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)

As detected by coimmunoprecipitation from PC12 cells, NGF induces rapid association between ERK1 (a growth factor-activated serine/threonine protein kinase) and gp140prototrk NGF receptors. In contrast, no such association is found with the closely related ERK2. Anti-trk immunocomplexes generated from NGF-treated cells also contain protein kinase activity that shares many properties with soluble ERK1. The association of both ERK1 protein and ERK-like kinase activity with gp140prototrk is maximal by 5 min of NGF treatment, persists for approximately 1 hr, and subsequently declines by 18 hr. Treatment with either basic fibroblast growth factor, epidermal growth factor, or orthovanadate also leads to association of ERK1 with gp140prototrk without tyrosine phosphorylation of the latter. The interaction between ERK1 and gp140prototrk may prove relevant to the NGF mechanism.
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PMID:NGF and other growth factors induce an association between ERK1 and the NGF receptor, gp140prototrk. 146 7

Amplification and/or overexpression of HER2/neu and HER3 genes have been implicated in the development of cancer in humans. The fact that these receptor tyrosine kinases (RTKs) are frequently coexpressed in tumor-derived cell lines and that heterodimers form high affinity binding sites for heregulin (HRG) suggests a novel mechanism for signal definition, diversification or amplification. In cells expressing HER2 and HER3, tyrosine phosphorylation of HER3 is markedly increased upon exposure to recombinant HRG. ATP binding site mutants of HER2 and HER3 demonstrate transphosphorylation of HER3 by HER2, but not vice versa. HRG-induced transphosphorylation of HER3 results in a substrate phosphorylation pattern distinct from HER2 cells and enhances association of the receptor with SHC and phosphoinositol 3-kinase in transfected 293 and mammary carcinoma-derived MCF-7 cells. The physiological relevance of HER2/HER3 heterodimerization is demonstrated by HRG-dependent transformation of NIH 3T3 cells coexpressing the two receptors. These findings demonstrate the acquisition of expanded signaling capacities for HER2 by HRG-induced heterodimerization with HER3 and provide a molecular basis for the involvement of receptor heteroactivation in the development of human malignancies.
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PMID:Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. 755 68

We have isolated rat cDNAs that encode two related receptor-like tyrosine kinases. One of these receptors, TIE-1, is the rat homolog of a recently described human receptor-like kinase termed TIE (Partanen et al., 1992). The related TIE-2 receptor has the same organization of amino acid sequence motifs characteristic of TIE-1: two immunoglobulin-like domains, three epidermal growth factor (EGF)-like domains and three fibronectin III-like repeats in the extracellular region and a short kinase insert sequence and C-terminal tail in the intracellular region. The amino acid sequences of the intracellular and extracellular regions of TIE-1 and TIE-2 are 79% and 32% identical respectively. Both tie genes are broadly expressed in embryonic, neonatal and adult tissues, accounted for largely by their coexpression in endothelial cells. The tie-2 gene is also uniquely expressed in several additional embryonic tissues, including the lens epithelium and the heart epicardium.
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PMID:Distinct rat genes with related profiles of expression define a TIE receptor tyrosine kinase family. 768 30

In order to study the function of tyrosine kinase receptors during Xenopus development, we have isolated Xek (Xenopus Elk-like kinase), a tyrosine kinase receptor, which shows significant homology to rat Elk and chicken cek5, members of the Eph family. Xek exists as a maternally expressed mRNA which decreases in expression at the mid blastula transition and reappears at late neurulation in Xenopus. Xek mRNA is expressed at higher levels in the anterior and dorsal regions of embryonic stages 16, 24 and 37. In adult Xenopus tissues, Xek appears to be ubiquitously expressed with higher expression observed in brain and ovary. In situ hybridization analysis demonstrates localized mRNA expression in the brain, brachial arches, trigeminal facial ganglion, and the retina of the swimming tadpole stage of development. The similarities in sequence and expression pattern suggest that Xek is an amphibian member of the Eph family and may play a role in the development or function of the central nervous system.
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PMID:Expression of an amphibian homolog of the Eph family of receptor tyrosine kinases is developmentally regulated. 770 Jun 36

Neuronal degeneration has been shown to be involved in various neurological disorders. Growth/trophic factors and their receptors are known to be important for the regeneration and survival of neurons. We report here the molecular cloning of a receptor-like protein tyrosine kinase, bsk, (for brain specific kinase). Bsk is highly related to the eph/elk receptor-like kinase family members. Northern blot analysis shows that it is expressed specifically in the brain, with no expression detected in adult heart, spleen, lung, liver, skeletal muscle, and kidney. In situ hybridization analysis of adult mouse brain sections indicates that bsk is expressed at high levels in the hippocampus, tenia tecta, indusium griseum, and the piriform cortex, major components of the limbic system that are important for learning and memory. In addition, elevated levels of expression are found in other areas of the limbic system such as the amygdala, medial septum, and nucleus of the diagonal band, and in the olfactory bulb, which has close connections to the limbic system. The highest level of expression is found in the CA3 region of the hippocampus and the pyramidal cell layer of the piriform cortex. In 16.5 day mouse embryos, bsk is expressed predominantly in the primordial cortex of the telencephalon. An antibody against a C-terminal peptide of bsk recognized a 105 kD protein in the 16.5 day embryonic head extract. Our analysis shows that bsk is a growth factor receptor-like protein tyrosine kinase and that its greatest expression in the adult brain is associated with components of the limbic system.
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PMID:Isolation and characterization of Bsk, a growth factor receptor-like tyrosine kinase associated with the limbic system. 814

Advances in screening technologies allowing the identification of growth factor receptors solely by virtue of DNA or protein sequence comparison call for novel methods to isolate corresponding ligand growth factors. The EPH-like receptor tyrosine kinase (RTK) HEK (human EPH-like kinase) was identified previously as a membrane antigen on the LK63 human pre-B-cell line and overexpression in leukemic specimens and cell lines suggested a role in oncogenesis. We developed a biosensor-based approach using the immobilized HEK receptor exodomain to detect and monitor purification of the HEK ligand. A protein purification protocol, which included HEK affinity chromatography, achieved a 1.8 X 10(6)-fold purification of an approximately 23-kDa protein from human placental conditioned medium. Analysis of specific sHEK (soluble extracellular domain of HEK) ligand interactions in the first and final purification steps suggested a ligand concentration of 40 pM in the source material and a Kd of 2-3 nM. Since the purified ligand was N-terminally blocked, we generated tryptic peptides and N-terminal amino acid sequence analysis of 7 tryptic fragments of the S-pyridylethylated protein unequivocally matched the sequence for AL-1, a recently reported ligand for the related EPH-like RTK REK7 (Winslow, J.W., Moran, P., Valverde, J., Shih, A., Yuan, J.Q., Wong, S.C., Tsai, S.P., Goddard, A., Henzel, W.J., Hefti, F., Beck, K.D., & Caras, I.W. (1995) Neuron 14, 973-981). Our findings demonstrate the application of biosensor technology in ligand purification and show that AL-1, as has been found for other ligands of the EPH-like RTK family, binds more than one receptor.
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PMID:Purification of a ligand for the EPH-like receptor HEK using a biosensor-based affinity detection approach. 863 7

Megakaryocytopoiesis is the process by which bone marrow progenitor cells develop into mature megakaryocytes, which in turn produce platelets required for normal hemostasis. The development of this hematopoietic lineage depends on a variety of growth factors and cytokines. Growth factor-dependent tyrosine kinase receptors important in megakaryocytopoiesis include c-Kit, fibroblast growth factor receptor, the RON receptor, and the macrophage colony-stimulating factor receptor. Binding of growth factors to their respective receptors results in receptor dimerization and subsequent autophosphorylation on tyrosine residues. Tyrosine autophosphorylations become sites of association for cytoplasmic signaling molecules via their SH2 domains. Some of these molecules are themselves cytoplasmic tyrosine kinases such as the Src kinases, TEC, and CHK. Others are molecules such as phospholipase C-gamma, phosphoinositol 3-kinase, Shc, GTPase-activating protein, and the SH2-containing tyrosine phosphatases SHP-1 and SHP-2. These molecules generate second messengers, regulate the phosphorylation of other downstream molecules, and also regulate the phosphorylation of the receptor itself. The different cytoplasmic components activate pathways involved in either changes in cell growth or changes in the cytoskeleton that affect maturation of the cell. Cytokine receptors also generate signals involved in growth and differentiation. Some of these second messengers overlap with those of the receptor tyrosine kinases. Others, such as the JAKs/STATs, are involved in transcriptional control and are unique to the signaling mediated by cytokine receptors. We describe the contribution of these different signals to the growth/differentiation processes of megakaryocytes. We also describe the contribution of receptor and nonreceptor tyrosine phosphatases to these processes. Lastly, we have compiled selected methods related to the study of protein phosphorylation in megakaryocytes.
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PMID:Regulation of megakaryocytopoiesis and platelet production by tyrosine kinases and tyrosine phosphatases. 1008 Sep 10

Glial cell line-derived neurotrophic factor (GDNF) has been shown to signal through a multicomponent receptor complex consisting of the Ret receptor tyrosine kinase and a member of the GFRalpha family of glycosylphosphatidylinositol-anchored receptors. In the current model of GDNF signaling, Ret delivers the intracellular signal but cannot bind ligand on its own, while GFRalphas bind ligand but are thought not to signal in the absence of Ret. We have compared signaling pathways activated by GDNF in two neuronal cell lines expressing different complements of GDNF receptors. In a motorneuron-derived cell line expressing Ret and GFRalphas, GDNF stimulated sustained activation of the Ras/ERK and phosphatidylinositol 3-kinase/Akt pathways, cAMP response element-binding protein phosphorylation, and increased c-fos expression. Unexpectedly, GDNF also promoted biochemical and biological responses in a line of conditionally immortalized neuronal precursors that express high levels of GFRalphas but not Ret. GDNF treatment did not activate the Ras/ERK pathway in these cells, but stimulated a GFRalpha1-associated Src-like kinase activity in detergent-insoluble membrane compartments, rapid phosphorylation of cAMP response element-binding protein, up-regulation of c-fos mRNA, and cell survival. Together, these results offer new insights into the dynamics of GDNF signaling in neuronal cells, and indicate the existence of novel signaling mechanisms directly or indirectly mediated by GFRalpha receptors acting in a cell-autonomous manner independently of Ret.
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PMID:Ret-dependent and -independent mechanisms of glial cell line-derived neurotrophic factor signaling in neuronal cells. 1040 32

Mitogen-activated protein kinases (MAPKs) and cyclin-dependent kinases (CDKs) are important proline-directed Ser/Thr kinases that play distinct roles in cell differentiation and proliferation. hPRP4 (pre-mRNA processing gene), a human homologue of S. pombe Prp4, is a recently isolated CDK-like kinase with homology to MAPKs. Little is known about the mRNA processing function of hPRP4 or about the signaling pathways with which it is associated. hPRP4 is expressed in a variety of human tissues with the highest expression in the brain, lung and liver. In this paper, we characterize the activation of hPRP4 in COS-7 cells and show that hPRP4 also possesses a transcription factor activation function. hPRP4 is activated by epidermal growth factor (EGF) or forskolin treatment, but not tetradecanoyl phorbol acetate (TPA) nor ultraviolet (UV) irradiation. Activated hPRP4 phosphorylates residue Thr-417 on Elk-1 resulting in Elk-1 activation. This site of Elk-1 phosphorylation is distinct from that of other MAPKs. Coexpression of hPRP4 with an Elk-1 reporter construct causes trans activation of the reporter. These findings suggest that hPRP4, a CDK-like kinase related to MAPKs, may play a distinct role in signal transduction in addition to its role in mRNA processing.
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PMID:Characterization of hPRP4 kinase activation: potential role in signaling. 1079 19

Functional evidence for the existence of plasma membrane estrogen receptors in a variety of cell types continues to accumulate. Many of these functions originate from rapid signaling events, transduced in response to 17beta-estradiol (E(2)). It has been convincingly shown that E(2) activates phosphoinositol 3-kinase and protein kinase B/AKT, and stimulates ERK and p38 MAP kinases. In part, this stems from G-protein activation and the resulting calcium flux. As a result, the link between E(2) action at the cell membrane and discrete biological actions in the cell has been strengthened. There is now convincing in vitro evidence that E(2) can modulate the functions of neural and vascular cells via non-genomic actions. Thus, the actions of discrete pools of E(2) receptors are likely to contribute to the overall effects of the sex steroids.
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PMID:Rapid actions of plasma membrane estrogen receptors. 1129 70


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