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 purpose of this study was to assess the physiologic training effects of functional electrical stimulation leg cycle ergometer (FES-LCE) exercise in persons with spinal cord injury (SCI) who were previously untrained in this activity. Ten persons with quadriplegia (C5 to C7) and eight with paraplegia (T4 to T11) performed FES-LCE training on an ERGYS I ergometer 10 to 30 minutes per day, 2 or 3 days per week for 12 to 16 weeks (36 total sessions). Training session power output (PO) ranged from 0.0W (no external resistance) to 30.6W. Each subject completed discontinuous graded FES-LCE and arm crank ergometer (ACE) tests before and after training for determinations of peak lower and upper extremity metabolic, pulmonary, and hemodynamic responses. Compared with pretraining, this SCI group exhibited significantly (p less than or equal to .05) higher posttraining peak PO (+45%), oxygen uptake ([O2], + 23%), pulmonary ventilation (+27%), heart rate (+11%), cardiac output ([Qt], + 13%) and significantly lower total peripheral resistance ([TPR], - 14%) during FES-LCE posttests. There were no significant changes in peak stroke volume (+6%), mean arterial pressure ([MAP], - 5%), or arteriovenous oxygen difference ([a-vO2diff], + 10%) during posttraining FES-LCE tests. In addition, no significant differences were noted for the peak level of any monitored variable during ACE posttests after FES-LCE training. The rise in total vascular conductance, implied by the significant decrease in posttraining TPR during FES-LCE tests, denotes that a peripheral circulatory adaptation developed in the persons with SCI during FES-LCE exercise training.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Physiologic effects of electrical stimulation leg cycle exercise training in spinal cord injured persons. 158 Jul 76

Growth hormone (GH) plays a central role in regulating growth and intermediary metabolism in vertebrates, although the mechanisms by which GH initiates these actions are largely unknown. The GH receptor, a member of the cytokine receptor superfamily, does not demonstrate homology with any known tyrosine kinases. However, addition of GH to cells in vitro has been shown to stimulate tyrosine phosphorylation of various intracellular proteins including mitogen-activated protein kinases (MAP kinases) and the newly described Janus kinase, JAK2. Subsequent steps in GH-mediated signal transduction have not been delineated. In the present study, we have examined early events in GH action in vivo. Hypophysectomized juvenile male rats were treated with GH for 15, 30, or 60 min. Rat liver whole cell and nuclear extracts were prepared and analyzed via SDS-polyacrylamide gel electrophoresis and Western blotting techniques. GH rapidly stimulated the tyrosine phosphorylation of at least 8 nuclear proteins of 205, 91, 83, 80, 65, 53, 44, and 42 kDa, and caused the dephosphorylation of a single approximately 149-kDa protein. Using specific antibodies, we have identified three of these nuclear phosphoproteins as 42- and 44-kDa MAP kinases, and as STAT91, a 91-kDa component of the interferon-stimulated gene factor-3 protein complex. One consequence of the activation of STAT91 in the nucleus is the appearance of GH-stimulated DNA binding activity, as assessed by gel-mobility shift assay using an oligonucleotide containing a c-sis-inducible element from the c-fos promoter. These results show that nuclear protein tyrosine phosphorylation is a prominent early event in GH action in vivo and demonstrate a link between GH-stimulated signal transduction and target gene expression.
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PMID:Rapid changes in nuclear protein tyrosine phosphorylation after growth hormone treatment in vivo. Identification of phosphorylated mitogen-activated protein kinase and STAT91. 751 Jun 76

The erythropoietin receptor (EpoR) belongs to the cytokine receptor family, members of which lack a tyrosine kinase domain. Recent studies, however, have shown that a cytoplasmic tyrosine kinase, JAK2, interacts with the cytoplasmic domain of the EpoR and becomes activated upon binding of Epo to the receptor. Epo has also been shown to stimulate activation of Ras and Raf-1. The present studies were undertaken to examine the possible involvement of Epo-induced tyrosine phosphorylation in activation of the Ras/mitogen-activated protein kinase (MAP kinase) pathway and to determine its significance on the growth signaling from the EpoR. In an interleukin (IL)-3-dependent cell line expressing the transfected wild-type EpoR, Epo, or IL-3 induced tyrosine phosphorylation of Shc and its association with Grb2. These cytokines also induced tyrosine phosphorylation and activation of MAP kinase isoforms ERK1 and ERK2. A mutant EpoR with a carboxyl-terminal deletion of 108 amino acids (H mutant), which is mitogenically functional but lacks tyrosine phosphorylation sites in the carboxyl-terminal region, showed markedly diminished abilities to induce tyrosine phosphorylation of Shc and to phosphorylate and activate MAP kinases. A mutant receptor (PM4 mutant) inactivated by a point mutation, Trp282 to Arg, which abrogates the interaction with JAK2, failed to induce any effect on Shc or MAP kinases. In cells expressing a mutant EpoR that is constitutively activated by a point mutation, Arg129 to Cys, in the extracellular portion of the receptor, neither tyrosine phosphorylation of Shc nor activation of MAP kinases by phosphorylation was detectable without stimulation with Epo or IL-3. These results suggest that the carboxyl-terminal region of EpoR may play a crucial role in activation of MAP kinases through the Ras signaling pathway which may be activated by tyrosine phosphorylation of Shc and its association with Grb2. The activation of MAP kinases, however, failed to correlate with the mitogenic activity of mutant EpoRs and thus may not be required for growth signaling from the EpoR.
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PMID:Activation of the mitogen-activated protein kinase pathway by the erythropoietin receptor. 796 95

Currently, more than 50% of married women of childbearing age are using a form of contraception. Between 1960-65 and 1985-90, the number of contraceptive users in all developing countries increased from 31 to 381 million, in East Asia from 18 to 217 million, in Latin America from 4 to 44 million, in South Asia from 8 to 94 million, and in Africa from 2 to 18 million. WHO has recently estimated that over 500,000 women die each year from causes related to pregnancy and childbirth. With a worldwide estimate of 36-53 million induced abortions performed each year, between 125,000 and 170,000 women die each year because of unsafe abortions. According to data from the World Fertility Survey, short spacing between births raises the average chances of offspring dying in infancy by 60-70% and the chances of dying before the age of 5 years by about 50%. WHO's minimal estimate for yearly incidence of bacterial and viral STDs (excluding HIV infection) is 130 million. Most STDs have more serious sequelae in women than in men and lead to pelvic inflammatory disease (PID), permanent infertility, and the risk of ectopic pregnancy. African countries with high incidence of STDs have the lowest prevalences of contraceptive use. A recent examination of the WHO international data base of 22,908 IUD insertions and 51,399 woman-years of follow-up indicates that the occurrence of PID in IUD users is most strongly related to the insertion process and to background STD risk and suggests that PID is an infrequent occurrence after the insertion period. A WHO Scientific Working Group review confirmed the beneficial effects of oral contraceptives in reducing the risk of ovarian cancer, endometrial cancer, and biopsy-proven benign breast diseases. A WHO collaborative study in 5 centers in Kenya, Mexico, and Thailand provided assurance that women who used DMPA for a long time and who initiated use many years previously are not at increased risk of breast cancer.
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PMID:Contraception and women's health. 832 13

Lysophosphatidic acid (LPA) added to serum-starved Swiss 3T3 cells induced, in a time- and concentration-dependent manner, tyrosine phosphorylation of multiple proteins, including proteins of 43, 64, 88 kDa and a group of proteins between 110 and 130 kDa. Among them, two proteins, p43 and p120, were identified as mitogen-activated protein kinase (MAP-kinase) and focal adhesion kinase (FAK), respectively, by immunoprecipitation and immunoblot analysis. Tyrosine phosphorylation of p64 peaked at 1 min and declined rapidly, whereas that of MAP-kinase and FAK peaked at 5 and 10 min after the addition of LPA, respectively. The activity of MAP-kinase determined as phosphorylation of myelin basic protein increased transiently about 3-fold at 5 min, and correlated with tyrosine phosphorylation. These results indicate that tyrosine phosphorylation of these proteins is a part of the signal transduction by LPA and may be involved in its mitogenic responses.
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PMID:Lysophosphatidic acid induces tyrosine phosphorylation and activation of MAP-kinase and focal adhesion kinase in cultured Swiss 3T3 cells. 836 68

Seated recovery [at 5, 15, 20, 40, and 60 min (R5,15,20,40,60)] body temperature (T) and blood pressure were examined after 45 min of cycling exercise (54 +/- 5% maximal O2 uptake) in 12 normotensive males to study the relationship between postexercise thermal and hemodynamic responses. Data were analyzed with a repeated-measures analysis of variance. Systolic (SBP, R15,20,40; P < 0.01) and mean arterial (MAP, R15,20; P < 0.05) blood pressures were significantly lower, but diastolic blood pressure (DBP) was unchanged. Heart rate (R5,15,20, P < 0.001) was above that measured at rest. Decreases in mean skin T (Tsk, R15,20,60; P < 0.01) and increases in core T (Tc, R5,15,20; P < 0.01) were found. Significant negative correlations averaging -0.68 (R15,20,40) and -0.69 (R15,20,40) were demonstrated for Tsk and SBP and MAP, respectively. Increases in thigh Tsk (R5,15,20; P < 0.00001) and decreases in calf (R15,20,40,60; P < 0.00001) and chest (Tchest, R5,15,20,40; P < 0.00001) Tsk were found. Significant negative correlations averaging -0.67 (R5,15,20,40) and -0.71 (R20,40,60) were demonstrated for Tchest and SBP and MAP, respectively. Inverse relationships between various regional Ts and blood pressure and the increased R Tc suggest a vasodilatory response in the visceral organs and/or lower limbs leading to a pooling of blood and transient decreases in blood pressure by a reduced venous return, although not affecting stroke volume and cardiac output.
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PMID:Blood pressure, hemodynamic, and thermal responses after cycling exercise. 837 70

Protein-tyrosine kinases (PTKs) of the JAK family have been characterized on the basis of their ability to mediate the rapid induction of transcription of interferon-responsive genes through the stimulation of a class of latent cytoplasmic transcription factors known as signal transducers and activators of transcription (STATs). STAT activation, which has been described as being Ras-independent, requires tyrosine phosphorylation, but STAT transactivating activity is enhanced by phosphorylation on serine as well, probably by extracellular signal-regulated kinase/mitogen-activated protein kinase(s) (ERK/MAPK). STATs can be activated upon binding of ligands to receptor PTKs, to G-protein-linked receptors, and to cytokine receptors. Whether JAKs are required for the activation of signaling pathways other than that leading to STAT activation is not known. The binding of growth hormone (GH) to its receptor (GHR) activates JAK2 and STATs as well as ERK/MAP kinases. We have used a transient transfection system in 293 cells to evaluate the requirement for JAK2 in the activation of ERK2/MAPK by GH. We found that JAK2 is required for GH-simulated activation of ERK2/MAPK. Employing the transient expression of dominant negative forms of H-Ras and Raf-1, we determined that the GHR/JAK2-mediated activation of ERK2/MAPK is dependent on both Ras and Raf. Thus, JAK protein-tyrosine kinases may represent a common component in the activation of the ERK2/MAPK and STAT signaling pathways, which appear to bifurcate upstream of Ras activation but converge with ERK/MAPK phosphorylation of STATs.
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PMID:JAK2, Ras, and Raf are required for activation of extracellular signal-regulated kinase/mitogen-activated protein kinase by growth hormone. 853 33

We employed the patch-clamp technique to investigate the effects of various phosphorylation pathways on activation and modulation of volume-activated Cl- currents (ICl,vol) in cultured endothelial cells from bovine pulmonary arteries (CPAE cells). Half-maximal activation of ICl,vol occurred at a hypotonicity of 27.5+/-1.2%. Run-down of the current upon repetitive activation was less than 15% within 60 min. Stimulation of protein kinase C (PKC) by phorbol-12-myristate-13-acetate (PMA) or by (-)-indolactam did not affect ICl,vol. Down regulation of PKC activity by a 24-h preincubation of the cells with 0.2 micromol/l PMA, or its inhibition by loading the cells with the specific inhibitory 19-31 pseudosubstrate peptide, did not influence ICl,vol. Trifluoperazine and tamoxifen fully blocked ICl,vol with concentrations required for half-maximal inhibition of 3.0 and 2.4 micromol/l respectively. This inhibitory effect is probably not mediated by the calmodulin-antagonistic action of these compounds, because it occurs at free intracellular [Ca2+] of 50 nmol/l, which are below the threshold for calmodulin activation. The tyrosine kinase inhibitor herbimycin A (1 micromol/l) and genistein (100 micromol/l) did not affect ICl,vol. Exposing CPAE cells to lysophosphatidic acid (1 micromol/l), an activator of p42 MAPkinase and the focal adhesion kinase p125(FAK) in endothelial cells, neither evoked a Cl- current nor affected ICl,vol. Neither wortmannin (10 micromol/l), an inhibitor of MAP kinases and of PI-3 kinase, nor rapamycin (0.1 mmol/l), which interferes with the p70S6 kinase pathway, affected ICl,vol. Exposure of CPAE cells to heat or Na-arsenite, both activators of a recently discovered stress-activated tyrosine phosphorylation pathway, neither activated a current nor affected the hypotonic solution-induced Cl- current. We conclude that none of the studied phosphorylation pathways is essential for the activation of the Cl- current induced by hypotonicity.
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PMID:The volume-activated chloride current in endothelial cells from bovine pulmonary artery is not modulated by phosphorylation. 859 97

Although the ability of growth hormone (GH) to stimulate body growth and regulate metabolism has been recognized for many years, only recently has insight been gained into the molecular mechanisms by which binding of GH to its receptor (GHR) elicits its diverse effects. This review provides an overview of what is currently known about the molecular mechanisms of GH action. The model presented is one in which GH binding to two GHRs causes dimerization of GHR, activation of the GHR-associated JAK2 tyrosine kinase, and tyrosyl phosphorylation of both JAK2 and GHR. These events recruit and/or activate a variety of signaling molecules, including MAP kinases, insulin receptor substrates, phosphatidylinositol 3' phosphate kinase, diacylglycerol, protein kinase C, intracellular calcium, and Stat transcription factors. These signaling molecules contribute to the GH-induced changes in enzymatic activity, transport function, and gene expression that ultimately culminate in changes in growth and metabolism.
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PMID:Molecular mechanism of growth hormone action. 881 91

This study examines the effects of demographics, lifestyle, and work characteristics on burnout in EMTs, and then determines the interaction of various EMT risk factors on cardiovascular changes. In phase 1, EMTs voluntarily completed a demographic data sheet and the Masslach Burnout Inventory (MBI). The MBI results were broken down into subgroups of Emotional Exhaustion (EE), Depersonalization (DP), and Personal Achievement (PA); these were then compared to national averages. Subgroup analysis was performed on the basis of sex, race, marital status, years with the service, smoking, and caffeine drinking habits. In phase 2, EMTs carried logbooks for 1 month, during which they recorded preshift and postshift blood pressure and pulse. Other information recorded for each shift was the amount of caffeine and cigarettes used, the number of advanced life support (ALS) and total runs, and whether the shift worked was day or night. Per-shift average caffeine use, average number of ALS and total runs, and average cross-shift changes in MAP (deltaMAP) and P (deltaP) were calculated for each EMT. The deltaMAP and deltaP were compared for discrete variables (sex, race, training levels, smoker v nonsmoker, marital status, and shift worked) and continuous variable (age, years with the service, total runs, ALS runs, and MBI subscale scores). Continuous variables were split into two groups using the median as a separator. Differences were detected at P < .05 by confidence interval analysis. Sixty-nine EMTs enrolled in phase 1. The EMTs scored significantly lower on the PA scale than the national average (28.1 v 34.6). The low PA score was only seen in the subgroup of EMTs with the service longer than 3 years (26.1 v 30.0). Forty EMTs completed phase 2 of the study. There were no significant differences in deltaMAP detected in any subgroup. There was a significant difference in deltaP based on marital status (single, -4.5 v married, 2.6), and age (younger than 32, -4.5 v older than 32, 0.6). There were no other detected deltaP changes. In conclusion, these results showed that PA is lower in our EMTs than in the general population; EMTs with the service longer than 3 years had the lowest values. There were no significant preshift to postshift changes in blood pressure in any subgroup. There was a statistically significant preshift to postshift decrease in pulse in unmarried EMTs and in those younger than 32 years of age. These results indicate little variation in stress between EMTs and the general population and do not indicate a need for more intensive intervention programs for the management of heart rate or pulse.
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PMID:Effect of individual and work characteristics of EMTs on vital sign changes during shiftwork. 890 60


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