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PubMed1990

Cloning of three human tyrosine phosphatases reveals a multigene family of receptor-linked protein-tyrosine-phosphatases expressed in brain.

A human brainstem cDNA library in bacteriophage lambda gt11 was screened under conditions of reduced hybridization stringency with a leukocyte common antigen (LCA) probe that spanned both conserved cytoplasmic domains. cDNA encoding a receptor-linked protein-tyrosine-phosphatase (protein-tyrosine-phosphate phosphohydrolase, EC 3.1.3.48), RPTPase alpha, has been cloned and sequenced. Human RPTPase alpha consists of 802 amino acids. The extracellular domain of 150 residues includes a hydrophobic signal peptide and eight potential N-glycosylation sites. This is followed by a transmembrane region and two tandemly repeated conserved domains characteristic of all RPTPases identified thus far. The gene for RPTPase alpha has been localized to human chromosome region 20pter-20q12 by analysis of its segregation pattern in rodent-human somatic cell hybrids. Northern blot analysis revealed the presence of two major transcripts of 4.3 and 6.3 kilobases. In addition to RPTPase alpha, two other RPTPases (beta and gamma), identified in the same screen, have been partially cloned and sequenced. Analysis of sequence comparisons among LCA, the LCA-related protein LAR, and RPTPases alpha, beta, and gamma reveals the existence of a multigene family encoding different RPTPases, each containing a distinct extracellular domain, a single hydrophobic transmembrane region, and two tandemly repeated conserved cytoplasmic domains.

Amino Acid Sequence↗
PubMed1995

CD45 protein-tyrosine phosphatase is specifically associated with a 116-kDa tyrosine-phosphorylated glycoprotein.

CD45 is a protein-tyrosine phosphatase expressed on all cells of hematopoietic origin. In an attempt to further characterize CD45 function, we set out to identify molecule(s) that specifically associate with CD45. A 116-kDa protein was detected in immunoprecipitates from CD45+ cells but not CD45- cells. The association between CD45 and this 116-kDa protein can be reconstituted by mixing lysates from CD45- cell lines with purified CD45. p116 appears to associate with CD45 through the external, transmembrane, or membrane-proximal region of CD45 since p116 is associated with a mutant form of CD45 possessing a truncated cytoplasmic domain. The association of p116 with CD45 is not isoform-specific as p116 associates equally well with various CD45 isoforms. We have determined that p116 is a tyrosine-phosphorylated glycoprotein and that it is associated with CD45 in all hematopoietic cells examined. Because of its broad distribution, it is possible that identification of p116 will provide additional insight into the function of CD45 in lymphoid as well as non-lymphoid hematopoietic cells.

Animals↗
PubMed2000

Epidermal growth factor-stimulated tyrosine phosphorylation of caveolin-1. Enhanced caveolin-1 tyrosine phosphorylation following aberrant epidermal growth factor receptor status.

Caveolin-1 is the major coat protein of caveolae and has been reported to interact with various intracellular signaling molecules including the epidermal growth factor (EGF) receptor. To investigate the involvement of caveolin-1 in EGF receptor action, we used mouse B82L fibroblasts transfected with (a) wild type EGF receptor, (b) a C-terminally truncated EGF receptor at residue 1022, (c) a C-terminally truncated EGF receptor at residue 973, or (d) a kinase-inactive EGF receptor (K721M). Following EGF treatment, there was a distinct electrophoretic mobility shift of the caveolin-1 present in cells expressing the truncated forms of the EGF receptor, but this shift was not detectable in cells bearing either normal levels of the wild type EGF receptor or a kinase-inactive receptor. This mobility shift was also not observed following the addition of other cell stimuli, such as platelet-derived growth factor, insulin, basic fibroblast growth factor, or phorbol 12-myristate 13-acetate. Analysis of caveolin-1 immunoprecipitates from EGF-stimulated or nonstimulated cells demonstrated that the EGF-induced mobility shift of caveolin-1 was associated with its tyrosine phosphorylation in cells expressing truncated EGF receptors. Maximal caveolin-1 phosphorylation was achieved within 5 min after exposure to 10 nM EGF and remained elevated for at least 2 h. Additionally, several distinct phosphotyrosine-containing proteins (60, 45, 29, 24, and 20 kDa) were co-immunoprecipitated with caveolin-1 in an EGF-dependent manner. Furthermore, the Src family kinase inhibitor, PP1, does not affect autophosphorylation of the receptor, but it does inhibit the EGF-induced mobility shift and phosphorylation of caveolin-1. Conversely, the MEK inhibitors PD98059 and UO126 could attenuate EGF-induced mitogen-activated protein kinase activation, they do not affect the EGF-induced mobility shift of caveolin-1. Because truncation and overexpression of the EGF receptor have been linked to cell transformation, these results provide the first evidence that the tyrosine phosphorylation of caveolin-1 occurs via an EGF-sensitive signaling pathway that can be potentiated by an aberrant activity or expression of various forms of the EGF receptor.

Animals↗
PubMed2006

Protein-tyrosine phosphatase (PTP) wedge domain peptides: a novel approach for inhibition of PTP function and augmentation of protein-tyrosine kinase function.

Inhibition of protein-tyrosine phosphatases (PTPs) counterbalancing protein-tyrosine kinases (PTKs) offers a strategy for augmenting PTK actions. Conservation of PTP catalytic sites limits development of specific PTP inhibitors. A number of receptor PTPs, including the leukocyte common antigen-related (LAR) receptor and PTPmu, contain a wedge-shaped helix-loop-helix located near the first catalytic domain. Helix-loop-helix domains in other proteins demonstrate homophilic binding and inhibit function; therefore, we tested the hypothesis that LAR wedge domain peptides would exhibit homophilic binding, bind to LAR, and inhibit LAR function. Fluorescent beads coated with LAR or PTPmu wedge peptides demonstrated PTP-specific homophilic binding, and LAR wedge peptide-coated beads precipitated LAR protein. Administration of LAR wedge Tat peptide to PC12 cells resulted in increased proliferation, decreased cell death, increased neurite outgrowth, and augmented Trk PTK-mediated responses to nerve growth factor (NGF), a phenotype matching that found in PC12 cells with reduced LAR levels. PTPmu wedge Tat peptide had no effect on PC12 cells but blocked the PTPmu-dependent phenotype of neurite outgrowth of retinal ganglion neurons on a PTPmu substrate, whereas LAR wedge peptide had no effect. The survival- and neurite-promoting effect of the LAR wedge peptide was blocked by the Trk inhibitor K252a, and reciprocal co-immunoprecipitation demonstrated LAR/TrkA association. The addition of LAR wedge peptide inhibited LAR co-immunoprecipitation with TrkA, augmented NGF-induced activation of TrkA, ERK, and AKT, and in the absence of exogenous NGF, induced activation of TrkA, ERK, and AKT. PTP wedge domain peptides provide a unique PTP inhibition strategy and offer a novel approach for augmenting PTK function.

Amino Acid Sequence↗
PubMed1992

Phenylalanine and tyrosine kinetics in relation to altered protein and phenylalanine and tyrosine intakes in healthy young men.

Plasma phenylalanine (Phe) and tyrosine (Tyr) turnover and the rate of conversion of phenylalanine to tyrosine (Phehyd) and of phenylalanine oxidation (Pheox) after reduced intakes of Phe and Tyr were determined in a metabolic study involving five healthy young adult men. In a pilot study, six postabsorptive young men received either 12- or 4-h infusions of [2H2]Phe and [1-13C]Tyr or [1-13C]Phe and [2H2]Tyro. From these results a primed 8-h constant infusion of [1-13C]Phe and [2H2]Tyr and [2H3]leucine was used in the metabolic study (first 3 h fasted, the 5 h fed) at the end of 1-wk periods during which subjects received an adequate nitrogen L-amino acid based-diet followed by a restricted intake of Phe and Tyr. This procedure was again repeated after 1 and 3 wk when subjects were given a diet low in both nitrogen and Phe and Tyr. Phe and Tyr fluxes were not significantly affected by diet during the fasted metabolic state but Tyr fluxes were lower when the restricted intakes were given. Compared with the rate during the fasting state, Pheox was significantly higher (P less than 0.01) when the adequate diet was consumed; Pheox and Phehyd for fed and fasted states were similar when Phe and Tyr were restricted.

Adult↗
PubMed2006

Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors.

The properties of several multitargeted receptor tyrosine kinase inhibitors have been studied for their inhibition of colony-stimulating factor-1 receptor (CSF-1R) signaling. A structurally novel, multitargeted tyrosine kinase inhibitor (ABT-869), imatinib (STI571), and four compounds currently in clinical development (AG013736, BAY 43-9006, CHIR258, and SU11248) were tested for inhibition of CSF-1R signaling in both the enzymatic and cellular assays. ABT-869 showed potent CSF-1R inhibition in both the enzyme and cell-based assays (IC50s < 20 nmol/L). In contrast to a previous report, we have found that imatinib has activity against human CSF-1R in both assays at submicromolar concentrations. In enzyme assays, we have found that the inhibition of CSF-1R by both ABT-869 and imatinib are competitive with ATP, with Ki values of 3 and 120 nmol/L, respectively. SU11248 is a potent inhibitor of CSF-1R in the enzyme assay (IC50 = 7 nmol/L) and inhibits receptor phosphorylation in the cellular assay (IC50 = 61 nmol/L). AG013736 was also a potent inhibitor of CSF-1R in both assays (enzyme, IC50 = 16 nmol/L; cellular, IC50 = 21 nmol/L), whereas BAY 43-9006 is less potent in the enzyme assay (IC50 = 107 nmol/L) than in the cellular system (IC50 = 20 nmol/L). In contrast, we found that CHIR258 had less activity in the cellular assay (IC50 = 535 nmol/L) relative to its enzymatic potency (IC50 = 26 nmol/L). These results show the use of a cell-based assay to confirm the inhibitory activity of lead compounds and drug candidates, such as ABT-869, against the CSF-1R protein in situ.

3T3 Cells↗
PubMedDate not supplied

N-acetyl-L-tyrosine as a tyrosine source in adult parenteral nutrition.

BACKGROUND: N-acetyl-L-tyrosine (NAT) is commonly used in place of tyrosine in parenteral nutrition, but human studies carried out to date indicate considerable amounts of it are excreted unchanged in the urine. NAT retention has not been well studied in parenterally fed adults. METHODS: NAT retention was measured in 13 adults receiving continuous parenteral nutrition with Aminosyn II 15% (Abbott Laboratories, Abbott Park, IL). RESULTS: Approximately 35% of administered NAT was excreted unchanged in the urine, with no important effect of infusion rate, N balance, or level of renal function on this value. Sufficient NAT was retained that the prescription of 1 g total amino acids/kg x day(-1) using this product exceeded the combined recommended dietary allowance for aromatic amino acids CONCLUSION: As used in the clinical setting, the phenylalanine and NAT composition of Aminosyn II is sufficient to meet the combined aromatic amino acid needs of adults with normal phenylalanine hydroxylase activity.

Adult↗
PubMedDate not supplied

Use of the soluble peptide gamma-L-glutamyl-L-tyrosine to provide tyrosine in total parenteral nutrition in rats.

Limited solubility restricts amounts of tyrosine (Tyr) in amino acid solutions used in total parenteral nutrition (TPN). Excess phenylalanine (Phe) is included in TPN for conversion to Tyr by liver Phe hydroxylase. However, this conversion is limited, especially in infants. We have confirmed that infants receiving TPN have low Tyr concentrations and high Phe/Tyr ratios in plasma compared with published values for enterally fed neonates. Tyr is important in the synthesis of proteins and other biomolecules, including catecholamines in the brain. We tested the soluble peptide gamma-glutamyl-tyrosine (Glu(Tyr)) as a possible precursor of Tyr in TPN. Groups of five rats were given infusions of TPN containing an amino acid mixture simulating a commercial formulation (group A), TPN in which Glu(Tyr) was substituted for half the Phe in the group A solution) (group B), or saline (group C). Control animals (group C) were fed rodent chow. Blood was sampled at 0 time and daily for 4 days. Brains were collected at 96 hours, and aromatic amino acids in plasma and brains were measured by high-performance liquid chromatography. Throughout the experiment, plasma of animals in group A had significantly elevated Phe and reduced Tyr concentrations compared with control values; plasma concentrations in groups B and C were similar. In groups A and B, brain Tyr levels were 31% and 63% of control values, respectively. In group B, Glu(Tyr) was not detected in brains. These data suggest that supplementing current TPN mixtures with Glu(Tyr), which is stable in solution, can produce normal plasma Tyr concentrations and Phe/Tyr ratios and improve the supply of Tyr to the brain.

Animals↗
PubMed1995

Birth-related up-regulation of mRNA encoding tyrosine hydroxylase, dopamine beta-hydroxylase, neuropeptide tyrosine, and prepro-enkephalin in rat adrenal medulla is dependent on postnatal oxygenation.

The transynaptic splanchnic regulation of the adrenal medulla is not functional in the newborn rat. Thus, synthesis and release of adrenal catecholamines and peptides are assumed to be regulated by nonneuronal mechanisms at this stage. In a previous study we reported 4-5-fold increases in the levels of mRNA encoding tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), and neuropeptide tyrosine (NPY) in the rat adrenal medulla immediately after birth. In the present in situ hybridization study the importance of postnatal oxygenation for the birth-related increase in expression of these mRNA, and of preproenkephalin (ENK) mRNA was investigated in rat pups. We report here that maternal hypoxia (11-13% O2) leads to 2-3-fold increases (p < 0.01) in fetal adrenal TH, DBH, and NPY mRNA levels on the day before birth. These mRNA then further increased 1-5-2-fold (p < 0.01) 12 h after birth in room air. Only ENK mRNA levels increased (5-fold; p < 0.01) when pups were born in 11-13% O2; however, still less (p < 0.01) than after birth in room air when it increased nine times (p < 0.01). Thus, the birth-related increases in TH, DBH, NPY, and ENK mRNA levels in the rat adrenal medulla are dependent on postnatal oxygenation.

Adrenal Medulla↗
PubMed2001

Inhibitory effect of a two day fast on reactive oxygen species (ROS) generation by leucocytes and plasma ortho-tyrosine and meta-tyrosine concentrations.

ABSTRACT Since glucose intake acutely increases reactive oxygen species (ROS) generation by polymorphonuclear leucocytes (PMN) and mononuclear cells (MNC), we have now investigated whether a fast over a period of 48h reduces ROS generation by these cells. Eight normal subjects were fasted for 48h. Blood samples were obtained at 0, 24h and 48h. ROS generation by PMN fell significantly at 24h (66.1 +/- 19.5% of basal) and further at 48h (45.9 +/- 23.0 % of basal; p < 0.001). ROS generation by MNC fell to 62.4 +/- 16.5% at 24h and by 48.4 +/- 16.5% (p < 0.001) by 48h. The level of p47(phox) subunit, an index of NADPH oxidase, the enzyme converting molecular oxygen to superoxide (O(.)(2)(-)) radical, also fell in parallel. Plasma o-tyrosine/phenylalanine ratio fell significantly from 0.326 +/- 0.053 mmol/mol to 0.303 +/- 0.055 mmol/mol at 48h and m-tyrosine/phenylalanine ratio fell from 0.363 +/- 0.063 mmol/mol to 0.340 +/- 0.064 mmol/mol (p < 0.05). Thus, a 48h fast may reduce ROS generation, total oxidative load and oxidative damage to amino acids.

Adult↗
PubMedDate not supplied

Replacement of tyrosine-197 and the corresponding tyrosine-195 to isoleucine in Cephalosporium acremonium and Streptomyces clavuligerus isopenicillin N synthase.

Isopenicillin N synthase (IPNS) is one of the key enzymes in the penicillin and cephalosporin biosynthetic pathway which catalyses the conversion of delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine to isopenicillin N. The IPNS from Penicillium chrysogenum 23X-80-269-37-2, a high penicillin V-producer, was found to possess an isoleucine residue instead of tyrosine at position 195. An attempt to increase the specific activity of IPNS from Cephalosporium acremonium and Streptomyces clavuligerus was undertaken by altering the corresponding tyrosine residue to an isoleucine at the corresponding location. Unfortunately, no apparent increase in specific activity was encountered when the purified mutant enzymes were analysed and thus, this amino acid difference is likely not responsible for high specific activity in IPNS.

Acremonium↗
PubMed2004

Comparison of O-(2-18F-fluoroethyl)-L-tyrosine PET and 3-123I-iodo-alpha-methyl-L-tyrosine SPECT in brain tumors.

UNLABELLED: The aim of this study was to compare PET with O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) and SPECT with 3-(123)I-iodo-alpha-methyl- L-tyrosine ((123)I-IMT) in patients with brain tumors. METHODS: Twenty patients with a suspected brain tumor were investigated by (18)F-FET PET, (123)I-IMT SPECT, and MRI within 3 wk. Region-of-interest analyses were performed on coregistered PET/SPECT/MRI images and the tumor-to-brain ratio (TBR), muscle-to-brain ratio (MBR), cerebellum-to-brain ratio (CerBR), and sinus-to-brain ratio (SBR) were calculated. In addition, the presence of tumor and the discrimination of anatomic structures on (18)F-FET PET and (123)I-IMT SPECT images were visually determined by 3 observers who were unaware of clinical data. RESULTS: The TBR of (18)F-FET and (123)I-IMT uptake in cerebral tumors showed a highly significant correlation (r = 0.96; P < 0.001). In the visual analysis for the presence or absence of tumors, no differences for (123)I-IMT SPECT and (18)F-FET PET were found in 19 of 20 patients; in one patient a low-grade glioma was only identified on (18)F-FET PET images but not on (123)I-IMT SPECT images. The contrast between tumor and normal brain was significantly higher in (18)F-FET PET (TBR, 2.0 +/- 0.9) than in (123)I-IMT SPECT (TBR, 1.5 +/- 0.5). The discrimination of anatomic structures yielded a significantly better score on (18)F-FET PET images (rating score, 2.6 +/- 0.9) compared with (123)I-IMT SPECT images (rating score, 1.7 +/- 0.9). The uptake of (18)F-FET in the muscles was significantly higher compared with (123)I-IMT (MBR (18)F-FET, 1.4 +/- 0.3; MBR (123)I-IMT, 0.6 +/- 0.2; P < 0.001) and (18)F-FET demonstrated a significantly higher blood-pool radioactivity than (123)I-IMT (SBR (18)F-FET, 1.3 +/- 0.2; SBR (123)I-IMT, 0.8 +/- 0.2; P < 0.001). CONCLUSION: The significant correlation of the TBRs of (18)F-FET and (123)I-IMT indicates that clinical experiences of brain tumor diagnostics with (123)I-IMT SPECT might be valid for (18)F-FET PET although substantial differences of the physiologic behavior were identified in extracerebral tissue. As (18)F-FET PET allows improved discrimination of anatomic structures and the tumor-to-brain contrast was significantly superior compared with (123)I-IMT SPECT scans, the results are encouraging for further evaluation of (18)F-FET for imaging brain tumors.

Adult↗
PubMed1992

Herbimycin A, an inhibitor of tyrosine kinase, prolongs survival of mice inoculated with myeloid leukemia C1 cells with high expression of v-abl tyrosine kinase.

Herbimycin A, a benzoquinonoid ansamycin antibiotic, reduces intracellular phosphorylation by some tyrosine kinases, including v-abl. The mouse megakaryoblastic cell line C1 expresses v-abl protein at high levels. Herbimycin A at about 20 ng/ml caused 50% inhibition of growth of C1 cells but at 100 ng/ml scarcely affected the growth of another mouse leukemia cell line, M1 cells, or of normal bone marrow cells. Injection of 10(6) C1 cells into nude mice resulted in death of all the mice within 30 days. Administration of herbimycin A significantly enhanced the survival of mice inoculated with C1 cells but scarcely affected the survival of mice inoculated with M1 cells. These results suggest that herbimycin A and/or related compounds may be useful for treatment of some types of leukemia in which tyrosine kinase activity is implicated as a determinant of the oncogenic state.

Animals↗
PubMed2006

Evaluation of D-isomers of O-11C-methyl tyrosine and O-18F-fluoromethyl tyrosine as tumor-imaging agents in tumor-bearing mice: comparison with L- and D-11C-methionine.

UNLABELLED: The aim of this study was to investigate whether D-amino acid isomers of O-(11)C-methyl tyrosine ((11)C-CMT) and O-(18)F-fluoromethyl tyrosine ((18)F-FMT) were better than the corresponding L-isomers as tumor- detecting agents with PET in comparison with the difference between L- and D-methyl-(11)C-methionine ((11)C-MET). METHODS: L- and D-(11)C-MET, (11)C-CMT, and (18)F-FMT were injected intravenously into BALB/cA Jcl-nu mice bearing HeLa tumor cells. At 5, 15, 30, and 60 min after injection, normal abdominal organs and xenotransplanted HeLa cells were sampled, and the uptake of each ligand was determined. Metabolic analyses of these compounds in the plasma were also performed. Accumulation of the d-isomers of (11)C-MET, (11)C-CMT, and (18)F-FMT in turpentine-induced inflammatory tissue was assayed in comparison with (18)F-FDG. The whole-body distribution of each tracer was imaged with a planar positron imaging system (PPIS). RESULTS: Although the tumor uptake (standardized uptake value [SUV]) levels of the D-isomers of (11)C-MET, (11)C-CMT, and (18)F-FMT were 261%, 72%, and 95% of each L-isomer 60 min after administration, the tumor-to-blood ratios of these D-isomers were 130%, 140%, and 182% of the corresponding L-isomers. In the blood, the D-isomers of these labeled compounds revealed a relatively faster elimination rate compared with their L-isomers, with a high peak uptake in the blood and kidney 5 min after administration. Compared with the natural amino acid ligand l-(11)C-MET, the uptake of L-isomers of (11)C-CMT and (18)F-FMT was relatively low and stable in the abdominal organs, whereas D-isomers revealed much lower levels and faster clearance rates compared with corresponding L-isomers. Among the abdominal organs, the pancreas showed a relatively high uptake of (11)C-CMT and (18)F-FMT; the uptake of these D-isomers was much lower than that of L-isomers. Pretreatment with cycloheximide, a protein synthesis inhibitor, resulted in a marked reduction of L-(11)C-MET uptake and a slight reduction of D-(11)C-MET uptake into protein fractions, whereas no significant changes were detected with L- and D-(11)C-CMT and (18)F-FMT. D-Isomers of (11)C-MET, (11)C-CMT, and (18)F-FMT did not accumulate in turpentine-induced inflammatory tissue, where (18)F-FDG revealed a high uptake. Whole-body imaging with a PPIS provided consistent distribution data obtained from the tissue dissection analysis. CONCLUSION: These results suggest that D-isomers of (11)C-CMT and (18)F-FMT could be potentially better tracers than L- and D-(11)C-MET for tumor imaging with PET.

Animals↗
PubMed1989

Immunohistochemical demonstration of tyrosine hydroxylase, serotonin and neuropeptide tyrosine in the epithelioid cells within arterial walls and carotid bodies of chicks.

By immunolight and electron microscopy, the epithelioid, granule-containing cells within the wall of circumscribed portions of the thoracic aorta, the common carotid artery, the carotid body artery and those composing the carotid body itself of newly hatched chicks were shown to contain serotonin (5-HT), neuropeptide tyrosine (NPY) and tyrosine hydroxylase (TH). No nerve fibres immunoreactive for any of these three substances were found in relation to the granule-containing cells. All the granule-containing cells were immunoreactive for 5-HT. The proportion of 5-HT cells simultaneously immunoreactive for NPY or TH in the total cell population varied in different portions of the arteries and the carotid body: NPY-immunoreactive cells were more numerous in the thoracic and common carotid arterial walls, while TH-immunoreactive cells were much more numerous in the carotid body. Since the granule-containing cells within the arterial wall, because of similarities in their anatomical features to the carotid body, are presumed to function as the arterial chemoreceptor, the difference in content of the amines and peptides among the granule-containing cells in different locations may reflect some differences in the chemoreceptive mechanism between the cells in different locations along the thoracocervical arterial tree.

Animals↗
PubMed1994

Uptake of radiolabelled tyrosine and iodo-methyl tyrosine in experimental rat tumours: influence of blood flow and tumour growth rate.

Radiolabelled amino acids combined with Positron Emission Tomography (PET) may be useful for delineation of the extent of viable tumour and may also provide a rapid and sensitive indicator of response to therapy. Promising early clinical reports led us to investigate the potential use of the amino acid analogue L-3-iodo-alpha-methyl tyrosine (IMT), which may be radioiodinated with isotopes suitable for PET or conventional single photon imaging. We have studied the biodistribution and kinetics of [125I]IMT using two transplantable tumour systems in hooded rats, and have compared the findings with those using the natural amino acid L-tyrosine (TYR) radiolabelled with tritium. Similar levels of IMT and TYR uptake were found in HSN and OES.HR1 tumours during tumour growth. Following arrest of OES.HR1 tumour growth by oestrogen ablation, reduced IMT and TYR uptake was found to be closely matched by a fall in tumour blood flow. Unlike IMT, a substantial proportion of TYR uptake in tumours was found to be protein incorporated, even following tumour growth arrest. Quantitative autoradiography revealed sharp delineation of tumour boundary using either radiotracer. We conclude that IMT and TYR kinetics are strongly influenced by blood flow and diffusion, and that tumour growth status may not be closely associated with amino acid uptake.

Animals↗
PubMed1994

[Roles of tyrosine phosphorylation in the proliferation of leukemic hematopoietic stem cells--analysis using a tyrosine phosphatase inhibitor].

I investigated the effects of a tyrosine phosphatase inhibitor, orthovanadate, on the proliferation of normal and CML hematopoietic progenitor cells stimulated by different colony stimulating factors. Orthovanadate decreased CFU-GM colony formation from normal bone marrow cells stimulated by IL-3 and GM-CSF in a dose dependent manner, except for G-CSF. But, BFU-E colony formation was not affected by the treatment with orthovanadate. In CML cells, CFU-GM colony formation was relatively more resistant to orthovanadate than that in normal bone marrow cells and orthovanadate, surprisingly, increased BFU-E colony formation. Western blot analysis showed that preincubation of CML cells with orthovanadate resulted in the enhancement of tyrosine-phosphorylation of p65 mainly, when stimulated with EPO. These results suggest that the second messenger system of IL-3, G-CSF, GM-CSF, and EPO in progenitor cells in CML is different from that in normal progenitor cells and that there is big difference in the second messenger system between myeloid and erythroid progenitor cells in CML cells.

Bone Marrow Cells↗
PubMed2001

Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase.

The protein-tyrosine phosphatase SHP-1 has been shown to be a negative regulator of multiple signaling pathways in hematopoietic cells. In this study, we demonstrate that SHP-1 dephosphorylates the lymphoid-specific Src family kinase Lck at Tyr-394 when both are transiently co-expressed in nonlymphoid cells. We also demonstrate that a GST-SHP-1 fusion protein specifically dephosphorylates Lck at Tyr-394 in vitro. Because phosphorylation of Tyr-394 activates Lck, the fact that SHP-1 specifically dephosphorylates this site suggests that SHP-1 is a negative regulator of Lck. The failure of SHP-1 to inactivate Lck may contribute to some of the lymphoid abnormalities observed in motheaten mice.

Catalytic Domain↗