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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study investigates the innervation of the embryonic chick ovary with regard to (i) development and compartmentalization of catecholaminergic nerves, and (ii) presence of adrenoceptors on steroidogenic target cells of catecholaminergic nerve terminals. Catecholaminergic nerve fibers visualized by glyoxylic acid-induced histofluorescence first appeared at embryonic day (E) 13. From E15 through E21 the density of fluorescent aminergic nerves increased markedly in parallel with the concentration of catecholamines and numbers of nerve bundles and single axons seen at the electron-microscopic level. Catecholaminergic nerves were confined to the ovarian medulla and closely associated with interstitial cells. Nerve terminals approached interstitial cells up to a distance of 20 nm and, in their majority, exhibited uptake of the false adrenergic transmitter 5-hydroxydopamine. Although adrenaline amounted to 14% of the total catecholamine content at E21, adrenaline immunoreactivity was only detected in adrenal chromaffin cells, but not in nerve fibers or cell bodies within the ovary. Interstitial cells structurally matured between E15 and E21 as documented by an increase of smooth endoplasmic reticulum and tubular mitochondria. Monoclonal antibodies mAB 120 and BRK 2 raised against avian beta 1- and mammalian beta 2-adrenergic receptors revealed the presence of beta 2-adrenoceptor-like immunoreactivity on the surface of interstitial cells, but not on any other cell type. The results are consistent with the notion of a dense adrenergic innervation of the embryonic chick ovarian medulla and its steroidogenic interstitial cells, and suggest the chick ovary as an excellent model for elucidating the functional role of a neural input to steroidogenic cells during development.
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PMID:Catecholaminergic nerves in the embryonic chick ovary: co-localization with beta 2-adrenoceptor-bearing steroidogenic cells. 284 26

Immunocytochemistry showed PKC alpha-positive hepatocytes around portal area after two-thirds PH, and they were distributed diffusely in lobules, and reached a peak in number 12 hrs. It's location was not only on membrane facing sinusoid or lateral membrane but also in rough endoplasmic reticulum or in cytosol. Combined technique of immunocytochemistry and ARG revealed presence of (H)-grains at 24 hrs in hepatocytes around the portal tract. PKC alpha was expressed in hepatocytes around central necrosis 6 hrs after administration of CCl4 and its immunoreactivity was visible not only on cytoplasmic membrane but also in cytoplasm, and PKC alpha-positive hepatocytes reached a peak in number at 24 hrs. (H)-labeled hepatocytes were observed around central necrosis at 48 hrs, and AFP was expressed in the same area at 96 hrs. These findings suggest that PKC alpha is expressed in proliferating lesion after PH or administration of CCl4, and that PKC alpha may make an important role in the early phase of cell proliferation, then it is closely associated with liver regeneration.
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PMID:[Expression and significance of PKC alpha in regenerating liver of rats after partial hepatectomy and CCl4 administration]. 892 5

Erythropoietin (EPO) is the major hormone regulating the proliferation of erythroid precursors and their differentiation into erythrocytes. Ligand binding to the erythropoietin receptor (EPO-R), a member of the cytokine receptor family, triggers Tyr phosphorylation of the surface form of the receptor, presumably mediated by the Janus kinase (JAK) 2. To study whether non-surface EPO-R can be phosphorylated, Ba/F3 cells stably transfected with EPO-R were treated with pervanadate (PV), which is widely used as a potent tool to inhibit cellular protein Tyr phosphatases, thus resulting in enhanced Tyr phosphorylation of cellular proteins. PV treatment caused the EPO-R to undergo Tyr phosphorylation in a time-dependent and dose-dependent manner. PV-mediated Tyr phosphorylation of EPO-R occurred at several intracellular sites including the endoplasmic reticulum (ER), because both endoglycosidase H (endo H)-resistant EPO-R and the ER-retained EPO-R mutant (DeltaWS1 EPO-R) were Tyr phosphorylated in response to PV. Moreover, in metabolic labelling experiments, endo H-sensitive EPO-R was also phosphorylated. The phosphorylated fraction accounted for only 30-50% of the newly synthesized EPO-R, the fraction that normally exits from the ER. Tyr phosphorylation could not be detected on proteolytic fragments of the EPO-R, suggesting that this is a highly regulated process. Unlike the wild-type (wt) EPO-R, which was phosphorylated both on EPO binding and after inhibition of Tyr phosphatases by PV treatment, an EPO-R mutant (W282R EPO-R) that does not activate JAK2 was phosphorylated after PV treatment but not by EPO binding. Both EPO-R and JAK2 were phosphorylated with similar kinetics by PV treatment, suggesting that JAK2, as well as protein Tyr kinases different from JAK2, might mediate PV-dependent EPO-R phosphorylation. Furthermore the Tyr-phosphorylated ER-retained EPO-R mutant DeltaWS1 co-immunoprecipitated with JAK2 kinase, indicating that the EPO-R might interact with JAK2 while in the ER.
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PMID:Phosphorylation of erythropoietin receptors in the endoplasmic reticulum by pervanadate-mediated inhibition of tyrosine phosphatases. 935 6

Tolyporphin (TP), a porphyrin extracted from cyanobacteria, was found to be a very potent photosensitizer of EMT-6 tumor cells grown both in vitro as suspensions or monolayers and in vivo in tumors implanted on the backs of C.B17/Icr severe combined immunodeficient mice. Thus, during photodynamic treatment (PDT) of EMT-6 tumor cells in vitro, the photokilling effectiveness of TP measured as the product of the reciprocal of D50 (the light dose necessary to kill 50% of cells) and the concentration of TP is approximately 5000 times higher than that of Photofrin II (PII), the only PDT photosensitizer thus far approved for clinical trials. TP almost exclusively localizes in the perinuclear region and specifically in the endoplasmic reticulum (ER), as shown by microspectrofluorometry on single living EMT-6 cells costained with the ER and/or Golgi fluorescent vital probes, 3,3'-dihexyloxacarbocyanine iodide and N-[4,4-difluoro-(5,7-dimethyl-BODIPY)-1-pentanoyl]-D-erythro-sphin gosine (Molecular Probes, Eugene, OR). As a result, the singlet oxygen-mediated photodynamic activity of TP induces an effective inactivation of the acyl CoA:cholesterol-O-acyltransferase, a sensitive marker of ER membrane integrity and alterations of the nuclear membrane. In vivo, with the EMT-6 mouse tumor model, an exceptional effectiveness is also observed as compared to that of PII and other second generation photosensitizers of the pheophorbide class, which are themselves much more potent than PII. The outstanding PDT activity of TP observed in vivo may be due to its unique biodistribution properties, in particular much less extraction by the liver, resulting in a higher delivery to other tissues, including tumor.
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PMID:Tolyporphin: a natural product from cyanobacteria with potent photosensitizing activity against tumor cells in vitro and in vivo. 972 63

We have derived a cell line, RE1, from a pre-implantation rat blastocyst, resembling morphologically the L2 cell line from a parietal yolk sac carcinoma of the rat, as well as parietal endoderm cell lines of the mouse. The sub-cellular organization and epithelial characteristics of RE1 cells are described. The cells express cytokeratins of simple epithelia, and vimentin; and demonstrate synthesis of proteins of the extracellular matrix, such as laminin and collagen IV. Extensive Reichert's-like basement membrane is formed by RE1 cells when grown in suspension as aggregates. Cells have a microvillous surface morphology and abundant, rough endoplasmic reticulum which is swollen with apparent secretory material. These morphological and cytochemical features are characteristic of parietal endoderm cells in vivo, and the RE1 cell line is deduced to be rat parietal endoderm. In addition, RE1 cells were examined for expression of stage-specific embryonic antigens: cells reacted with antibody against SSEA-1/TEC-1 and EMA-1, constituting the first observation of parietal endoderm cells expressing the respective epitopes. RE1-cell monolayers did not generate transepithelial resistances or potential differences in vitro, consistent with their formation of leaky epithelia. Our observations on RE1-cell morphology and ultrastructure are consistent with the occurrence of epithelial-mesenchyme transitions in culture.
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PMID:Parietal endoderm cell line from a rat blastocyst. 1116 60

The desensitization of the GH-induced Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) signaling pathway plays a crucial role in GH regulation of hepatic genes. Previous studies have demonstrated that the inactivation of the GH-induced JAK2/STAT5 pathway is regulated by protein translation and suppressors of cytokine signaling (SOCS). In this study we sought to explore the relationships between endoplasmic reticulum stress, GH-induced JAK2/STAT5 activity and SOCS expression. 1,2-bis(o-Aminophenoxy)ethane-N,N,N,N-tetraacetic acid (acetoxymethyl)ester (BAPTA-AM), used to provoke endoplasmic reticulum stress, caused a drastic inhibition of protein translation that correlated with the phosphorylation of the eukaryotic translation initiation factor 2alpha. Both GH and BAPTA-AM caused a rapid induction of the transcription factor C/EBP homology protein (CHOP) and an additive effect was observed with combined treatment, which suggests a regulatory role of GH on endoplasmic reticulum stress. Endoplasmic reticulum stress did not interfere with the rapid GH activation of STAT5 DNA binding activity. However, BAPTA-AM prolonged the DNA binding activity of STAT5 without affecting STAT5 or JAK2 protein levels. GH-induced phosphorylation of JAK2 and STAT5 DNA binding activity were prolonged in the presence of BAPTA-AM, suggesting that endoplasmic reticulum stress prevents the inactivation of STAT5 DNA binding activity by modulating the rate of JAK2/STAT5 dephosphorylation. Like BAPTA-AM, the endoplasmic reticulum stressors dithiothreitol and A23187 also prolonged the GH-induced STAT5 DNA binding activity. We were not able to correlate BAPTA-AM effects to the GH-dependent expression of SOCS proteins or SOCS mRNA, suggesting that endoplasmic reticulum stress modulates the rate of JAK2/STAT5 dephosphorylation through mechanisms other than inhibition of SOCS expression. This study indicates that cellular stress may modulate transcription through the JAK/STAT pathway.
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PMID:Endoplasmic reticulum stress prolongs GH-induced Janus kinase (JAK2)/signal transducer and activator of transcription (STAT5) signaling pathway. 1151 96

We show that Janus kinase 2 (JAK2), and more specifically just its intact N-terminal domain, binds to the erythropoietin receptor (EpoR) in the endoplasmic reticulum and promotes its cell surface expression. This interaction is specific as JAK1 has no effect. Residues 32 to 58 of the JAK2 JH7 domain are required for EpoR surface expression. Alanine scanning mutagenesis of the EpoR membrane proximal region reveals two modes of EpoR-JAK2 interaction. A continuous block of EpoR residues is required for functional, ligand-independent binding to JAK2 and cell surface receptor expression, whereas four specific residues are essential in switching on prebound JAK2 after ligand binding. Thus, in addition to its kinase activity required for cytokine receptor signaling, JAK is also an essential subunit required for surface expression of cytokine receptors.
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PMID:The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. 1177 7

The erythropoietin receptor transduces signals leading to the growth, differentiation, and survival of red blood cell precursors via interaction with Janus kinase 2 (JAK2). This interaction was thought to occur only at the plasma membrane. Recent evidence, however, shows that JAK2 assembles with newly synthesized erythropoietin receptors in the endoplasmic reticulum, and that this assembly is essential for efficient expression of the receptors at the cell surface.
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PMID:Quality control of receptor-kinase signaling complexes. 1178 6

Integrin receptors mediate the formation of adhesion complexes and play important roles in signal transduction from the extracellular matrix. Integrin-based adhesion complexes (IAC) contain proteins that link integrins to the cytoskeleton and recruit signaling molecules, including vinculin, paxillin, focal adhesion kinase, talin and alpha-actinin. In this study, we describe a approximately 160 kDa protein that is markedly enriched at IAC induced by clustering integrins with fibronectin-coated beads. Protein sequence analysis reveals that this approximately 160 kDa protein is kinectin. Kinectin is an integral membrane protein found in endoplasmic reticulum, and it serves as a receptor for the motor protein kinesin. Fibronectin-induced IAC sequestered over half of the total cellular content of kinectin within 20 minutes. In addition, two other ER-resident proteins, RAP [low-density lipoprotein receptor-related protein (LRP) receptor-associated protein] and calreticulin, were found to be clustered at IAC, whereas kinesin was not. Our results identify a novel class of constituents of IAC.
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PMID:Integrin clustering induces kinectin accumulation. 1197 45

The regulatory effect of growth hormone (GH) on its target cells is mediated via the GH receptor (GHR). GH binding to the GHR results in the formation of a GH-(GHR)(2) complex and the initiation of signal transduction cascades via the activation of the tyrosine kinase JAK2. Subsequent endocytosis and transport to the lysosome of the ligand-receptor complex is regulated via the ubiquitin system and requires the presence of an intact ubiquitin-dependent endocytosis (UbE) motif in the cytosolic tail of the GHR. Recently, the model of ligand-induced receptor dimerization has been challenged. In this study, ligand-independent GHR dimerization is demonstrated in the endoplasmic reticulum and at the cell surface by coimmunoprecipitation of an epitope-tagged truncated GHR with wild-type GHR. In addition, evidence is provided that the extracellular domain of the GHR is not required to maintain this interaction. Internalization of a chimeric receptor, which fails to dimerize, is independent of an intact UbE-motif. Therefore, we postulate that dimerization of GHR molecules is required for ubiquitin system-dependent endocytosis.
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PMID:Ligand-independent growth hormone receptor dimerization occurs in the endoplasmic reticulum and is required for ubiquitin system-dependent endocytosis. 1210 75


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