Bevacizumab (Avastin(TM)), a monoclonal antibody against VEGF, was efficient in two randomized clinical trials investigating the treatment of metastatic colorectal cancer. It is also currently investigated for the therapy of pancreatic cancer in combination with gemcitabine. Other promising new drugs currently under preclinical and clinical evaluation, are VEGFR2 inhibitor PTK787/ZK 222584, thalidomide, farnesyl transferase inhibitor R115777 (tipifarnib, Zarnestra(TM)), matrix metalloproteinase inhibitors, proteasome inhibitor bortezomib (Velcade(TM)), mammalian target of rapamycin (mTOR) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, platelet derived growth factor receptor (PDGF-R) inhibitors, protein kinase C (PKC) inhibitors, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors, Rous sarcoma virus transforming oncogene (SRC) kinase inhibitors, histondeacetylase (HDAC) inhibitors, small hypoxia-inducible factor (HIF) inhibitors, aurora kinase inhibitors, hedgehog inhibitors, and TGF-beta signalling inhibitors.
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PMID:Molecularly targeted therapy for gastrointestinal cancer. 1589 18


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