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)

Acromegalic patients present with volume expansion and arterial hypertension, but the renal sites and molecular mechanisms of direct antinatriuretic action of GH remain unclear. Here, we show that acromegalic GC rats, which are chronically exposed to very high levels of GH, exhibited a decrease of furosemide-induced natriuresis and an increase of amiloride-stimulated natriuresis compared with controls. Enhanced Na(+),K(+)-ATPase activity and altered proteolytic maturation of epithelial sodium channel (ENaC) subunits in the cortical collecting ducts (CCDs) of GC rats provided additional evidence for an increased sodium reabsorption in the late distal nephron under chronic GH excess. In vitro experiments on KC3AC1 cells, a murine CCD cell model, revealed the expression of functional GH receptors and IGF-I receptors coupled to activation of Janus kinase 2/signal transducer and activator of transcription 5, ERK, and AKT signaling pathways. That GH directly controls sodium reabsorption in CCD cells is supported by: 1) stimulation of transepithelial sodium transport inhibited by GH receptor antagonist pegvisomant; 2) induction of alpha-ENaC mRNA expression; and 3) identification of signal transducer and activator of transcription 5 binding to a response element located in the alpha-ENaC promoter, indicative of the transcriptional regulation of alpha-ENaC by GH. Our findings provide the first evidence that GH, in concert with IGF-I, stimulates ENaC-mediated sodium transport in the late distal nephron, accounting for the pathogenesis of sodium retention in acromegaly.
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PMID:Epithelial sodium channel is a key mediator of growth hormone-induced sodium retention in acromegaly. 1838 93

To know the root adjustment in response to iron deficiency, differentially displayed proteins in tomato roots of wild type and its iron uptake inefficient mutant T3238fer were analyzed by 2-DE and MALDI-TOF MS-based proteomic method under iron sufficiency and deficiency. Ninety-seven proteins were identified, 63 of them were classified in various metabolic pathways. About 40 proteins involved in starch degradation, TCA and ascorbate cycles were upregulated under iron deficiency and grouped in a network together with glycolysis, whereas proteins for fructose metabolism were decreased. Proteins involved in methionine synthesis, cell wall synthesis, mitochondria ATP synthesis, vacuole ATPase, HSP70/90, etc. also revealed enhanced expression under iron deficiency, while proteins about redox homeostasis, transcription factors, kinases, etc. showed diversified changes. The responses are closely associated with energy metabolism, organic acid formation, root morphological change, redox and sulfur homeostasis, and signal transduction, which enhance iron uptake, reutilization and other adaptive changes. Most of the proteins affected by iron deficiency and fer mutation showed similar effect on individual proteins or pathways, but the independent function of FER to iron deficiency were statistically indicated.
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PMID:Proteomic response to iron deficiency in tomato root. 1845 29

The JAK2(V617F) mutation is frequently observed in classical myeloproliferative disorders, and disease progression is associated with a biallelic acquisition of the mutation occurring by mitotic recombination. In this study, we examined whether JAK2 activation could lead to increased homologous recombination (HR) and genetic instability. In a Ba/F3 cell line expressing the erythropoietin (EPO) receptor, mutant JAK2(V617F) and, to a lesser extent, wild-type (wt) JAK2 induced an increase in HR activity in the presence of EPO without modifying nonhomologous end-joining efficiency. Moreover, a marked augmentation in HR activity was found in CD34(+)-derived cells isolated from patients with polycythemia vera or primitive myelofibrosis compared with control samples. This increase was associated with a spontaneous RAD51 foci formation. As a result, sister chromatid exchange was 50% augmented in JAK2(V617F) Ba/F3 cells compared with JAK2wt cells. Moreover, JAK2 activation increased centrosome and ploidy abnormalities. Finally, in JAK2(V617F) Ba/F3 cells, we found a 100-fold and 10-fold increase in mutagenesis at the HPRT and Na/K ATPase loci, respectively. Together, this work highlights a new molecular mechanism for HR regulation mediated by JAK2 and more efficiently by JAK2(V617F). Our study might provide some keys to understand how a single mutation can give rise to different pathologies.
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PMID:JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders. 1851 59

In interleukin-2 (IL-2)-induced human blood lymphocytes, the Na+/K+ pump function (assessed by ouabain-sensitive Rb+ influx), the abundance of Na+, K+-ATPase alpha1-subunit (determined by Western blotting) and the alpha1- and beta1-subunits mRNA of Na+, K+-ATPase (RT-PCR), as well as the phosphorylation of STAT5 and STAT3 family proteins and ERK1/2 kinase have been examined. A 3.5-4.0-fold increase in the expression of alpha1- and beta1-subunits mRNA of Na+, K+-ATPase was found at 24 h of IL-2 stimulation. The inhibitors of JAK3 kinase (B-42, WHI-P431) was shown to decrease both the phosphorylation of STATs and the rise in the oubain-sensitive rubidium influx as well as the increased abundance of Na+, K+-ATPase alpha1-subunit. The inhibition of the protein kinases ERK1/2 by PD98059 (20 microM) suppressed the alpha1-subunit accumulation. All the kinase inhibitors tested did not alter the intracellular content ofmonovalent cations in resting and IL-2-stimulated lymphocytes. It is concluded that MAPK and JAK/STAT signaling pathways mediate the IL-2-dependent regulation of the Na+, K+-ATPase expression during the lymphocyte transition from resting stage to proliferation.
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PMID:[Long-term regulation of Na+, K+-ATPase pump in human lymphocytes: the role of JAK/STAT- and MAPK-signaling pathways]. 1866 16

Despite the growing body of evidence supporting prolactin (PRL) actions in human breast cancer, little is known regarding PRL regulation of its own receptor in these cells. Ligand-initiated endocytosis is a key process in the regulation of receptor availability and signaling cascades that may lead to oncogenic actions. Although exposure to exogenous PRL accelerates degradation of the long isoform of the PRL receptor (lPRLR), neither the signals initiated by PRL that lead to lPRLR internalization and subsequent down-regulation, nor the relationship to downstream pathways are understood in breast cancer cells. In this study, we showed that PRL-induced down-regulation of the lPRLR was reduced by inhibition of src family kinases (SFKs), but not Janus kinase 2, in MCF-7 cells. Inhibition of SFKs also resulted in accumulation of a PRL-induced PRLR fragment containing the extracellular domain, which appeared to be generated from newly synthesized PRLR. lPRLR was constitutively associated with SFKs in lipid rafts. PRL-induced SFK activation led to recruitment of the guanosine triphosphatase, dynamin-2, to an internalization complex, resulting in endocytosis. Inhibition of endocytosis by small interfering RNA-mediated knockdown of dynamin-2 blocked PRL-induced down-regulation of lPRLR, confirming that internalization is essential for this process. Endocytosis also was required for optimal phosphorylation of ERK1/2 and Akt, but not for Janus kinase 2 or signal transducer and activator of transcription 5, indicating that internalization selectively modulates signaling cascades. Together, these data indicate that SFKs are key mediators of ligand-initiated lPRLR internalization, down-regulation, and signal transduction in breast cancer cells, and underscore the importance of target cell context in receptor trafficking and signal transduction.
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PMID:SRC family kinases accelerate prolactin receptor internalization, modulating trafficking and signaling in breast cancer cells. 1905 63

KCl (40 mM) caused reproducible relaxations in frog esophagus. N(G)-nitro-L-arginine (L-NOARG; 1-100 microM), a steriospecific inhibitor of nitric oxide synthase (NOS), completely inhibited the relaxations induced by KCl but not those induced by vasoactive intestinal polypeptide (VIP) antagonist. The inhibitory effect of L-NOARG was prevented by L-arginine (L-ARG; 0.1-1 mM), the precursor of nitric oxide (NO) biosynthesis, but not by D-arginine (D-ARG; 0.1-0.5 mM), the enantiomer of L-arginine. L-ARG or D-ARG alone did not significantly modify the effect of KCl. The relaxations to KCl were significantly inhibited by omega conotoxin (omega-conotoxin; 0.1 microM), a selective blocker of N-type calcium channels. Propranolol (0.1-1 microM), a nonselective blocker of beta-adrenergic receptors, prazosine (0.01-0.1 microM), a selective blocker of alpha(1)-adrenergic receptors, phentolamine (0.1-1 microM), a nonselective blocker of adrenergic receptors, atropine, a selective blocker of muscarinic cholinergic receptors, and lidocaine (1-10 microM), a blocker of sodium channels, had no effect on KCl-evoked relaxations. Caffeine (500 microM), an intracellular calcium releasing agent, did not significantly modify the effect of KCl. In contrast, ruthenium red (100 microM), a selective blocker of ryanodine receptors (intracellular Ca(2+) channels), significantly inhibited these relaxations. Similarly, potassium channel blockers such as 4-aminopyridine (4-AP; 100 microM) and tetraethylammonium (TEA; 100 microM) caused a significant inhibition on relaxations to KCl. In addition, ouabain (100 microM), a specific blocker of Na(+)-K(+)-ATPase, also caused a significant inhibition on these relaxations. The results suggest that NO, Na(+)-K(+)-ATPase and potassium channels may have a role on relaxations induced by 40 mM KCl in the frog esophagus.
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PMID:Molecular mechanism of KCl-induced relaxation of the esophagus. 1917 Nov 33

PTK6 (also known as Brk) is an intracellular tyrosine kinase whose expression is up-regulated in several tumour types. Because localization of protein tyrosine kinases plays an important role in the development of cancers, we investigated the relationship between subcellular localization of PTK6 and its oncogenic properties. PTK6 was targeted to the plasma membrane or the nucleus of HEK 293 cells using the Src myristoylation signal (Myr) or SV40 T-antigen nuclear localization signal (NLS), respectively. The profile of cellular proteins phosphorylated by Myr-PTK6 was quite different from those phosphorylated by NLS-PTK6. Localization of PTK6 to the plasma membrane enhanced the ability of PTK6 to promote proliferation, cell survival and migration and to permit anchorage-independent colony formation. In contrast, nuclear localization of PTK6 impaired these functions. Our results demonstrate that recruitment of PTK6 to the plasma membrane is required for oncogenic function.
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PMID:Oncogenic functions of PTK6 are enhanced by its targeting to plasma membrane but abolished by its targeting to nucleus. 1930 89

This study was designed to determine whether FPS-1, the water-soluble polysaccharide isolated from fuzi, protected against hepatic damage in hepatic ischemia-reperfusion injury in rats, and its mechanism. SD rats were subjected to 60 min of hepatic ischemia, followed by 120 min reperfusion. FPS-1 (160 mg/kg/day) was administered orally for 5 days before ischemia-reperfusion injury in treatment group. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin (ALB) were assayed to evaluate liver functions. Liver samples were taken for histological examination and determination of malondialdehyde (MDA), superoxide dismutase (SOD), that catalase (CAT) in liver. Na(+)-K(+)-ATPase and Ca(2+)-ATPase in mitochondria were measured with colorimetry method. Morphological changes were also investigated by using both light microscopy and electron microscopy (EM). In addition, apoptosis and oncosis were detected by Annexin V-FITC/PI immunofluorescent flow cytometry analysis. Serum AST and ALT levels were elevated in groups exposed to ischemia-reperfusion (p < 0.05). Ischemia-reperfusion caused a marked increase in MDA level, and significant decreases in hepatic SOD and CAT (p < 0.05). Na(+)-K(+)-ATPase and Ca(2+)-ATPase were reduced in ischemia-reperfusion groups compared to the sham group (p < 0.05). Oncosis and apoptosis were also observed in ischemia-reperfusion groups. Pretreatment with FPS-1 reversed all these biochemical parameters as well as histological alterations, evidently by increased SOD, CAT, reduced MDA and histological scores compared to the model group (p < 0.05). FPS-1 could attenuate the necrotic states by the detection of immunofluorescent flow cytometry analysis. Pretreatment with FPS-1 reduced hepatic ischemia-reperfusion injury through its potent antioxidative effects and attenuation of necrotic states.
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PMID:Study on pretreatment of FPS-1 in rats with hepatic ischemia-reperfusion injury. 1950 75

Hyphal tip-growing organisms often rely upon an internal hydrostatic pressure (turgor) to drive localized expansion of the cell. Regulation of the turgor in response to osmotic shock is mediated primarily by an osmotic MAP kinase cascade which activates osmolyte synthesis and ion uptake to effect turgor recovery. We characterized a Neurospora crassa homolog (PTK2) of ser/thr kinase regulators of ion transport in yeast to determine its role in turgor regulation in a filamentous fungi. The ptk2 mutant is osmosensitive, and has lower turgor poise than wildtype. The cause appears to be lower activity of the plasma membrane H+-ATPase. Its role in osmoadaptation is unrelated to the activity of the osmotic MAP kinase cascade. Instead, it acts in an alternative pathway that, like the osmotic MAP kinase cascade, also involves ion transport mediated osmoadaptation.
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PMID:Ptk2 contributes to osmoadaptation in the filamentous fungus Neurospora crassa. 1977 28

We wanted to examine the cellular locations of four Neurospora crassa proteins that transport calcium. However, the structure and distribution of organelles in live hyphae of N. crassa have not been comprehensively described. Therefore, we made recombinant genes that generate translational fusions of putative organellar marker proteins with green or red fluorescent protein. We observed putative endoplasmic reticulum proteins, encoded by grp-78 and dpm, in the nuclear envelope and associated membranes. Proteins of the vacuolar membrane, encoded by vam-3 and vma-1, were in an interconnected network of small tubules and vesicles near the hyphal tip, while in more distal regions they were in large and small spherical vacuoles. Mitochondria, visualized with tagged ARG-4, were abundant in all regions of the hyphae. Similarly, we tagged the four N. crassa proteins that transport calcium with green or red fluorescent protein to examine their cellular locations. NCA-1 protein, a homolog of the SERCA-type Ca(2+)-ATPase of animal cells, colocalized with the endoplasmic reticulum markers. The NCA-2 and NCA-3 proteins are homologs of Ca(2+)-ATPases in the vacuolar membrane in yeast or in the plasma membrane in animal cells. They colocalized with markers in the vacuolar membrane, and they also occurred in the plasma membrane in regions of the hyphae more than 1 mm from the tip. The cax gene encodes a Ca(2+)/H(+) exchange protein found in vacuoles. As expected, the CAX protein localized to the vacuolar compartment. We observed, approximately 50 to 100 mum from the tip, a few spherical organelles that had high amounts of tagged CAX protein and tagged subunits of the vacuolar ATPase (VMA-1 and VMA-5). We suggest that this organelle, not described previously in N. crassa, may have a role in sequestering calcium.
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PMID:Structure and distribution of organelles and cellular location of calcium transporters in Neurospora crassa. 1980 18


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