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)

During human pregnancy specialized placental cells of fetal origin, termed cytotrophoblasts, invade the uterus and its blood vessels. This tumor-like process anchors the conceptus to the mother and diverts the flow of uterine blood to the placenta. Previously, we showed that the expression of molecules with important functional roles, including a number of extracellular matrix integrin receptors, is precisely modulated during cytotrophoblast invasion in situ. Here we exploited this observation to study the role of the focal adhesion kinase (FAK), which transduces signals from the extracellular matrix and recruits additional signaling proteins to focal adhesions. Immunolocalization studies on tissue sections showed that FAK is expressed by cytotrophoblasts in all stages of differentiation. Because extracellular matrix-induced integrin clustering results in FAK (auto)phosphorylation on tyrosine 397 (Y397FAK), we also localized this form of the molecule. Immunolocalization experiments detected Y397FAK in a subset of cytotrophoblasts near the surface of the uterine wall. To assess the functional relevance of this observation, we used an adenovirus strategy to inhibit cytotrophoblast expression of FAK as the cells differentiated along the invasive pathway in vitro. Compared to control cells transduced with a wild-type virus, cytotrophoblasts that expressed antisense FAK exhibited a striking reduction in their ability to invade an extracellular matrix substrate. When cytotrophoblast differentiation was compromised (hypoxia in vitro, preeclampsia in vivo), Y397FAK levels associated with the plasma membrane were strikingly lower, although total FAK levels did not change. Together our results suggest that (auto)phosphorylation of Y397 on FAK is a critical component of the signaling pathway that mediates cytotrophoblast migration/invasion.
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PMID:Plasma membrane-associated pY397FAK is a marker of cytotrophoblast invasion in vivo and in vitro. 1143 58

The understanding of epilepsy has advanced substantially in the past decade, and new anticonvulsant drugs with novel mechanisms of action are continually being developed. Some of these newer (and older) medications have been discussed in this article. A wide variety of other drugs is occasionally used in the management of epilepsy. Although parenteral magnesium sulfate is used mainly for the prevention and control of seizures in severe preeclampsia or eclampsia, parenteral magnesium sulfate may also be useful in controlling epileptic seizures associated with low plasma magnesium concentrations. Although considered obsolete, bromides have been useful in the management of tonic-clonic or myoclonic seizures in some infants and preadolescent children when other drugs were unsuitable. Acetazolamide may be useful in the management of refractory partial, myoclonic, absence or primary generalized tonic-clonic seizures; however, tolerance develops to the effect of the drug. Corticotropin and corticosteroids are sometimes used in the management of myoclonic seizures in infants. Steroids may be used in seizures due to intracerebral malignancies and metastasis but are more effective in blunting the intracranial swelling associated with these diseases. Recognition of these new drugs may allow the paramedic or EMT to identify seizure patients in the field. Knowledge of the side effects of these medications may be used to guide patients into appropriate treatment pathways.
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PMID:Anticonvulsant medications. 1145 38

The human placenta is an invasive structure in which highly proliferative, migratory, and invasive extravillous trophoblast (EVT) cells migrate and invade the uterus and its vasculature. Using in vitro propagated normal first-trimester EVT cells and immortalized EVT cells, which share all of the phenotypic and functional characteristics of the normal EVT cells, it has been shown that migration/invasion of human EVT cells is stringently regulated by many growth factors, their binding proteins, extracellular matrix (ECM) components, and some adhesion molecules in an autocrine/paracrine manner at the fetal-maternal interface in human pregnancy. Transforming growth factor beta (TGF-beta), decorin (a proteoglycan in the ECM), and melanoma cell adhesion molecule (Mel-CAM) inhibit, and insulin-like growth factor II (IGF-II), IGF-binding protein 1 (IGFBP-1), and endothelin 1 (ET-1) stimulate EVT cell migration/invasion. Inhibition of EVT cell migration by TGF-beta has been suggested to be due to upregulation of integrins, which make the cells more adhesive to the ECM. Its antiinvasive action is due to an upregulation of tissue inhibitor of matrix metalloprotease 1 (TIMP-1) and plasminogen activator inhibitor (PAI-1) and a downregulation of urokinase-type plasminogen activator (uPA). Molecular mechanisms of inhibition of migration/invasion of EVT cells by decorin and Mel-CAM remain to be identified. IGF-II action has been shown to be mediated by IGF type I receptors (IGF-RII) independently of IGF type I receptors (IGF-RI) and IGFBPs. This action of IGF-II appears to involve inhibitory G proteins and phosphorylation of mitogen-activated protein kinase (MAPK) (extracellular signal-regulated protein kinases 1 and 2 (ERK-1 and ERK-2)). IGFBP-1 stimulation of EVT cell migration appears to occur by binding its Arg-Gly-Asp (RGD) domain to alpha5beta1 integrin, leading to phosphorylation of focal adhesion kinase (FAK) and MAPK (ERK-1 and ERK-2). These studies may improve our understanding of diseases related to abnormal placentation, viz. hypoinvasiveness in preeclampsia and hyperinvasiveness in trophoblastic neoplasms.
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PMID:Regulation of human trophoblast migration and invasiveness. 1193 54

Pre-eclampsia is one of the most common causes of perinatal and maternal morbidity and mortality. High blood pressure and proteinuria are important clinical signs of pre-eclampsia. Sympathetic overactivity and elevated level of circulating vaso active substances, such as monoamines has been shown. Extracellular concentrations of monoamines are normally kept low by specific transporter proteins of which many are expressed in the placenta. In this study we used in situ hybridization and real-time PCR to study the gene expression of monoamine transporters, such as NET, SERT, VMAT2, EMT and OCT1/2, in normal as well as in pre-eclamptic placentae. We demonstrated high expression of NET mRNA in the trophoblast cells of the anchoring villi and a lower expression intensity in the chorionic villi. SERT mRNA was mainly detected in chorionic villi. VMAT2 mRNA was not detected in the central part of the placenta but was present in the spiral arteries of placenta bed biopsies, in cytokeratin positive cells. EMT mRNA was mainly detected in the intra lobular septa and together with OCT1 and OCT2 mRNAs also expressed in scattered cells of placental vessel adventitias. Moreover, quantitative analysis showed a significant lower expression of NET and EMT mRNAs in pre-eclamptic placentae as compared to the control group. A defective gene expression or function of these monoamines transporters might explain the elevated concentrations of monoamines in pre-eclamptic patients. Monoamine transporters may serve as a protective mechanism preventing vasoconstriction in the placental vascular bed and thereby securing a stable blood flow to the fetus.
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PMID:Norepinephrine transporter (NET), serotonin transporter (SERT), vesicular monoamine transporter (VMAT2) and organic cation transporters (OCT1, 2 and EMT) in human placenta from pre-eclamptic and normotensive pregnancies. 1513 35

Adiponectin and leptin, two adipose-tissue-derived proteins, have been reported to be elevated in women with established PE (pre-eclampsia). The aim of the present study was to investigate whether alterations in adiponectin and leptin levels predate the development of PE and FGR (fetal growth restriction) in women at increased risk of these complications, as assessed by Doppler examination of the uterine arteries during the second trimester of pregnancy. We also sought to investigate the circulating levels of adiponectin and leptin in women with established severe early-onset FGR. The study included three groups of pregnant women at 23-25 weeks: Group A (n=44) with normal uterine artery Doppler waveforms, Group B (n=49) with abnormal Doppler waveforms and normal fetal growth at the time of the examination, and Group C (n=15) with established severe FGR and abnormal Doppler waveforms. All women had plasma adiponectin and leptin measured by sensitive immunoassays. In Group B, 19 women had a normal outcome, 17 delivered infants with FGR and 13 developed PE. The women who developed PE delivered smaller babies earlier than women with a normal outcome (P<0.001). There were no significant differences in adiponectin levels between any of the groups (overall P=0.3). Leptin concentrations, expressed as MoM (multiples of the median) of Group A, were higher in women in Group C, i.e. established severe FGR at 2.5 (1.2-2.7) MoMs (overall P<0.001), compared with all of the other groups and subgroups. In conclusion, we found that, in pregnancies complicated by severe early-onset FGR, the maternal plasma concentration of leptin is twice as high as in normal pregnancies. However, the second trimester levels of maternal plasma adiponectin and leptin in pregnancies that subsequently develop PE and/or FGR are not significantly different from normal and, consequently, it is unlikely that these markers will be useful as predictors of these pregnancy complications.
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PMID:Circulating levels of adiponectin and leptin at 23-25 weeks of pregnancy in women with impaired placentation and in those with established fetal growth restriction. 1821 Dec 60

Our objective was to determine if sonographic estimate of fetal weight (SEFW) can identify fetal growth restriction (FGR; birthweight < 10% for gestational age [GA]) among patients with preterm (28 to 32 weeks) severe preeclampsia (P SPE). At two centers, all singletons with reliable GA, P SPE, and SEFW within 3 weeks of birth were identified retrospectively. Intrauterine growth restriction was SEFW < or = 10% for GA. Likelihood ratio (LR) and guidelines by an Evidence-Based Medicine Working Group were used. At the two centers, IUGR was suspected in 20% (4 of 20) and 28% (5 of 18) of P SPE, and FGR was noted in 35% and 44%. At one center, suspected intrauterine growth restriction (IUGR) was associated with actual FGR in 50% of the cases and at center II, in 80%. The LR for IUGR to identify FGR was 3.0. We concluded that SEFW is not a useful diagnostic test in identifying FGR among patients with preterm SPE.
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PMID:Detection of fetal growth restriction with preterm severe preeclampsia: experience at two tertiary centers. 1854

During early pregnancy, cytotrophoblast cells differentiate into extravillous trophoblast (EVT) cells and invade the uterine spiral arteries. This physiological process is essential for the development of maternal-fetal circulation. Because EVT cells are exposed to a low-oxygen environment during this process, we investigated the role of hypoxia in the mechanism that regulates the invasive behavior of EVT cells. Real-time PCR and immunofluorescent analysis were performed to investigate how hypoxia influences the expression of E-cadherin in villous explants cultures and in trophoblast-derived BeWo cells. We determined that hypoxia induced E-cadherin down-regulation through Snail up-regulation in villous explant cultures. The influence of E-cadherin loss was examined by analyzing the expression of alpha(5)-integrin and phosphorylated focal adhesion kinase (FAK) by Western blot and evaluating trophoblast invasion using a matrigel invasion assay. E-cadherin loss induced the up-regulation of alpha(5)-integrin, which leads to the tyrosine phosphorylation of FAK, resulting in an increase in the invasive activity of EVT cells. An alpha(5)-integrin neutralizing antibody inhibited the invasion of EVT cells by attenuating FAK tyrosine phosphorylation. Immunohistochemical analysis using clinical placental bed biopsies revealed that alpha(5)-integrin was up-regulated and FAK tyrosine phosphorylated (Try(861)) as EVT cells invade the uterine myometrium, whereas E-cadherin expression was down-regulated. These results suggest that alpha(5)-integrin up-regulation induced by E-cadherin loss under hypoxia has a crucial role in regulating the migration of EVT cells. This finding should help us reach a better understanding of the pathogenesis of critical gestational diseases, such as preeclampsia.
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PMID:Up-regulation of alpha5-integrin by E-cadherin loss in hypoxia and its key role in the migration of extravillous trophoblast cells during early implantation. 1949 79

Pentraxin 3 (PTX3) and C-reactive protein (CRP) levels were measured in the first trimester of pregnancy in women who subsequently developed preeclampsia (PE, n=16) and fetal growth restriction (FGR, n=12) requiring iatrogenic delivery before 37 weeks, and those who had uncomplicated pregnancies delivering at term (n=60). Mean PTX3 levels were significantly higher in women who subsequently developed PE (7.31 ng/ml, SD = 4.12) when compared to those with normal pregnancy outcome (4.92 ng/ml, SD = 1.94, p=0.0046). There were no significant differences between PTX3 levels in women with FGR (4.82 ng/ml, SD = 2.35) compared to normal pregnancy outcome (p=0.88). The median CRP levels did not vary significantly between the three groups (p=0.26). PTX3 levels in women who subsequently develop PE are already elevated in the first trimester, but not in those that develop FGR. This supports the hypothesis of an excessive maternal inflammatory response to pregnancy in the etiology of PE.
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PMID:First trimester PTX3 levels in women who subsequently develop preeclampsia and fetal growth restriction. 1954 2

Previous results from our group have demonstrated the expression of the 5-HT(2A) receptor and a mitogenic effect of serotonin in human trophoblast. The objectives of the present study were to investigate the role of the 5-HT(2A) receptor in trophoblast cells and to determine the signalling pathways activated by this receptor. We investigated the effect of (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), a selective 5-HT(2A) agonist, on cell cycle progression and cell viability in BeWo and JEG-3 cells. We also investigated, by co-immunoprecipitation and western blot analysis, the involvement of the MEK-ERK1/2 and JAK2-STAT3 signalling pathways following activation of the placental 5-HT(2A) receptor. Our results showed a concentration-dependent increase of cell viability by DOI, which was reversed by ketanserin, a selective 5-HT(2A) receptor antagonist. Furthermore, activation of the 5-HT(2A) receptor by DOI increased cell entry into the G2/M and S phase (DNA synthesis) in BeWo and JEG-3 cells, respectively. In addition, stimulation of BeWo and JEG-3 cells by DOI activated both the MEK-ERK1/2 and the JAK2-STAT3 signalling pathways. This study demonstrated that the 5-HT(2A) receptor increases cell viability and affects cell cycle progression in human trophoblast cell lines as well as activates the MEK-ERK1/2 and JAK2-STAT3 intracellular signalling pathways, which are related to survival, differentiation, migration and invasion. These findings indicate that serotonin through the activation of the 5-HT(2A) receptor is a key regulator of placentation and may play a role in the pathophysiology of certain pregnancy disorders associated with alterations in placental development, such as preeclampsia, gestational diabetes and preterm birth.
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PMID:The 5-HT 2A serotonin receptor enhances cell viability, affects cell cycle progression and activates MEK-ERK1/2 and JAK2-STAT3 signalling pathways in human choriocarcinoma cell lines. 2033 35

Among pregnancy pathologies preeclampsia and fetal growth restriction are among the leading causes of maternal and perinatal mortality and morbidity. For both syndromes, the etiologies are still unclear in many facets. For the development of preeclampsia the presence of the placenta is a prerequisite, while for FGR a variety of other factors may be decisive. Cases with a combination of FGR and preeclampsia are the most severe cases and need clinical intervention. Studies on such cases have misled scientists and clinicians to hypothesize that a failure of trophoblast invasion is a specific feature of the early onset type of preeclampsia. Recent development in preeclampsia specific biomarkers and the intense use of Doppler ultrasound measurements already in the first trimester of pregnancy has resulted in a new understanding of the pathways leading to preeclampsia or FGR.
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PMID:Placental pathology in pregnancy complications. 2126 54


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