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Factor XI (FXI), the zymogen of the blood coagulation protease FXIa, and the structurally homologous protein plasma prekallikrein circulate in plasma in noncovalent complexes with H-kininogen (HK). HK binds to the heavy chains of FXI and of prekallikrein. Each chain contains four apple domains (F1-F4 for FXI and P1-P4 for prekallikrein). Previous studies indicated that the HK-binding site on FXI is located in F1, whereas the major HK-binding site on prekallikrein is in P2. To determine the contribution of each FXI apple domain to HK-FXI complex formation, we examined binding of recombinant single apple domain-tissue plasminogen activator fusion proteins to HK. The order of affinity from highest to lowest is F2 F4 > F1 F3. Monoclonal antibodies against F2 are superior to F4 or F1 antibodies as inhibitors of HK binding to FXI. Antibody alphaP2, raised against prekallikrein, cross-reacts with FXI F2 and inhibits FXI-HK binding with an IC(50) of 8 nm. HK binding to a platelet-specific FXI variant lacking the N-terminal half of F2 is reduced > 5-fold compared with full-length FXI. A chimeric FXI molecule in which F2 is replaced by P2 is cleaved within P2 during activation by factor XIIa, resulting in greatly reduced HK binding capacity. In contrast, wild-type FXI is not cleaved within F2, and its binding capacity for HK is unaffected by factor XIIa. Our data show that HK binding to FXI involves multiple apple domains, with F2 being most important. The findings demonstrate a similarity in mechanism for FXI and prekallikrein binding to HK.
Cholecystokinin (CCK) and related peptides are potent growth factors in the gastrointestinal tract and may be important for human cancer. CCK exerts its growth modulatory effects through G(q)-coupled receptors (CCK(A) and CCK(B)) and activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). In the present study, we investigated the different mechanisms participating in CCK-induced activation of ERK1/2 in pancreatic AR42J cells expressing both CCK(A) and CCK(B). CCK activated ERK1/2 and Raf-1 to a similar extent as epidermal growth factor (EGF). Inhibition of EGF receptor (EGFR) tyrosine kinase or expression of dominant-negative Ras reduced CCK-induced ERK1/2 activation, indicating participation of the EGFR and Ras in CCK-induced ERK1/2 activation. However, compared with EGF, CCK caused only small increases in tyrosine phosphorylation of the EGFR and Shc, Shc-Grb2 complex formation, and Ras activation. Signal amplification between Ras and Raf in a CCK-induced ERK cascade appears to be mediated by activation of protein kinase Cepsilon (PKCepsilon), because 1) down-modulation of phorbol ester-sensitive PKCs inhibited CCK-induced activation of Ras, Raf, and ERK1/2 without influencing Shc-Grb2 complex formation; 2) PKCepsilon, but not PKCalpha or PKCdelta, was detectable in Raf-1 immunoprecipitates, although CCK activated all three PKC isoenzymes. In addition, the present study provides evidence that the Src family tyrosine kinase Yes is activated by CCK and mediates CCK-induced tyrosine phosphorylation of Shc. Furthermore, we show that CCK-induced activation of the EGFR and Yes is achieved through the CCK(B) receptor. Together, our data show that different signals emanating from the CCK receptors mediate ERK1/2 activation; activation of Yes and the EGFR mediate Shc-Grb2 recruitment, and activation of PKC, most likely PKCepsilon, augments CCK-stimulated ERK1/2 activation at the Ras/Raf level.
In PC12 cells, a well studied model for neuronal differentiation, an elevation in the intracellular cAMP level increases cell survival, stimulates neurite outgrowth, and causes activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2). Here we show that an increase in the intracellular cAMP concentration induces tyrosine phosphorylation of two receptor tyrosine kinases, i.e. the epidermal growth factor (EGF) receptor and the high affinity receptor for nerve growth factor (NGF), also termed Trk(A). cAMP-induced tyrosine phosphorylation of the EGF receptor is rapid and correlates with ERK1/2 activation. It occurs also in Panc-1, but not in human mesangial cells. cAMP-induced tyrosine phosphorylation of the NGF receptor is slower and correlates with Akt activation. Inhibition of EGF receptor tyrosine phosphorylation, but not of the NGF receptor, reduces cAMP-induced neurite outgrowth. Expression of dominant-negative Akt does not abolish cAMP-induced survival in serum-free media, but increases cAMP-induced ERK1/2 activation and neurite outgrowth. Together, our results demonstrate that cAMP induces dual signaling in PC12 cells: transactivation of the EGF receptor triggering the ERK1/2 pathway and neurite outgrowth; and transactivation of the NGF receptor promoting Akt activation and thereby modulating ERK1/2 activation and neurite outgrowth.
Erratum in: Correction: Cyclic AMP induces transactivation of the receptors for epidermal growth factor and nerve growth factor, thereby modulating activation of MAP kinase, Akt, and neurite outgrowth in PC12 cells. Journal of biological chemistry 2020 Oct 23;295(43):14792. doi: 10.1074/jbc.AAC120.016177.
Erratum for: Cyclic AMP induces transactivation of the receptors for epidermal growth factor and nerve growth factor, thereby modulating activation of MAP kinase, Akt, and neurite outgrowth in PC12 cells.Journal of biological chemistry, 2002 Nov 15;277(46):43623-30. doi: 10.1074/jbc.M203926200. Epub 2002 Sep 5.
Soluble guanylyl cyclase (sGC) is the major cytosolic receptor for nitric oxide (NO) that converts GTP into the second messenger cGMP in a NO-dependent manner. Other factors controlling this key enzyme are intracellular proteins such as Hsp90 and PSD95, which bind to sGC and modulate its activity, stability, and localization. To date little is known about the effects of posttranslational modifications of sGC, although circumstantial evidence suggests that reversible phosphorylation may contribute to sGC regulation. Here we demonstrate that inhibitors of protein-tyrosine phosphatases such as pervanadate and bisperoxo(1,10-phenanthroline)oxovanadate(V) as well as reactive oxygen species such as H2O2 induce specific tyrosine phosphorylation of the β1 but not of the α1 subunit of sGC. Tyrosine phosphorylation of sGCβ1 is also inducible by pervanadate and H2O2 in intact PC12 cells, rat aortic smooth muscle cells, and in rat aortic tissues, indicating that tyrosine phosphorylation of sGC may also occur in vivo. We have mapped the major tyrosine phosphorylation site to position 192 of β1, where it forms part of a highly acidic phospho-acceptor site for Src-like kinases. In the phosphorylated state Tyr(P)-192 exposes a docking site for SH2 domains and efficiently recruits Src and Fyn to sGCβ1, thereby promoting multiple phosphorylation of the enzyme. Our results demonstrate that sGC is subject to tyrosine phosphorylation and interaction with Src-like kinases, revealing an unexpected cross-talk between the NO/cGMP and tyrosine kinase signaling pathways at the level of sGC.
Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC) is the major cytosolic receptor for NO, catalyzing the conversion of GTP to cGMP. In a search for proteins specifically interacting with human sGC, we have identified the multidomain protein AGAP1, the prototype of an ArfGAP protein with a GTPase-like domain, Ankyrin repeats, and a pleckstrin homology domain. AGAP1 binds through its carboxyl terminal portion to both the α1 and β1 subunits of sGC. We demonstrate that AGAP1 mRNA and protein are co-expressed with sGC in human, murine, and rat cells and tissues and that the two proteins interact in vitro and in vivo. We also show that AGAP1 is prone to tyrosine phosphorylation by Src-like kinases and that tyrosine phosphorylation potently increases the interaction between AGAP1 and sGC, indicating that complex formation is modulated by reversible phosphorylation. Our findings may hint to a potential role of AGAP1 in integrating signals from Arf, NO/cGMP, and tyrosine kinase signaling pathways.
Tensiomyography measures the radial displacement of a muscle during an electrically evoked twitch contraction. The rate of muscle displacement is increasingly reported to assess contractile properties. Several formulas currently exist to calculate the rate of displacement during the contraction phase of the maximal twitch response. However, information on the reproducibility of these formulas is scarce. Further, different rest intervals ranging from 10 s to 30 s are applied between consecutive stimuli during progressive electrical stimulation until the maximum twitch response. The effect of different rest intervals on the rate of displacement has not been investigated so far. The first aim of this study is to investigate the within and between-day reliability of the most frequently used formulas to calculate the rate of displacement. The second aim is to investigate the effect of changing the inter-stimulus interval on the rate of displacement. We will determine the rectus femoris and biceps femoris rate of displacement of twenty-four healthy subjects’ dominant leg on two consecutive days. The maximum displacement curve will be determined two times within three minutes on the first day and a third time 24 h later. On day two, we will also apply three blocks of ten consecutive stimuli at a constant intensity of 50 mA. Inter-stimuli intervals will be 10 s, 20 s or 30 s in each block, respectively, and three minutes between blocks. The order of inter-stimulus intervals will be randomized. This study will allow a direct comparison between the five most frequently used formulas to calculate the rate of displacement in terms of their reproducibility. Our data will also inform on the effect of different inter-stimulus intervals on the rate of displacement. These results will provide helpful information on methodical considerations to determine the rate of displacement and may thus contribute to a standardized approach.
Cervical cancer has caused substantial morbidity and mortality for millions of women over the past decades. While enormous progress has been made in diagnosis, prevention and therapy, the disease is still fatal for many women—especially in low-income countries. Since no detailed studies are available on the worldwide research landscape, we here investigated the global scientific output related to this cancer type by an established protocol. The “New Quality and Quantity Indices in Science” platform assessed all relevant cervical cancer research published in the Web of Science since 1900. A detailed analysis was conducted including country-specific research productivity, indicators for scientific quality, and relation of research activity to socioeconomic and epidemiologic figures. Visualization of data was generated by the use of density equalizing map projections. Our approach identified 22,185 articles specifically related to cervical cancer. From a global viewpoint, the United States of America was the dominating country in absolute numbers, being followed by China and Japan. By contrast, the European countries Sweden, Austria, and Norway were positioned first when the research activity was related to the population number. When the scientific productivity was related to annual cervical cancer cases, Scandinavian countries (Finland #1, Sweden #4, Norway #5, Denmark #7), the Alpine countries Austria (#2) and Switzerland (#6), and the Netherlands (#3) were leading the field. Density equalizing mapping visualized that large parts of Africa and South America were almost invisible regarding the global participation in cervical cancer research. Our data documented that worldwide cervical cancer research activity is continuously increasing but is imbalanced from a global viewpoint. Also, the study indicated that global and public health aspects should be strengthened in cervical carcinoma research in order to empower more countries to take part in international research activities.
Objective: After stratifying for age, sex and multimorbidity at baseline, our aim is to analyse time trends in incident multimorbidity and polypharmacy in the 15-year clinical trajectories of individual patients in a family medicine setting.
Methods: This study was carried out using data from the Registration Network Family Medicine in the South of the Netherlands. The clinical trajectories of 10037 subjects during the 15-year period (2000–2014) were analyzed in a repeated measurement of using a generalized estimating equations model as well as a multilevel random intercept model with repeated measurements to determine patterns of incident multimorbidity and polypharmacy. Hierarchical age-period-cohort models were used to generate age and cohort trajectories for comparison with prevalence trends in multimorbidity literature.
Results: Multimorbidity was more common in females than in males throughout the duration of the 15-year trajectory (females: 39.6%; males: 33.5%). With respective ratios of 11.7 and 5.9 between the end and the beginning of the 15-year period, the youngest female and male groups showed a substantial increase in multimorbidity prevalence. Ratios in the oldest female and male groups were 2.2 and 1.9 respectively. Females had higher levels of multimorbidity than males in the 0-24-year and 25-44-year age groups, but the levels converged to a prevalence of 92.2% in the oldest male and 90.7% in the oldest female group. Similar, albeit, moderate differences were found in polypharmacy patterns.
Conclusions: We sought to specify the progression of multimorbidity from an early age. As a result, our study adds to the multimorbidity literature by specifying changes in chronic disease accumulation with relation to polypharmacy, and by tracking differences in patient trajectories according to age and sex. Multimorbidity and polypharmacy are common and their prevalence is accelerating, with a relatively rapid increase in younger groups. From the point of view of family medicine, this underlines the need for a longitudinal approach and a life course perspective in patient care.
Purpose: Monocentric, prospective study to investigate whether concomitant support of cochlear implant (CI) patients by CI-trained otolaryngologists and application of a standardized head bandage can minimize potential complications during magnetic resonance imaging (MRI).
Methods: Thirty-seven patients with 46 CIs underwent MRI with a prophylactic head bandage. All participants and the otolaryngologist at the CI center completed pre- and post-MRI questionnaires documenting body region scanned, duration of MRI and bandage wear, field strength during the scan, and any complications. If pain was experienced, it was assessed using a visual analog scale (1–10).
Results: MRI was performed without adverse events in 37.8% of cases. Magnet dislocation requiring surgical revision occurred in 2% of cases. Pain was reported in 86% of cases, often due to the tightness of the dressing. Patients with rotating, MRI-compatible magnets reported significantly less pain than participants with older-generation implants. In 11% of cases, the MRI was discontinued.
Conclusion: Serious complications during MRI in cochlear implant patients are rare. Pain is the most common adverse event, probably mainly due to the tight bandage required by most implant types. With newer generations of magnets, these patients experience less pain, no dislocation of the magnets, and no need for bandaging. Although magnet dislocation cannot be completely prevented in older generations of implants, it appears to be reduced by good patient management, which recommends examination under the guidance of physicians trained in the use of hearing implants.