Actin-related protein nomenclature and classification.
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Actins↗
Biomedical subjects
J A Cooper
Publications and source records attributed to J A Cooper.
Slowed central processing in simple and go/no-go reaction time tasks in Parkinson's disease.
Studies of cognition and motor control have independently suggested that patients with Parkinson's disease show deficits in both attentional control and the preprogramming of movement. However, few studies have examined directly the involvement of cognitive processes in the origin of their slowed response. We examined the performance of 100 Parkinson's disease patients on simple reaction time (SRT) and a series of go/no-go cross-modality choice reaction time (CRT) tasks, in which motor response was constant; correct positive responses required attention to a progressively increasing number of dimensions of visual and auditory stimuli. The results showed that Parkinson's disease patients became increasingly impaired in response speed as choice complexity increased. Slowed response speed in Parkinson's disease involved two factors: (i) a 'perceptuomotor' factor which was constant across conditions and independent of choice complexity. Depression affected this factor selectively and independently of confounding associations with impoverished motor control; (ii) a 'cognitive-analytical' factor, which played an increasingly important role as complexity of choice increased. The characteristics of the relationship between response latency and cognitive complexity indicate that the deficit was due to a constant proportional slowing in cognitive speed across all SRT and CRT conditions. A cognitive deficit affecting the monitoring of stimulus-response compatibility may contribute to delayed response in Parkinson's disease. This cognitive-analytical deficit is present in early, untreated cases and, in contrast to perceptuomotor processes, is weakly related to depression.
Aged↗
Clustering of human T lymphotropic virus type I seropositive in Montserrat, West Indies: evidence for an environmental factor in transmission of the virus.
A community survey of human T cell lymphotropic virus type I (HTLV-I) in Montserrat, West Indies, identified 22 instances in which 2 HTLV-I-seropositive adults lived within 60 m of each other (close pairs), compared with 7.8 expected (P < .001). Five of these close pairs were mother-offspring or husband-wife. The remaining 17 pairs were of unrelated members in separate households. The percentages of male-female (41%), female-female (41%), and male-male (18%) types in these 17 pairs were very similar to those among the 1377 similarly defined pairs in which neither or only 1 member was seropositive, affording no support for extramarital heterosexual activity as an explanation for the clustering observed. Thus, the demography of HTLV-I was not accounted for completely by sexual and mother-to-offspring transmission. The predominance of clustering of unrelated HTLV-I-seropositive individuals in locations with high mosquito infestation raised the possibility of sporadic transmission of HTLV-I by hematophagous insects.
Adolescent↗
Myocardial perfusion imaging with pharmacologic stress in a 9-year-old girl.
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Child↗
Factor VIII, ABO blood group and the incidence of ischaemic heart disease.
Relations of factor VIII activity, FVIIIC, and von Willebrand factor antigen (vWFAg), with ischaemic heart disease (IHD) were examined in 1393 men aged between 40 and 64 years at entry to the Northwick Park Heart Study (NPHS) who experienced 178 first major episodes of IHD during an average follow-up period of 16.1 years. After allowing for the large factor VIII differences between the main ABO blood groups, FVIIIC was probably associated with IHD incidence, possibly more strongly with fatal than non-fatal episodes. Thus, an increase of 1 standard deviation in FVIIIC raised the risk of fatal IHD by about 28%. vWFAg was also significantly associated with fatal events. The observed relation of FVIIIC with IHD incidence probably underestimates the true strength of the association because of the considerable within-person and laboratory variability in factor VIII measurements. FVIIIC and vWFAg were strongly correlated (r = 0.57) and in statistical terms there may be little to choose between them in long-term studies of IHD. Taking account of evidence that haemophiliacs seem to experience less IHD than expected, high factor VIII levels may contribute to the incidence of IHD by increasing thrombogenic potential. The incidence of IHD was significantly higher in those of blood group AB than in those of groups O, A or B, particularly for fatal events. There was no evidence that the FVIIIC and vWFAg associations with IHD are determined by ABO group. The factor VIII and ABO blood group effects therefore appeared to be independent. Group AB may be a genetic marker of characteristics influencing other indices of IHD risk such as short stature, NPHS men (though not women) of group AB being about 2 cm shorter than those of other groups.
ABO Blood-Group System↗
A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase.
Autophosphorylated growth factor receptors provide binding sites for the src homology 2 domains of intracellular signaling molecules. In response to epidermal growth factor (EGF), the activated EGF receptor binds to a complex containing the signaling protein GRB2 and the Ras guanine nucleotide-releasing factor Sos, leading to activation of the Ras signaling pathway. We have investigated whether the platelet-derived growth factor (PDGF) receptor binds GRB2-Sos. In contrast with the EGF receptor, the GRB2 does not bind to the PDGF receptor directly. Instead, PDGF stimulation induces the formation of a complex containing GRB2; 70-, 80-, and 110-kDa tyrosine-phosphorylated proteins; and the PDGF receptor. Moreover, GRB2 binds directly to the 70-kDa protein but not to the PDGF receptor. Using a panel of PDGF beta-receptor mutants with altered tyrosine phosphorylation sites, we identified Tyr-1009 in the PDGF receptor as required for GRB2 binding. Binding is inhibited by a phosphopeptide containing a YXNX motif. The protein tyrosine phosphatase Syp/PTP1D/SHPTP2/PTP2C is approximately 70 kDa, binds to the PDGF receptor via Tyr-1009, and contains several YXNX sequences. We found that the 70-kDa protein that binds to the PDGF receptor and to GRB2 comigrates with Syp and is recognized by anti-Syp antibodies. Furthermore, both GRB2 and Sos coimmunoprecipitate with Syp from lysates of PDGF-stimulated cells, and GRB2 binds directly to tyrosine-phosphorylated Syp in vitro. These results indicate that GRB2 interacts with different growth factor receptors by different mechanisms and the cytoplasmic phosphotyrosine phosphatase Syp acts as an adapter between the PDGF receptor and the GRB2-Sos complex.
3T3 Cells↗
Csk suppression of Src involves movement of Csk to sites of Src activity.
Csk phosphorylates Src family members at a key regulatory tyrosine in the C-terminal tail and suppresses their activities. It is not known whether Csk activity is regulated. To examine the features of Csk required for Src suppression, we expressed Csk mutants in a cell line with a disrupted csk gene. Expression of wild-type Csk suppressed Src, but Csk with mutations in the SH2, SH3, and catalytic domains did not suppress Src. An SH3 deletion mutant of Csk was fully active against in vitro substrates, but two SH2 domain mutants were essentially inactive. Whereas Src repressed by Csk was predominantly perinuclear, the activated Src in cells lacking Csk was localized to structures resembling podosomes. Activated mutant Src was also in podosomes, even in the presence of Csk. When Src was not active, Csk was diffusely located in the cytosol, but when Src was active, Csk colocalized with activated Src to podosomes. Csk also localizes to podosomes of cells transformed by an activated Src that lacks the major tyrosine autophosphorylation site, suggesting that the relocalization of Csk is not a consequence of the binding of the Csk SH2 domain to phosphorylated Src. A catalytically inactive Csk mutant also localized with Src to podosomes, but SH3 and SH2 domain mutants did not, suggesting that the SH3 and SH2 domains are both necessary to target Csk to places where Src is active. The failure of the catalytically active SH3 mutant of Csk to regulate Src may be due to its inability to colocalize with active Src.
Animals↗
Mediation of lung neutrophil uptake after endotoxin by CD18-integrin-dependent and -independent mechanisms.
We studied polymorphonuclear neutrophil (PMN) uptake in lungs of endotoxemic rabbits using 111In-labeled PMN and isotope imaging by gamma scintigraphy. Rabbits were challenged intravenously with 100 micrograms Escherichia coli endotoxin either 4 or 24 h before an intravenous injection of 111In-labeled PMN, which was obtained from donor rabbits. The contribution of CD18 glycoprotein (beta 2-integrin) on PMN was examined using an anti-CD18 monoclonal antibody (MAb) IB4 infused 20 min before 111In-labeled PMN injection. In control rabbits, 111In-labeled PMN uptake in lungs was maximal within 5 min [36 +/- 2% increase above baseline (+/- SE)] and then fell exponentially with a disappearance half-time (t1/2) of 10 +/- 2 min. In rabbits challenged with endotoxin for either 4 or 24 h, maximum 111In-labeled PMN lung uptake and t1/2 values increased to 52 +/- 3 and 56 +/- 3% and to 26 +/- 2 and 31 +/- 6 min, respectively. Pretreatment with MAb IB4 (0.5 mg/kg iv) did not alter the PMN uptake response and t1/2 values in the 4-h endotoxin-challenged rabbits (i.e., maximum uptake of 52 +/- 3% above baseline and t1/2 of 26 +/- 2 min), whereas MAb IB4 prevented the increases in lung PMN uptake and t1/2 in 24-h endotoxin-challenged rabbits (maximum PMN uptake of 26 +/- 5% and t1/2 of 7 +/- 3 min; P < 0.001). In contrast, the control MAb OKM-1 did not prevent lung PMN uptake and the disappearance of PMN from lungs at either times.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Alteration of cellular cytosolic calcium and chemotactic peptide binding by an inhibitor of neutrophil function.
The lung is frequently exposed to particulate material that can potentially stimulate release of factors that attract polymorphonuclear neutrophils (PMN). However, few PMN are noted in the airways of normal subjects, suggesting there is some mechanism to dampen influx of these cells. We have isolated from bronchial lavage a peptide that inhibits PMN chemotaxis to formyl-methionyl-leucyl-phenylalanine (FMLP). In the present study we examined effects of this molecule on 1) chemotaxis to other agonists, 2) FMLP-stimulated PMN superoxide production, 3) PMN calcium fluxes, and 4) binding of FMLP. Our results show that purified inhibitor attenuates PMN chemotaxis to C5a and leukotriene B4. This molecule also inhibits PMN superoxide release in response to FMLP. Exposure to this inhibitor causes an abrupt rise in cytosolic calcium concentration due to a pertussis toxin-sensitive shift of intracellular calcium and attenuates subsequent influx of extracellular calcium in response to FMLP. Binding studies demonstrate the inhibitor induces increased FMLP binding at 37 degrees C but has no effects at 4 degrees C. Inhibition of chemotaxis and increased FMLP binding mediated by this molecule are attenuated by buffering PMN calcium transients. These studies suggest an inhibitor of neutrophil function present in the bronchial environment alters PMN through effects on calcium homeostasis.
Bronchoalveolar Lavage Fluid↗
Hyperoxia stimulates interleukin-8 release from alveolar macrophages and U937 cells: attenuation by dexamethasone.
Pulmonary oxygen toxicity is associated with histological evidence of polymorphonuclear neutrophil (PMN) infiltration into lung parenchyma. What guides infiltration of these cells is unknown. A number of chemoattractants for PMN have been documented including interleukin-8 (IL-8), a cytokine released by alveolar macrophages (AM) and other cell types. The purposes of this study were to 1) determine whether human AM and the histiocytic U937 cell line release IL-8 in response to hyperoxia, 2) assess whether hyperoxia results in increased IL-8 steady-state mRNA levels in U937 cells and 3) establish whether dexamethasone could attenuate noted effects of hyperoxia. Our study shows that hyperoxia stimulates human AM and U937 cell release of IL-8. Hyperoxia also increases IL-8 mRNA levels in U937 cells. IL-8 released in response to hyperoxia by AM was biologically active as evidenced by ability to induce PMN chemotaxis. A polyclonal antibody to IL-8 partially attenuated this chemotactic activity. Finally, dexamethasone at concentrations of 10 microM, 1 microM, and 100 nM markedly reduced hyperoxia-induced IL-8 release and mRNA synthesis by U937 cells. We conclude that IL-8 may be important in the pathogenesis of pulmonary oxygen toxicity and that therapeutic concentrations of dexamethasone can suppress production of this cytokine.
Antibodies, Monoclonal↗
Transient localized accumulation of actin in Caenorhabditis elegans blastomeres with oriented asymmetric divisions.
During Caenorhabditis elegans embryogenesis, specific cells in the P1 lineage rotate their duplicated centrosome pair onto the anterior-posterior axis; this rotation is correlated with and necessary for a differential inheritance of cytoplasmic determinants in the daughter cells. Centrosome pair rotation is sensitive to inhibitors of actin and microtubule polymerization and may require microtubule attachment to a specific cortical site. We show that actin and the barbed-end binding protein, capping protein, transiently accumulate at this cortical site, possibly by assembly onto persistent remnants of previous cell divisions. Based on these observations, we propose a model for the molecular basis of centrosome rotation that is consistent with the dependence of rotation on actin filaments and microtubules.
Actins↗
The effects of intravenous Triton WR-1339 on factor VII coagulant activity and plasma lipoproteins in normocholesterolaemic and hypercholesterolaemic rabbits.
The hypothesis that lipolysis of large lipoproteins by lipoprotein lipase (LPL) has an important influence on the activation of the contact system of coagulation and subsequently on factor VII activation was tested in rabbits rendered hyperlipidaemic by dietary means and/or by injection of Triton WR-1339. The dietary treatment involved a control diet and two isocaloric diets containing either a 0.5% cholesterol or 0.5% cholesterol and 7.5% safflower oil supplement. Other groups of rabbits were given either a standard diet or the standard diet supplemented with 1% cholesterol. All supplemented diets increased many-fold the concentrations of cholesterol associated with the chylomicron, very low-(VLDL), intermediate-(IDL) and low-density (LDL) lipoprotein fractions. Factor VII coagulant activity (FVIIc) increased significantly in all groups of rabbits fed the cholesterol supplement. The intravenous injection of Triton WR-1339 into rabbits fed either the standard or 1% cholesterol-supplemented diet resulted in increases of plasma cholesterol and triglyceride concentrations up to 36-48 h thereafter, followed by decreases up to completion of the experiment at 72 h. Most of these increases in plasma lipids were associated with the chylomicron and VLDL fractions. Following injection of Triton into rabbits fed either the standard or cholesterol-supplemented diet, changes in FVIIc were biphasic with a decrease in activity in the early intervals when rates of accumulation of plasma lipid were constant, and a progressive increase in activity at later intervals when rates of lipid accumulation declined and then reversed.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Tomographic imaging of the distal extremities using cone-beam collimation.
UNLABELLED: We evaluated the feasibility of cone-beam tomography (SPECT with a converging collimator) for detecting bone pathology of the distal extremities. METHODS: We examined 11 patients: seven with hand or wrist pain, three with ankle pain and one with tibial pain. Cone-beam tomography was performed using a high-resolution converging collimator with a 45-cm focal length. Tomograms were then compared to high-resolution planar images. RESULTS: Cone-beam tomography was successfully performed in all patients and tomograms were reconstructed in time for inclusion in the clinical report. In five patients, cone-beam tomography identified abnormalities that were equivocal or poorly defined on planar images. All other cone-beam studies provided the same information as the planar images. CONCLUSIONS: Tomographic imaging of the distal extremities can be successfully performed by using cone-beam tomography which has been found to be feasible and potentially useful in the clinical setting.
Adult↗
Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine 1009, on the human platelet-derived growth factor receptor.
Much progress has been made in elucidating early events in signal transduction by growth factor receptors with intrinsic tyrosine kinase activity. Upon ligand addition, these receptors dimerize and activate, becoming phosphorylated at a number of tyrosyl residues. These phosphorylation sites serve as docking points for proteins containing src homology-2 (SH2) domains. However, little is known about how phosphotyrosine phosphatases (PTPs), participate in these events. Recently, we and others molecularly cloned a ubiquitously expressed SH2 domain-containing PTP, SH-PTP2 (Syp, PTP1D, PTP2C), and found that it interacts directly with several activated growth factor receptors via its SH2 domains. Using a peptide competition assay, we now demonstrate that the major binding site for SH-PTP2 on the platelet-derived growth factor receptor is phosphotyrosine 1009. Immunoprecipitation studies indicate that SH-PTP2 is the previously unidentified "64-kDa" protein known to bind at this site. Addition of a phosphotyrosyl peptide comprising the region around Tyr-1009 stimulates SH-PTP2 activity 5-10-fold, whereas other phosphotyrosyl peptides from the platelet-derived growth factor receptor have no stimulatory effect. Our data suggest that binding of SH-PTP2 to the activated receptor in vivo should result in stimulation of SH-PTP2 activity.
Animals↗
Plasma renin activity and ischemic heart disease.
BACKGROUND: An earlier prospective study reported an association between high levels of plasma renin activity (as measured by the renin-sodium profile) and the incidence of myocardial infarction in patients with hypertension. We have investigated the relation between plasma renin activity and ischemic heart disease in the Northwick Park Heart Study. METHODS: The study included 803 white men 40 to 64 years of age selected from industrial workers in London. Plasma renin activity and established risk factors for ischemic heart disease were measured at entry, which was between 1972 and 1978. Ascertainment of the primary clinical end points of fatal or nonfatal myocardial infarction and sudden death from coronary causes was carried out until the end of 1991. RESULTS: In an analysis of the 86 first coronary events, we found an independent relation between higher systolic blood pressure and coronary end points (relative risk per 1 SD increase in blood pressure, 1.47; 95 percent confidence interval, 1.16 to 1.85; P < 0.001), but no relation between plasma renin activity and coronary end points (relative risk per 1 SD increase in the level of plasma renin activity, 1.04; 95 percent confidence interval, 0.84 to 1.30). In the 242 men who had hypertension of a degree similar to that of the subjects in the earlier prospective study of the renin profile, and in whom 44 of the 86 coronary events occurred, the relative risk of those in the highest as compared with the lowest third for plasma renin activity was 1.26 (95 percent confidence interval, 0.63 to 2.56). CONCLUSIONS: Our results suggest that there is no association between plasma renin activity and myocardial infarction or sudden death from coronary causes, at least in normotensive men.
Adult↗
Deletion of the SH3 domain of Src interferes with regulation by the phosphorylated carboxyl-terminal tyrosine.
A current model for the regulation of the Src protein-tyrosine kinase proposes that the COOH-terminal phosphotyrosine, Tyr-527, binds to the Src homology 2 (SH2) region in an intramolecular interaction that represses the kinase domain. This model is consistent with the activation of Src by mutations in the SH2 domain or COOH terminus. Mutations in the SH3 domain also activate Src, although this region is not thought to bind phosphotyrosine. Seidel-Dugan et al. (Seidel-Dugan, C., Meyer, B. E., Thomas, S. M., and Brugge, J. S. (1992) Mol. Cell. Biol. 12, 1835-1845) have shown that Src mutants with deletions in the SH2 or SH3 domain transform chicken embryo fibroblasts and have increased kinase activity. These mutant proteins are underphosphorylated at Tyr-527, a change that could in itself activate the mutants. Therefore, it is not possible to distinguish whether the SH2 and SH3 domains are needed for phosphorylation of Tyr-527 or for Src to adopt or maintain the repressed state. We have artificially increased the level of Tyr-527 phosphorylation of SH2 and SH3 deletion mutants by coexpressing them with the Tyr-527 kinase, Csk, in yeast cells. We find that both the SH2 and SH3 domains are needed for inhibition of Src by Csk. The SH2 domain is needed for efficient phosphorylation by Csk, both in yeast cells and in vitro. The SH3 domain is needed for Src to be inhibited when Tyr-527 is phosphorylated by Csk. This suggests that the SH3 domain cooperates with the SH2 domain and phosphorylated Tyr-527 to inhibit the kinase domain. Dephosphorylation of SH3 domain mutants at Tyr-527 in fibroblasts could be a consequence of a failure of the proposed SH2/phosphotyrosine interaction.
Animals↗
Positive association between self-reported fatty food consumption and factor VII coagulant activity, a risk factor for coronary heart disease, in 4246 middle-aged men.
Raised levels of factor VII coagulant activity (VIIc) have been reported to increase the incidence of CHD. Preliminary evidence from observational and experimental studies suggests that dietary fat intake is positively associated with VIIc. We explored this further in 4,246 men aged 45-69, who were found to be free of major CHD when screened for a primary prevention trial of antithrombotic medication. All men were asked about their consumption of fatty foods and changes in consumption in the last month. In the 9% of men who reported avoidance of fatty foods in the month before interview, age adjusted VIIc was 7.8% of standard (95% CI 5.1-10.6%) lower than in the remainder. Serum cholesterol and body mass index (BMI) were also significantly lower. The extent to which fat consumed in the past month had deviated from usual intake was significantly and positively related with VIIc, serum cholesterol and BMI. Thus, the VIIc difference between those eating much less fatty food than usual and those eating much more than usual was 11% of standard, with those eating their usual amount having an intermediate level. This study adds to the evidence that dietary fat intake influences VIIc and coagulability. The effect is rapid, so that much of the benefit of dietary fat reduction on thrombogenic risk in CHD is likely to occur within a short time. Thus, the results reinforce the value of a low fat diet, even in individuals with advanced atheroma, in whom dietary intervention has sometimes been considered unlikely to be effective.
Antigens↗
Mammalian Ras interacts directly with the serine/threonine kinase Raf.
We have identified proteins that interact with H-Ras using a two hybrid system screen of a mouse cDNA library. Approximately 50% of the clones identified encoded portions of the c-Raf and A-Raf serine/threonine kinases. Overlaps among these clones define a conserved 81 residue region of the N-terminus of Raf as the Ras interaction region. We show that Raf interacts with wild-type and activated Ras, but not with an effector domain mutant of Ras or with a dominant-interfering Ras mutant. Using purified bacterially expressed fusion proteins, we show, furthermore, that Ras and the N-terminal region of Raf associate directly in vitro and that this interaction is dependent on GTP bound to Ras.
Amino Acid Sequence↗