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At least 973 records · Page 54Linked to original sources
PubMed2005

Comparison of the signaling mechanisms by which VEGF, H2O2, and phosphatase inhibitors activate endothelial cell ERK1/2 MAP-kinase.

VEGF-induced ERK1/2 activation is mediated by a signaling mechanism involving the sequential activation of PLCgamma-PKC-Raf1-MEK-ERK1/2. This signaling pathway is necessary, but not sufficient for ERK1/2 activation, as VEGF-induced generation of reactive oxygen species (ROS) is also required. The molecular interaction by which VEGF-induced ROS generation is coordinated with the PLCgamma plus PKC-dependent pathway is not certain, and the goal of this study was to clarify this issue. Prior investigations examining ROS-induced signaling have focused on the cellular protein tyrosine phosphatases (PTPs), and we asked whether a PTP participates in ERK1/2 activation in endothelial cells. We show that both the general PTP inhibitor vanadate, and a dominant negative inhibitor of SHP-1, mimics the effects of VEGF in activating ERK1/2. The phosphatase inhibitors induce ERK1/2 activation in endothelial cells lacking VEGF receptors, indicating that the inhibitors target a downstream effector. As is the case after VEGF treatment, the phosphatase inhibitors do lead to the activation of PLCgamma, and a pharmacological inhibitor of the Src kinases blocks this. These results lead to the conclusion that inhibition of a protein tyrosine phosphatase activates endothelial cell ERK1/2 by a signaling mechanism involving the sequential activation of Src-PLCgamma-PKC-Raf1-MEK-ERK1/2. VEGF treatment most likely activates this pathway by inhibiting SHP-1 through a ROS-dependent mechanism.

Cells, Cultured↗
PubMed2004

Deferential regulation of placenta growth factor (PlGF)-mediated signal transduction in human primary term trophoblast and endothelial cells.

Increasing evidence supports that many common obstetrical complications may involve the disruption of normal placental and/or uterine vascular function. Placenta growth factor (PlGF) is an angiogenic factor that is abundantly expressed in the placenta, with primary site of synthesis being trophoblast. Receptors for PlGF include products of the fms-like tyrosine kinase (flt-1) gene which is expressed in several cell types including endothelial cells and trophoblast. PlGF activation of flt-1 in trophoblast induces the stress activated protein kinase (SAPK) signal transduction pathways, JNK (c-Jun-N-Terminal Kinase) and p38, with little induction of the extracellular signal-regulated protein kinase (ERK)-1/2 pathways. In contrast, PlGF induces strong ERK-1/2 activation, but little JNK or p38 responses in human umbilical vein endothelial cells (HUVEC). To better understand the biochemical functions of PlGF in trophoblast, we studied upstream signal regulatory molecules to determine those that are responsible for directing the divergent PlGF signal transduction responses in these cell types. PlGF induced similar activation of Nck and PLC-gamma in trophoblast and HUVEC. In marked contrast, SHP-2 and Gab2 were strongly activated by PlGF in endothelial cells but not trophoblast. These results suggest a general role for Nck and PLC-gamma in mediating PlGF signal transduction responses independent of the different downstream MAPK pathways activated. However, SHP-2 and Gab2 are regulatory molecules involved in the PlGF induction of different terminal pathways in HUVEC and trophoblast.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Study of EPR, optical properties and electrical conductivity of vanadyl doped Bi2O3.PbO.B2O3 glasses.

Heavy metal based oxide glasses having composition xBi(2)O(3).(0.30 - x)PbO.0.70B(2)O(3) have been prepared (0.00 < or = x < or = 0.15, mol%) containing 2.0mol% of V(2)O(5) by normal melt-quenching technique. Electron paramagnetic resonance (EPR), optical spectra and dc conductivity of these glasses have been studied. Spin Hamiltonian parameters (SHP) of VO(2+) ions, dipolar hyperfine parameter, P and Fermi contact interaction parameter, K, molecular orbital coefficients (alpha(2) and gamma(2)) and optical band gap have been calculated. It is observed that in these glasses, the tetragonal nature of V(4+)O(6) complex increases with Bi(2)O(3) content. Increase in Bi(2)O(3):PbO ratio results in the contraction of 3d(xy) orbit of the unpaired electron in the vanadium ion, and the SHP are dependent on the theoretical optical basicity, Lambda(th). In present glasses, the conductivity (activation energy) first decreases (increases) with increase in mol% of Bi(2)O(3) content upto x = 0.08 and then shows a maxima (minima) at x = 0.10 and then starts decreasing (increasing) upto x < or = 0.15 with mol% of Bi(2)O(3) content.

Borates↗
PubMed2005

Investigation of protein-tyrosine phosphatases by in-gel assays.

Renaturation permits the detection of protein-tyrosine phosphatase (PTP) activities subsequent to separation by SDS-PAGE in the presence of the (32)P-labeled poly(Glu(4)Tyr) as a macromolecular substrate. An efficient corresponding method has been developed by Burridge and Nelson [Anal. Biochem. 232 (1995) 56]. We describe here the modification of the basic method, its extension to two-dimensional gel electrophoresis, and applications to identify PTPs in signaling complexes and reversibly oxidized PTPs. Particular attention is given to the preparation of samples, to interpretation of the results as well as to advantages and limitations of the technique. Immunodepletion and the use of cells from knockout animals have been successful in the identification of individual PTPs. Readily detectable in cell lysates are PTP-PEST, SHP-2, SHP-1, PTP1B, and T-cell PTP. A much greater complexity of activity bands is, to a large extent, due to the generation of active fragments of PTPs. In-gel detection of PTPs can be employed to monitor cell fractionations and potential PTP activity changes.

Electrophoresis, Polyacrylamide Gel↗
PubMed2003

The coming of age of our understanding of the enterohepatic circulation of bile salts.

Recent advances in molecular biology have greatly accelerated knowledge relating to the significance of the enterohepatic circulation of bile salts. This review highlights the role that both oxysterols and bile salts play as ligands which, when bound to nuclear hormone receptors, activate transcription factors that set into play feed-forward catabolism of cholesterol to bile salts and feedback control of bile acid synthesis. The nuclear hormone receptors, liver X receptor (LXR) and farnesoid X receptor (FXR) both combined as heterodimers with retinoid X receptor and with oxysterols and bile salts, respectively as their ligands, initiate powerful genetic controls over cholesterol and bile acid homeostatic mechanisms. LXR/RXR signals molecular control of feed-forward catabolism of cholesterol to bile acids while FXR/RXR initiates feedback control of bile acid synthesis. An additional nuclear hormone receptor, small heterodimer partner (SHP), is required to inhibit the competence factor, liver receptor homolog-1 to achieve repression of bile acid synthesis in the liver and in so doing SHP autoregulates its own function. Additionally, while bile acid synthesis is repressed, pool size is preserved by the action of FXR/RXR at both hepatic and intestinal levels, which genetically signals enhanced hepatocyte bile salt transport by the bile salt export pump (BSEP) and the ileal bile acid binding protein (IBABP) for ileal reabsorption. During activation of cholesterol catabolism, LXR/RXR enhances reverse cholesterol transport by increasing cholesterol efflux via the ABC-1 transporter from extrahepatic cells. This cholesterol is then taken up by high-density lipoprotein (HDL) and transported back to the liver for further cholesterol catabolism and elimination in bile. The genetic coordination of nuclear hormone receptor function within the territory of the enterohepatic of bile salts allows for normal cholesterol and bile acid homeostasis thereby preventing atherosclerosis.

Arteriosclerosis↗
PubMed2004

Autologous salvaged blood transfusion in spontaneous hemopneumothorax.

Spontaneous hemopneumothorax (SHP) is a rare clinical entity, and an emergent operation due to continuous bleeding or hypovolemic shock is at times necessary. Although allogeneic blood transfusions are urgently required for significant blood loss, autologous blood transfusions can also be considered in patients with SHP. We herein report two cases of successful autologous blood transfusions using blood in the pleural space, decreasing or obviating the need for allogeneic blood transfusion.

Adult↗
PubMed1999

Cytochrome c" from the obligate methylotroph Methylophilus methylotrophus, an unexpected homolog of sphaeroides heme protein from the phototroph Rhodobacter sphaeroides.

The complete primary structure of an unusual soluble cytochrome c isolated from the obligate methylotrophic bacterium Methylophilus methylotrophus has been determined to contain 124 amino acids and to have an average molecular mass of 14293.0 Da. The sequence has two unusual features: firstly, the location of the heme-binding cysteines is far downstream from the N-terminus, namely at positions 49 and 52; secondly, an extra pair of cysteine residues is present near the C-terminus. In both respects, cytochrome c" is similar to the oxygen-binding heme protein SHP from the purple phototrophic bacterium Rhodobacter sphaeroides. In contrast to SHP, cytochrome c" changes from low-spin to high-spin upon reduction, due to dissociation of a sixth heme ligand histidine which is identified as His-95 by analogy to the class I cytochromes c. The distance of His-95 from the heme (41 residues) and the presence of certain consensus residues suggests that cytochrome c" is the second example of a variant class I cytochrome c.

Amino Acid Sequence↗
PubMed1999

Cloning and sequence analysis of the gene encoding Methylophilus methylotrophus cytochrome c", a unique protein with a perpendicular orientation of the histidinyl ligands.

Cytochrome c" from Methylophilus methylotrophus is an unusual monohaem protein that undergoes a major redox-linked spin-state transition: one of the two axial histidines bound to the iron in the oxidised form is detached upon reduction and a proton is taken up. A 3.5-kb DNA fragment, containing the gene encoding cytochrome c" (cycA), has been cloned and sequenced. The cytochrome c" gene codes for a pre-protein with a typical prokaryotic 20-residue signal sequence, suggesting that the protein is synthesised as a precursor which is processed during its secretion into the periplasm. The C-terminus of cytochrome c" has homology with the corresponding region of an oxygen-binding haem protein (SHP) from phototrophically grown Rhodobacter sphaeroides. SHP is similar in size and in the location of its haem-binding site. Immediately downstream from cytochrome c" a second open reading frame (ORF) codes for a 23-kDa protein with similarity to the cytochrome b-type subunit of Ni-Fe hydrogenase. The possibility of coordinated expression of cycA and this ORF is discussed.

Amino Acid Sequence↗
PubMed2003

Molecular cloning, biochemical and structural analysis of elongation factor-1 alpha from Leishmania donovani: comparison with the mammalian homologue.

The Src-homology 2 domain containing protein tyrosine phosphatase-1 (SHP-1) is involved in the pathogenesis of infection with Leishmania. Recently, we identified elongation factor-1 alpha (EF-1 alpha) from Leishmania donovani as a SHP-1 binding and activating protein [J. Biol. Chem. 277 (2002) 50190]. To characterize this apparent Leishmania virulence factor further, the cDNA encoding L. donovani EF-1 alpha was cloned and sequenced. Whereas nearly complete sequence conservation was observed amongst EF-1 alpha proteins from trypanosomatids, the deduced amino acid sequence of EF-1 alpha of L. donovani when compared to mammalian EF-1 alpha sequences showed a number of significant changes. Protein structure modeling-based upon the known crystal structure of EF-1 alpha for Saccharomyces cerevisiae-identified a hairpin loop present in mammalian EF-1 alpha and absent from the Leishmania protein which corresponded to a 12 amino acid deletion. Consistent with these structural differences, the sub-cellular distributions of L. donovani EF-1 alpha and host EF-1 alpha were strikingly different. Interestingly, infection of macrophages with L. donovani caused redistribution of host as well as pathogen EF-1 alpha. Since EF-1 alpha is essential for survival, the distinct biochemical and structural properties of Leishmania EF-1 alpha may provide a novel target for drug development.

Amino Acid Sequence↗
PubMed2003

Identification and characterization of a new pair of immunoglobulin-like receptors LMIR1 and 2 derived from murine bone marrow-derived mast cells.

We have identified and characterized two mouse cDNAs in a mouse antigen-stimulated bone marrow-derived mast cell cDNA library, both of which encode type I transmembrane proteins. The genes were closely mapped in the distal region of mouse chromosome 11 and expressed not only in mast cells but also widely in leukocytes. The extracellular domains of their encoded proteins contain a single variable immunoglobulin (Ig) motif sharing about 90% identity with amino acids, showing that they comprise a pair of molecules and belong to the Ig superfamily. We named these molecules leukocyte mono-Ig-like receptor1 and 2 (LMIR1 and 2). The intracellular domain of LMIR1 contains several immunoreceptor tyrosine-based inhibition motifs (ITIMs). When cross-linked, the intracellular domain was tyrosine phosphorylated and capable of recruiting tyrosine phosphatases, SHP-1 and SHP-2 and inositol polyphosphate 5-phosphatase, SHIP. LMIR2, on the other hand, contains a short cytoplasmic tail and a characteristic transmembrane domain carrying two positively charged amino acids associated with three kinds of immunoreceptor tyrosine-based activation motif (ITAM)-bearing molecules, DAP10, DAP12, and FcRgamma. These findings suggest that a new pair of ITIM/ITAM-bearing receptors, LMIR1 and 2, regulate mast cell-mediated inflammatory responses through yet to be defined ligand(s).

Amino Acid Sequence↗
PubMed2004

Tyrosine phosphorylation of BIT on photic stimulation in the rat retina.

BIT is a transmembrane glycoprotein with three immunoglobulin-like domains in its extracellular region and tyrosine phosphorylation sites in its cytosolic region. We have previously shown that BIT was tyrosine phosphorylated in the hypothalamic suprachiasmatic nucleus in response to light exposure during the dark period, and suggested that it was involved in the light entrainment of the circadian clock. To further investigate the function of BIT in the nervous system, we examined the effect of photic stimulation on its tyrosine phosphorylation in the rat retina. It was found that the tyrosine phosphorylation level of BIT in the retina was higher in the light period than in the dark period. In addition, a light stimulation during the dark period resulted in a rapid phosphorylation of BIT and a subsequent association of BIT with SHP-2. The phosphorylation state was quickly reverted when the light was turned off. The light-dependent phosphorylation of BIT was also observed in isolated cultured retinas, and this was blocked by a specific Src-family inhibitor, PP-2. Immunohistochemical study showed that BIT was highly enriched in the inner and outer plexiform layers in the retina, where the immunoreactivity to anti-SHP-2 antibody was also detected. These results suggest that tyrosine phosphorylation of BIT is involved in neuronal transmission in the retina.

Animals↗
PubMed2004

Gene silencing by nuclear orphan receptors.

Nuclear orphan receptors represent a large and diverse subgroup in the nuclear receptor superfamily. Although putative ligands for these orphan members remain to be identified, some of these receptors possess intrinsic activating, inhibitory, or dual regulatory functions in development, differentiation, homeostasis, and reproduction. In particular, gene-silencing events elicited by chicken ovalbumin upstream promoter-transcription factors (COUP-TFs); dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1); germ cell nuclear factor (GCNF); short heterodimer partner (SHP); and testicular receptors 2 and 4 (TR2 and TR4) are among the best characterized. These orphan receptors are critical in controlling basal activities or hormonal responsiveness of numerous target genes. They employ multiple and distinct mechanisms to mediate target gene repression. Complex cross-talk exists between these orphan receptors at their cognate DNA binding elements and an array of steroid?nonsteroid hormone receptors, other transcriptional activators, coactivators and corepressors, histone modification enzyme complexes, and components of basal transcriptional components. Therefore, perturbation induced by these orphan receptors at multiple levels, including DNA binding activities, receptor homo- or heterodimerization, recruitment of cofactor proteins, communication with general transcriptional machinery, and changes at histone acetylation status and chromatin structures, may contribute to silencing of target gene expression in a specific promoter or cell-type context. Moreover, the findings derived from gene-targeting studies have demonstrated the significance of these orphan receptors' function in physiologic settings. Thus, COUP-TFs, DAX-1, GCNF, SHP, and TR2 and 4 are known to be required for multiple physiologic and biologic functions, including neurogenesis and development of the heart and vascular system steroidogenesis and sex determination, gametogenesis and embryonic development, and cholesterol?lipid homeostasis.

Animals↗
PubMed1999

Differential influence of tyrosine residues of the common receptor beta subunit on multiple signals induced by human GM-CSF.

BACKGROUND: GM-CSF induces the proliferation and differentiation of a broad range of hematopoietic cells. Stimulation with this cytokine results in the induction of rapid tyrosine phosphorylation of cellular proteins, including the common beta subunit of its receptor. However, the significance of beta subunit phosphorylation with regard to regulation of signaling molecules and the functions of GM-CSF is less well understood. OBJECTIVE: To investigate the role of cytoplasmic tyrosine residues, we performed mutational analyses of the beta subunit. METHODS: A series of beta subunit mutants with 1, some, or all of 8 cytoplasmic tyrosines converted to phenylalanines were constructed. These beta subunit mutants were expressed in murine BA/F3 cells together with the wild-type human alpha subunit, and their potentials to transmit signals were examined. RESULTS: A mutant beta subunit lacking all cytoplasmic tyrosines (Fall) activated JAK2, but not Shc, SHP-2, the Raf/ERK cascade, signal transducer and activator of transcription 5 (STAT5), or the c-fos promoter, nor did it effectively induce proliferation. Adding back each tyrosine to Fall revealed that (1) Tyr577 was necessary and sufficient for Shc phosphorylation; (2) Tyr577, Tyr612, and Tyr695 were involved in activation of SHP-2, the Raf/ERK cascade, and c-fos transcription; and (3) all tyrosines, but particularly Tyr612, Tyr695, Tyr750, and Tyr806, facilitated STAT5 activation. Impaired cell growth was also partly restored by any of the tyrosines. Interestingly, the Fall mutant was still capable of suppressing apoptosis and maintaining cell viability. CONCLUSION: These results provide evidence that beta subunit tyrosines possess distinct, yet overlapping, roles in the activation of multiple signaling pathways induced by GM-CSF. In addition, GM-CSF may activate both beta subunit tyrosine-dependent and -independent pathways, with the latter being sufficient to transmit survival signals.

Animals↗
PubMed1999

Differences in phosphorylation of the IL-2R associated JAK/STAT proteins between HTLV-I(+), IL-2-independent and IL-2-dependent cell lines and uncultured leukemic cells from patients with adult T-cell lymphoma/leukemia.

To determine activation status of the IL-2R-associated (Jak/STAT) pathway in the HTLV-I infected cells, we examined tyrosine phosphorylation of Jak3, STAT3, and STAT5 in several HTLV-I(+) T-cell lines and in uncultured leukemic T cells isolated from patients with adult T-cell lymphoma/leukemia (ATLL). Constitutive basal phosphorylation of Jak3 and, usually, STAT3 and STAT5 was detected in all four IL-2-independent cell lines tested, but in none of the three IL-2-dependent cell lines. Similarly, there was no detectable basal phosphorylation of Jak3 and STAT5 in the leukemic cells from ATLL patients (0/8 and 0/3, respectively). However, stimulation with IL-2 resulted in Jak3 and STAT5 phosphorylation in both leukemic ATLL cells and IL-2-dependent lines. Furthermore, expression of SHP-1 phosphatase which is a negative regulator of cytokine receptor signaling, was lost in most IL-2 independent cell lines (3/4) but not in the leukemic ATLL cells (0/3). Finally, the HTLV-I(+) T-cell lines (313) but not the control, HTLV-I(-) T-cell lines were resistant to rapamycin and its novel analog RAD. We conclude that (1) HTLV-I infection per se does not result in a constitutive phosphorylation of the Jak3, STAT3, and STAT5 proteins; (2) malignant transformation in at least some cases of ATLL does not require the constitutive, but may require IL-2-induced, activation of the IL-2R Jak/STAT pathway; and (3) there are major differences in T-cell immortalization mechanism(s) which appear to involve SHP-1 and target molecules for rapamycin and RAD.

DNA-Binding Proteins↗
PubMed1996

Function of killer cell inhibitory receptors for MHC class I molecules.

NK- and T-cells express at their surface, members of a multigenic family of killer-cell inhibitory receptors (KIR) for MHC Class I molecules. KIR engagement leads to the inhibition of NK- and T-cell activation programs. These receptors recruit the protein tyrosine phosphatases (PTPase), SHP-1 and SHP-2, upon tyrosine phosphorylation of immunoreceptor tyrosine-based inhibition motif (ITIM) expressed in both human and mouse KIR. We further define the ITIM amino acids sequence required in that recognition and demonstrate the critical role of the phosphoY-2 amino acid residue in this V/IxYxxL/V motif. In addition, using RBL-2H3 cells expressing endogenous Fc epsilonRI receptors as well as transfected CD25/CD3zeta chimera and p58.183 human KIR, we show that KIR inhibitory function requires co-engagement of KIR and ITAM-containing receptors. These results document the pathway used by KIR to down-regulate NK- and T-cell activation programs.

Amino Acid Sequence↗
PubMed2002

Perception of posture and cerebral blood flow.

The perception of posture in man is made possible by the information of the vestibular organs, the visual system, the proprioception and the blood volume distribution. The present study examined the cerebral blood flow velocity (CBFV) and the fluid volume of the thoracic cavity under different pressure conditions and their effects on the perception of posture. Changes in blood flow velocity were measured by transcranial Doppler sonography (TCD), and changes in the blood volume distribution of the upper torso were registered by impedance plethysmography. The results indicated that the cerebral blood flow volume and the thoracic blood volume changed in the same manner. Lower Body Positive Pressure (+30 mmHg) led to an increase in central volume and CBFV. During the Lower Body Negative Pressure Treatment (-30 mmHg), the central blood volume and the cerebral blood flow velocity decreased while venous pooling occurred. Additionally, the changes in both parameters were associated with an altered posture perception. The correlations between the SHP and the two physiological parameters cerebral blood flow velocity and fluid shift in the upper thorax indicate that the fluid shift in the thoracic cavity was more closely related to the SHP than to the changes in cerebral blood volume.

Adult↗
PubMed2000

Early signaling via inhibitory and activating NK receptors.

This review focuses on recent findings on the structural features of inhibitory NK cell receptors containing immunoreceptor tyrosine-based inhibition motif (ITIM) and of NK cell activating receptors, both in human and mouse. First, the study of the inhibitory killer cell immunoglobulin-like receptors (KIR) unveiled the presence of intracytoplasmic ITIM and their capacity to recruit protein tyrosine phosphatases such as SHP-1 in vivo. A brief summary of the known SHP-1 targets may help us to understand the inhibition mediated by the KIR. The characterization of ITIM thus allowed the definition of a large group of inhibitory cell surface receptors. The second part of the review describes the known NK cell activating receptors. Most of them require association with ITAM-containing polypeptides in order to mediate cell activation.

Amino Acid Motifs↗
PubMed2001

Signal transduction by VEGF receptor-1 wild type and mutant proteins.

The role of the vascular endothelial growth factor receptor-1 (VEGFR-1) in endothelial cell function is unclear. We have previously identified four tyrosine phosphorylation sites in the C-terminal tail of this receptor. We now show that the wild type VEGFR-1 expressed in porcine aortic endothelial (PAE/VEGFR-1) cells was able to transduce signals for increased DNA synthesis and proliferation. Tyrosine phosphorylation of phospholipase Cgamma (PLCgamma), tyrosine phosphatase SHP-2, Crk, and extracellular regulated kinases 1 and 2 (Erk1/2) was registered in response to VEGF-A treatment of the PAE/VEGFR-1 cells. VEGFR-1 mutated at Y1213, Y1242, and Y1333 were constructed and expressed in PAE cells, to the same level as that of PAE/VEGFR-1 cells. The affinities of the wild type and mutated receptors for VEGF-A(165) binding were similar. The mutated VEGFR-1 Y1213F expressed in PAE cells was kinase inactive. PAE cells expressing the mutated VEGFR-1 Y1242F and Y1333F receptors mediated increased tyrosine phosphorylation of PLCgamma in response to VEGF-A stimulation. However, these two mutant VEGFR-1 failed to mediate increased mitogenesis and were unable to stimulate increased tyrosine phosphorylation of SHP-2, Crk, and Erk1/2, indicating that the mutations lead to a perturbation in VEGF-A-induced signal transduction.

Animals↗