Glutamate carboxypeptidase II (GCPII, also known as PSMA or FOLH1) is responsible for the cleavage of N-acetyl-aspartyl-glutamate (NAAG) to N-acetyl-aspartate and glutamate in the central nervous system and facilitates the intestinal absorption of folate by processing dietary folyl-poly-γ-glutamate in the small intestine. The physiological function of GCPII in other organs like kidneys is still not known. GCPII inhibitors are neuroprotective in various conditions (e.g., ischemic brain injury) in vivo; however, their utilization as potential drug candidates has not been investigated in regard to not yet known GCPII activities. To explore the GCPII role and possible side effects of GCPII inhibitors, we performed parallel metabolomic and lipidomic analysis of the cerebrospinal fluid (CSF), urine, plasma, and brain tissue of mice with varying degrees of GCPII deficiency (fully deficient in Folh1, -/-; one allele deficient in Folh1, +/-; and wild type, +/+). Multivariate analysis of metabolites showed no significant differences between wild-type and GCPII-deficient mice (except for NAAG), although changes were observed between the sex and age. NAAG levels were statistically significantly increased in the CSF, urine, and plasma of GCPII-deficient mice. However, no difference in NAAG concentrations was found in the whole brain lysate likely because GCPII, as an extracellular enzyme, can affect only extracellular and not intracellular NAAG concentrations. Regarding the lipidome, the most pronounced genotype-linked changes were found in the brain tissue. In brains of GCPII-deficient mice, we observed statistically significant enrichment in phosphatidylcholine-based lipids and reduction of sphingolipids and phosphatidylethanolamine plasmalogens. We hypothesize that the alteration of the NAA-NAAG axis by absent GCPII activity affected myelin composition. In summary, the absence of GCPII and thus similarly its inhibition do not have detrimental effects on metabolism, with just minor changes in the brain lipidome.

• Klíčová slova
• FOLH1, N-acetyl-aspartyl-glutamate, folyl-poly-γ-glutamyl hydrolase I, glutamate carboxypeptidase II, lipidomics, metabolomics,
• MeSH
• dipeptidy metabolismus   MeSH
• glutamátkarboxypeptidasa II * genetika   metabolismus   MeSH
• kyselina glutamová MeSH
• lipidomika * MeSH
• lipidy chemie   MeSH
• metabolomika * MeSH
• mozek metabolismus   MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dipeptidy MeSH
• Folh1 protein, mouse MeSH Prohlížeč
• glutamátkarboxypeptidasa II * MeSH
• isospaglumic acid MeSH Prohlížeč
• kyselina glutamová MeSH
• lipidy MeSH

Hippocampal lesions in newborn rats alter the development of mechanisms involved in the processing of nociception. The hippocampal lesion was induced by the bilateral infusion, into the lateral cerebral ventricles, of 0.25 microL of saline containing either 0.25 micromol quinolinic acid (QUIN) and/or 0.25 micromol N-acetyl-L-aspartyl-L-glutamate (NAAG) on postnatal day 12. The same amount of sterile saline was injected into the sham-operated animals (group SHAM). It was expected that the QUIN- and NAAG-lesioned rats would exhibit some differences in thermal pain perception; however, we wanted to know if the control rats would exhibit, at least in part, similar changes in pain perception as their chemically lesioned siblings with which they were housed. Young adult NAAG-injured rats exhibited increased withdrawal latencies in the tail-flick and plantar tests, whereas young adult QUIN-injured animals exhibited only marginally decreased latencies. Nociceptive responses in the SHAM rats paralleled the littermates that had been neonatally treated with QUIN or NAAG, i.e. the responses in the SHAM(QUIN) group decreased, whereas the responses in the SHAM(NAAG) group increased. No significant changes in nociception were observed in intact animals, regardless of which group they were housed with. Our results show that social factors, which were originally demonstrated only for the pain behavior, may also influence basal nociceptive sensitivity in rats. We concluded that the "sham operation" may have had a long-term, nonspecific impact on nociceptive behavior by inducing behavioral mimicry of other animals.

• MeSH
• dipeptidy farmakologie   MeSH
• hipokampus zranění   MeSH
• interpretace statistických dat MeSH
• krysa rodu Rattus MeSH
• kyselina chinolinová farmakologie   MeSH
• měření bolesti účinky léků   MeSH
• nociceptory účinky léků   fyziologie   MeSH
• novorozená zvířata fyziologie   MeSH
• reakční čas účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dipeptidy MeSH
• isospaglumic acid MeSH Prohlížeč
• kyselina chinolinová MeSH

N-Acetyl-aspartyl-glutamate (NAAG), an agonist at Group II metabotropic glutamate receptors (mGluR II), also activates the NMDA-type of ionotropic glutamate receptors and, at high micromolar concentrations, has previously been shown to induce neuronal cell death. In the present study we have morphologically quantified the neurotoxic action of intracerebroventricularly administered NAAG on the hippocampal formation and compared it to the action of the selective endogenous NMDA agonist quinolinic acid. Finally, we examined whether the action of NAAG can be modified by NMDA receptor antagonists and mGluR II ligands. NAAG-induced neurodegeneration was found to be less severe than that induced by quinolinate. It was prevented by inhibitors of NMDA receptors and also by an mGluR II agonist (DCG IV) but not by an mGluR II antagonist (EGlu).

• MeSH
• antagonisté excitačních aminokyselin farmakologie   MeSH
• buněčná smrt účinky léků   MeSH
• dipeptidy aplikace a dávkování   farmakologie   MeSH
• dizocilpinmaleát farmakologie   MeSH
• hipokampus cytologie   účinky léků   fyziologie   MeSH
• injekce intraventrikulární MeSH
• krysa rodu Rattus MeSH
• kyselina chinolinová aplikace a dávkování   farmakologie   MeSH
• kyseliny pipekolové farmakologie   MeSH
• ligandy MeSH
• mozkové komory účinky léků   fyziologie   MeSH
• neurony cytologie   účinky léků   fyziologie   MeSH
• neurotoxiny MeSH
• potkani Wistar MeSH
• receptory metabotropního glutamátu fyziologie   MeSH
• receptory N-methyl-D-aspartátu agonisté   antagonisté a inhibitory   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antagonisté excitačních aminokyselin MeSH
• dipeptidy MeSH
• dizocilpinmaleát MeSH
• isospaglumic acid MeSH Prohlížeč
• kyselina chinolinová MeSH
• kyseliny pipekolové MeSH
• ligandy MeSH
• neurotoxiny MeSH
• receptory metabotropního glutamátu MeSH
• receptory N-methyl-D-aspartátu MeSH
• selfotel MeSH Prohlížeč

Nearly two decades ago, Joe Coyle published a single-authored review with the provocative title, The Nagging Question of the Function of N-Acetylaspartylglutamate (Coyle, 1997). In this review, Coyle documented NAAG's localization to subpopulations of glutamatergic, cholinergic, GABAergic, and noradrenergic neurons, Ca(2+)-dependent release, mGlu3 receptor agonist and NMDA receptor antagonist activity, and cleavage by the glial enzyme glutamate carboxypeptidase II (GCPII). However, at the time of his review, NAAG's physiological function as a neurotransmitter remained elusive. Ironically his review was published months following the discovery of the first potent and selective GCPII inhibitor, 2-(phosphonomethyl)pentanedioc acid (2-PMPA) (Jackson et al., 1996). Over the ensuing decades, over a dozen independent laboratories used 2-PMPA and other GCPII inhibitors to elucidate two distinct neurotransmitter functions for NAAG. Under basal conditions, when GCPII activity is relatively low, intact NAAG dampens synaptic activity via presynaptic mGlu3 receptor activation and NMDA receptor blockade. However, under stimulated conditions, NAAG release and GCPII activity are enhanced resulting in excess glutamate generation, activating NMDA and other glutamate receptors, often pathologically. Diverse classes of GCPII inhibitors have been synthesized and shown to increase NAAG, decrease glutamate, and provide robust efficacy in many disease models wherein abnormal glutamatergic transmission is presumed pathogenic. In addition, over the past 20 years, basic questions regarding NAAG's synthesis, packaging into vesicles, and receptor selectivity profile have been eloquently elucidated. The purpose of this chapter is to summarize these advances and the promise of regulating NAAG metabolism through GCPII inhibition as a therapeutic strategy.

• Klíčová slova
• GCPII, Glutamate, NAAG, NAAG peptidase, NAALADase, NMDA, NR2A, NR2B, mGlu3,
• MeSH
• antigeny povrchové MeSH
• dipeptidy metabolismus   MeSH
• glutamátkarboxypeptidasa II antagonisté a inhibitory   MeSH
• kyselina glutamová metabolismus   MeSH
• lidé MeSH
• neuroglie metabolismus   MeSH
• neurotransmiterové látky metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antigeny povrchové MeSH
• dipeptidy MeSH
• FOLH1 protein, human MeSH Prohlížeč
• glutamátkarboxypeptidasa II MeSH
• isospaglumic acid MeSH Prohlížeč
• kyselina glutamová MeSH
• neurotransmiterové látky MeSH

Animal models are important for the investigation of mechanisms and therapeutic approaches in various human diseases, including schizophrenia. Recently, two neurodevelopmental rat models of this psychosis were developed based upon the use of subunit selective N-methyl-D-aspartate receptor agonists--quinolinic acid (QUIN) and N-acetyl-aspartyl-glutamate (NAAG). The aim of this study was to evaluate pain perception in these models. QUIN or NAAG was infused into lateral cerebral ventricles neonatally. In the adulthood, the pain perception was examined. The rats with neonatal brain lesions did not show any significant differences in acute mechanical nociception and in formalin test compared to controls. However, the neonatally lesioned rats exhibited significantly higher pain thresholds in thermal nociception. Increased levels of mechanical hyperalgesia, accompanying the sciatic nerve constriction (neuropathic pain), were also observed in lesioned rats. Although hyperalgesia was more pronounced in QUIN-treated animals, the number of c-Fos-immunoreactive neurons of the lumbar spinal cord was similar in experimental and control rats. We conclude that neonatal brain lesions attenuated the thermal perception in both nociceptive and neuropathic pain whereas mechanical pain was increased in the model of neuropathic pain only. Thus, nociceptive and neuropathic pain belongs--in addition to behavioral changes--among the parameters which are affected in described animal models of schizophrenia.

• MeSH
• dipeptidy farmakologie   MeSH
• fyzikální stimulace MeSH
• injekce intraventrikulární MeSH
• krysa rodu Rattus MeSH
• kyselina chinolinová farmakologie   MeSH
• lidé MeSH
• měření bolesti MeSH
• modely nemocí na zvířatech * MeSH
• neuralgie patofyziologie   MeSH
• nociceptory fyziologie   MeSH
• novorozená zvířata MeSH
• potkani Wistar * MeSH
• práh bolesti fyziologie   MeSH
• protoonkogenní proteiny c-fos metabolismus   MeSH
• receptory N-methyl-D-aspartátu agonisté   MeSH
• schizofrenie chemicky indukované   patofyziologie   MeSH
• věkové faktory MeSH
• vysoká teplota MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dipeptidy MeSH
• isospaglumic acid MeSH Prohlížeč
• kyselina chinolinová MeSH
• protoonkogenní proteiny c-fos MeSH
• receptory N-methyl-D-aspartátu MeSH

Glutamate carboxypeptidase II (GCPII) is a transmembrane glycoprotein expressed in various tissues. When expressed in the brain it cleaves the neurotransmitter N-acetylaspartylglutamate (NAAG), yielding free glutamate. In jejunum it hydrolyzes folylpoly-gamma-glutamate, thus facilitating folate absorption. The prostate form of GCPII, known as prostate specific membrane antigen (PSMA), is an established cancer marker. The NAAG-hydrolyzing activity of GCPII has been implicated in a number of pathological conditions in which glutamate is neurotoxic (e.g. amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, epilepsy, schizophrenia, and stroke). Inhibition of GCPII was shown to be neuroprotective in tissue culture and in animal models. GCPII is therefore an interesting putative therapeutic target. However, only very limited and controversial data on the expression and localization of GCPII in human brain are available. Therefore, we set out to analyze the activity and expression of GCPII in various compartments of the human brain using a radiolabeled substrate of the enzyme and the novel monoclonal antibody GCP-04, which recognizes an epitope on the extracellular portion of the enzyme and is more sensitive to GCPII than to the homologous GCPIII. We show that this antibody is more sensitive in immunoblots than the widely used antibody 7E11. By Western blot, we show that there are approximately 50-300 ng of GCPII/mg of total protein in human brain, depending on the specific area. Immunohistochemical analysis revealed that astrocytes specifically express GCPII in all parts of the brain. GCPII is enzymatically active and the level of activity follows the expression pattern. Using pure recombinant GCPII and homologous GCPIII, we conclude that GCPII is responsible for the majority of overall NAAG-hydrolyzing activity in the human brain.

• MeSH
• aktivace enzymů fyziologie   MeSH
• antigeny povrchové analýza   imunologie   metabolismus   MeSH
• astrocyty enzymologie   MeSH
• dipeptidy metabolismus   MeSH
• glutamátkarboxypeptidasa II analýza   imunologie   metabolismus   MeSH
• imunohistochemie metody   MeSH
• kyselina glutamová biosyntéza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mapování epitopu metody   MeSH
• molekulární modely MeSH
• mozek anatomie a histologie   enzymologie   MeSH
• protilátky imunologie   MeSH
• radioligandová zkouška metody   MeSH
• rekombinantní fúzní proteiny metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• terciární struktura proteinů fyziologie   MeSH
• western blotting MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny povrchové MeSH
• dipeptidy MeSH
• FOLH1 protein, human MeSH Prohlížeč
• glutamátkarboxypeptidasa II MeSH
• isospaglumic acid MeSH Prohlížeč
• kyselina glutamová MeSH
• protilátky MeSH
• rekombinantní fúzní proteiny MeSH

N-Acetyl-L-aspartyl-L-glutamate (NAAG) is one of the most abundant neuroactive compounds in the mammalian CNS. Our recent observations have suggested that NAAG administered into rat cerebral ventricles can cause neuronal death by apparently excitotoxic mechanisms that can be antagonized by the N-methyl-D-aspartate-receptor blockers and by ligands of metabotropic glutamate receptor of Group II. Therefore, the principal aim of the present study has been to use quantitative morphology, electron microscopy and terminal deoxynucleotidyl transferase-mediated biotin dUTP nick-end labeling to study a dose- and time-dependence as well as regional distribution of neurodegeneration in hippocampi of rats after the intraventricular infusion of 0.25 micromol NAAG/ventricle and of equimolar doses of L-glutamate (L-GLU) and N-acetyl-L-aspartate (NAA), breakdown products of NAAG. The degenerative changes were observed after the infusion of 0.25 and 1.25 micromol of NAAG/ventricle, but not when a dose of 0.05 micromol of NAAG/ventricle was injected into each lateral cerebral ventricle. With a dose of 0.25 micromol of NAAG/ventricle the number of degenerated neurons reached a maximum on the fourth day after the infusion. The neuronal damage following bilateral administration of 0.25 micromol of NAAG/lateral cerebral ventricle exhibited features of a delayed neuronal degeneration, expressed mainly in the layer of dentate granule neurons. The degeneration was characterized on the basis of ultrastructural appearance and DNA-fragmentation. The morphological changes caused by L-glutamate and NAA were much smaller than those observed after the administration of NAAG and displayed a different pattern of regional distribution. The present findings suggest that NAAG can cause a loss of hippocampal neurons in vivo, apparently resulting from the neurotoxicity of NAAG itself.

• MeSH
• agonisté excitačních aminokyselin metabolismus   farmakologie   MeSH
• buněčná smrt účinky léků   MeSH
• časové faktory MeSH
• degenerace nervu chemicky indukované   MeSH
• dipeptidy metabolismus   farmakologie   MeSH
• elektronová mikroskopie MeSH
• fragmentace DNA MeSH
• glutamátové receptory metabolismus   MeSH
• hipokampus účinky léků   patologie   ultrastruktura   MeSH
• injekce intraventrikulární MeSH
• koncové značení zlomů DNA in situ MeSH
• krysa rodu Rattus MeSH
• kyselina aspartová analogy a deriváty   farmakologie   MeSH
• kyselina glutamová farmakologie   MeSH
• neurony účinky léků   patologie   ultrastruktura   MeSH
• neuropeptidy farmakologie   MeSH
• neurotoxiny metabolismus   farmakologie   MeSH
• počet buněk MeSH
• potkani Wistar MeSH
• receptory N-methyl-D-aspartátu agonisté   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• agonisté excitačních aminokyselin MeSH
• dipeptidy MeSH
• glutamátové receptory MeSH
• isospaglumic acid MeSH Prohlížeč
• kyselina aspartová MeSH
• kyselina glutamová MeSH
• N-acetylaspartate MeSH Prohlížeč
• neuropeptidy MeSH
• neurotoxiny MeSH
• receptory N-methyl-D-aspartátu MeSH

N-acetyl-L-aspartyl-L-glutamate (NAAG) is a dipeptide that could be considered a sequestered form of L-glutamate. As much as 25% of L-glutamate in brain may be present in the form of NAAG. NAAG is also one of the most abundant neuroactive small molecules in the CNS: it is an agonist at Group II metabotropic glutamate receptors (mGluR II) and, at higher concentrations, at the N-methyl-D-aspartate (NMDA) type of ionotropic glutamate receptors. As such, NAAG can be either neuroprotective or neurotoxic and, in fact, both characteristics have been discussed and described in the literature. In the present studies, 250 nmol NAAG was infused into each lateral cerebral ventricle of 12-day-old rat pups and, using Nissl-stained sections, neurodegeneration in the hippocampus was evaluated 24 or 96 h after the infusion. In several experiments, the neuronal death was also visualised by Fluoro-Jade B staining and studied by TUNEL technique. Some of the NAAG-treated animals were allowed to survive until 50 days post partum and subjected to behavioural (open field) tests. The administration of NAAG to 12-day-old rats resulted in extensive death of neurons particularly in the dentate gyrus of the hippocampus. The neurodegeneration was, in part, prevented by administration of an NMDA receptor antagonist MK-801 (0.1 mg/kg). The nuclear DNA-fragmentation demonstrated by TUNEL technique pointed to the presence of non-specific single-strand DNA cleavage. The NAAG-associated neonatal neuronal damage may have perturbed development of synaptic circuitry during adolescence as indicated by an altered performance of the experimental animals in the open field testing (changes in grooming activity) at postnatal day 50. The results underscore the potential neurotoxicity of NAAG in neonatal rat brain and implicate neonatally induced, NMDA receptor-mediated neuronal loss in the development of abnormal behaviour in young adult rats.

• MeSH
• chování zvířat * účinky léků   MeSH
• dipeptidy aplikace a dávkování   fyziologie   MeSH
• fragmentace DNA MeSH
• hipokampus účinky léků   růst a vývoj   patologie   MeSH
• injekce intraventrikulární MeSH
• koncové značení zlomů DNA in situ MeSH
• krysa rodu Rattus MeSH
• neurodegenerativní nemoci chemicky indukované   patologie   patofyziologie   MeSH
• neurony účinky léků   patologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dipeptidy MeSH
• isospaglumic acid MeSH Prohlížeč

Intracerebroventricular administration of N-acetyl-L-aspartyl-L-glutamate (NAAG), an agonist at group II metabotropic and NR1/NR2D-containing N-methyl-D-aspartate (NMDA) ionotropic glutamate receptors, increased the permeability of the blood-brain barrier (BBB) to serum albumin in the striatum, but produced no similar effects in the entorhinal cortex or in the hippocampal formation. Electron microscopy showed that NAAG, but not its hydrolytic products L-glutamate and N-acetyl-L-aspartate, increased the number of transport vesicles in the hippocampal endothelial cells. Furthermore, immunocytochemistry detected NR2D subunits on hippocampal capillaries. Consequently, NAAG may have influenced the vesicular transport via NMDA receptors. There was, however, no correlation with the regional pattern of BBB changes (increased permeability in the striatum) that, in turn, could not be directly related to the NAAG-induced neurodegeneration described previously in the hippocampus where no significant changes in BBB permeability were detected.

• MeSH
• cévní endotel chemie   účinky léků   ultrastruktura   MeSH
• corpus striatum účinky léků   metabolismus   MeSH
• cortex entorhinalis účinky léků   metabolismus   MeSH
• dipeptidy farmakologie   MeSH
• elektronová mikroskopie MeSH
• hematoencefalická bariéra účinky léků   MeSH
• hipokampus krevní zásobení   účinky léků   metabolismus   MeSH
• kapiláry chemie   účinky léků   ultrastruktura   MeSH
• krysa rodu Rattus MeSH
• neuroprotektivní látky farmakologie   MeSH
• neurotoxiny farmakologie   MeSH
• potkani Wistar MeSH
• receptory N-methyl-D-aspartátu účinky léků   MeSH
• sérový albumin farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dipeptidy MeSH
• isospaglumic acid MeSH Prohlížeč
• neuroprotektivní látky MeSH
• neurotoxiny MeSH
• NR2A NMDA receptor MeSH Prohlížeč
• receptory N-methyl-D-aspartátu MeSH
• sérový albumin MeSH

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis. The previous research determined that PSMA cleavage of small peptides generated via matrix metalloprotease-mediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells, integrin signaling and angiogenesis, although the specific peptide substrates were not identified. Herein, using enzymatic analyses and LC/MS, we unequivocally demonstrate that several laminin-derived peptides containing carboxy-terminal glutamate moieties (LQE, IEE, LNE) are bona fide substrates for PSMA. Subsequently, the peptide products were tested for their effects on angiogenesis in various models. We report that LQ, the dipeptide product of PSMA cleavage of LQE, efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo. Importantly, LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation (E424S). Endothelial cell activation by LQ was dependent on integrin beta-1-induced activation of focal adhesion kinase. These results characterize a novel PSMA substrate, provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapies.

• Klíčová slova
• Angiogenesis, Extracellular matrix, GCPII, Laminin, PSMA, Peptides,
• MeSH
• angiogenní proteiny metabolismus   MeSH
• antigeny CD29 metabolismus   MeSH
• antigeny povrchové genetika   metabolismus   MeSH
• buněčná adheze MeSH
• dipeptidy metabolismus   MeSH
• endoteliální buňky pupečníkové žíly (lidské) MeSH
• endoteliální buňky cytologie   metabolismus   MeSH
• fyziologická neovaskularizace MeSH
• glutamátkarboxypeptidasa II genetika   metabolismus   MeSH
• hydrolýza MeSH
• laminin metabolismus   MeSH
• lidé MeSH
• mutantní proteiny genetika   metabolismus   MeSH
• peptidové fragmenty metabolismus   MeSH
• proteolýza MeSH
• substrátová specifita MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• angiogenní proteiny MeSH
• antigeny CD29 MeSH
• antigeny povrchové MeSH
• dipeptidy MeSH
• FOLH1 protein, human MeSH Prohlížeč
• glutamátkarboxypeptidasa II MeSH
• isospaglumic acid MeSH Prohlížeč
• laminin MeSH
• mutantní proteiny MeSH
• peptidové fragmenty MeSH