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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Collecting duct carcinoma is a highly aggressive renal epithelial malignancy, although it accounts for less than 1% of the incidence of renal epithelial neoplasms. Differential diagnoses between collecting duct carcinoma, pelvic urothelial carcinoma with marked invasion to the renal parenchyma (invasive urothelial carcinoma), and papillary renal cell carcinoma is often challenging. In our current study, we examined the utility of using commercially available antibodies, in conjunction with lectin histochemistry, for such differential diagnoses. We examined 17 cases of collecting duct carcinoma, 10 cases of invasive urothelial carcinoma and 15 cases of papillary renal cell carcinoma (type 1, 6 cases; type 2, 9 cases) in these evaluations. Our results indicated that Ulex europaeus agglutinin 1, E-cadherin, and c-KIT were frequently positive in collecting duct carcinoma and invasive urothelial carcinoma, in comparison with papillary renal cell carcinoma, which had negative results for CD10 and alpha-methylacyl CoA racemase. We found, however, that collecting duct carcinoma showed positivity for high-molecular-weight cytokeratin and low-molecular-weight cytokeratin at a low frequency compared with invasive urothelial carcinoma, and that these distinctions need further careful evaluation. In addition, high-molecular-weight cytokeratin positivity was not a reliable marker for collecting duct carcinoma. We conclude that Ulex europaeus agglutinin 1 reactivity and positivity for E-cadherin and c-KIT are effective in distinguishing collecting duct carcinoma from papillary renal cell carcinoma, and that negative results for alpha-methylacyl CoA racemase and CD10 are potentially useful hallmarks of this distinction also. In contrast, a differential diagnosis for collecting duct carcinoma and invasive urothelial carcinoma will require careful examination of multiple routinely stained specimens, particularly in cases of in situ neoplastic lesions in the pelvic mucosa.
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PMID:Collecting duct carcinoma of the kidney: an immunohistochemical evaluation of the use of antibodies for differential diagnosis. 1860 72

This review provides an overview of the molecular mechanisms of K transport in the mammalian connecting tubule (CNT) and cortical collecting duct (CCD), both nephron segments responsible for the regulation of renal K secretion. Aldosterone and dietary K intake are two of the most important factors regulating K secretion in the CNT and CCD. Recently, angiotensin II (AngII) has also been shown to play a role in the regulation of K secretion. In addition, genetic and molecular biological approaches have further identified new mechanisms by which aldosterone and dietary K intake regulate K transport. Thus, the interaction between serum-glucocorticoid-induced kinase 1 (SGK1) and with-no-lysine kinase 4 (WNK4) plays a significant role in mediating the effect of aldosterone on ROMK (Kir1.1), an important apical K channel modulating K secretion. Recent evidence suggests that WNK1, mitogen-activated protein kinases such as P38, ERK, and Src family protein tyrosine kinase are involved in mediating the effect of low K intake on apical K secretory channels.
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PMID:Regulation of potassium (K) handling in the renal collecting duct. 1883 6

NH3 movement across plasma membranes has traditionally been ascribed to passive, lipid-phase diffusion. However, ammonia-specific transporters, Mep/Amt proteins, are present in primitive organisms and mammals express orthologs of Mep/Amt proteins, the Rh glycoproteins. These findings suggest that the mechanisms of NH3 movement in mammalian tissues should be reexamined. Rh C glycoprotein (Rhcg) is expressed in the collecting duct, where NH3 secretion is necessary for both basal and acidosis-stimulated ammonia transport. To determine whether the collecting duct secretes NH3 via Rhcg or via lipid-phase diffusion, we generated mice with collecting duct-specific Rhcg deletion (CD-KO). CD-KO mice had loxP sites flanking exons 5 and 9 of the Rhcg gene (Rhcg(fl/fl)) and expressed Cre-recombinase under control of the Ksp-cadherin promoter (Ksp-Cre). Control (C) mice were Rhcg(fl/fl) but Ksp-Cre negative. We confirmed kidney-specific genomic recombination using PCR analysis and collecting duct-specific Rhcg deletion using immunohistochemistry. Under basal conditions, urinary ammonia excretion was less in KO vs. C mice; urine pH was unchanged. After acid-loading for 7 days, CD-KO mice developed more severe metabolic acidosis than did C mice. Urinary ammonia excretion did not increase significantly on the first day of acidosis in CD-KO mice, despite an intact ability to increase urine acidification, whereas it increased significantly in C mice. On subsequent days, urinary ammonia excretion slowly increased in CD-KO mice, but was always significantly less than in C mice. We conclude that collecting duct Rhcg expression contributes to both basal and acidosis-stimulated renal ammonia excretion, indicating that collecting duct ammonia secretion is, at least in part, mediated by Rhcg and not solely by lipid diffusion.
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PMID:Collecting duct-specific Rh C glycoprotein deletion alters basal and acidosis-stimulated renal ammonia excretion. 1932 95

Rhesus glycoprotein homologs RhAG, RhBG, and RhCG comprise a recently identified branch of the Mep/Amt ammonia transporter family. Animal studies have shown that RhBG and RhCG are present in the kidney distal tubules. Studies in mouse and rat tissue suggest a basolateral localization for RhBG in cells of the distal tubules including the alpha-intercalated cells (alpha-IC), but no localization of RhBG has been reported in human tissue. To date RhCG localization has been described as exclusively apical plasma membrane in mouse and rat kidney, or apical and basolateral in humans, and some mouse and rat tissue studies. We raised novel antibodies to RhBG and RhCG to examine their localization in the human kidney. Madin-Darby canine kidney (MDCKI) cell lines stably expressing human green fluorescent protein-tagged RhBG or RhCG and human tissue lysates were used to demonstrate the specificity of these antibodies for detecting RhBG and RhCG. Using immunoperoxidase staining and antigen liberation techniques, both apical and basolateral RhCG localization was observed in the majority of the cells of the distal convoluted tubule and IC of the connecting tubule and collecting duct. Confocal microscopic imaging of normal human kidney cryosections showed that RhCG staining was predominantly localized to the apical membrane in these cells with some basolateral and intracellular staining evident. A proportion of RhCG staining labeled kAE1-positive cells, confirming that RhCG is localized to the alpha-IC cells. Surprisingly, no RhBG protein was detectable in the human kidney by Western blot analysis of tissue lysates, or by immunohistochemistry or confocal microscopy of tissue sections. The same antibodies, however, could detect RhBG in rat tissue. We conclude that under normal conditions, RhCG is the major putative ammonia transporter expressed in the human kidney and RhBG is not expressed at detectable levels.
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PMID:RhCG is the major putative ammonia transporter expressed in the human kidney, and RhBG is not expressed at detectable levels. 1935 82

Vasopressin's action in renal cells to regulate water transport depends on protein phosphorylation. Here we used mass spectrometry-based quantitative phosphoproteomics to identify signaling pathways involved in the short-term V2-receptor-mediated response in cultured collecting duct cells (mpkCCD) from mouse. Using Stable Isotope Labeling by Amino acids in Cell culture (SILAC) with two treatment groups (0.1 nM dDAVP or vehicle for 30 min), we carried out quantification of 2884 phosphopeptides. The majority (82%) of quantified phosphopeptides did not change in abundance in response to dDAVP. Analysis of the 273 phosphopeptides increased by dDAVP showed a predominance of so-called "basophilic" motifs consistent with activation of kinases of the AGC family. Increases in phosphorylation of several known protein kinase A targets were found. In addition, increased phosphorylation of targets of the calmodulin-dependent kinase family was seen, including autophosphorylation of calmodulin-dependent kinase 2 at T286. Analysis of the 254 phosphopeptides decreased in abundance by dDAVP showed a predominance of so-called "proline-directed" motifs, consistent with down-regulation of mitogen-activated or cyclin-dependent kinases. dDAVP decreased phosphorylation of both JNK1/2 (T183/Y185) and ERK1/2 (T183/Y185; T203/Y205), consistent with a decrease in activation of these proline-directed kinases in response to dDAVP. Both ERK and JNK were able to phosphorylate residue S261of aquaporin-2 in vitro, a site showing a decrease in phosphorylation in response to dDAVP in vivo. The data support roles for multiple vasopressin V2-receptor-dependent signaling pathways in the vasopressin signaling network of collecting duct cells, involving several kinases not generally accepted to regulate collecting duct function.
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PMID:Quantitative phosphoproteomic analysis reveals vasopressin V2-receptor-dependent signaling pathways in renal collecting duct cells. 2013

We previously demonstrated that K depletion inhibited ROMK-like small-conductance K channels (SK) in the cortical collecting duct (CCD) and that the effect was mediated by superoxide anions that stimulated Src family protein tyrosine kinase (PTK) and mitogen-activated protein kinase (MAPK) (51). However, because animals on a K-deficient diet had a severe hypokalemia, superoxide-dependent signaling may not regulate ROMK channels under physiological conditions with a normal plasma K concentration. In the present study, we used the patch-clamp technique and Western blot to examine the effect of a moderate K restriction on ROMK-like SK channels and the role of PTK and MAPK in regulating apical K channels in the CCD of animals on a low-K diet (LK; 0.1% K). Rats and mice fed a LK diet for 7 days had a normal plasma K concentration. However, a LK intake increased the expression of angiotensin II type 1 receptor in the kidney. Moreover, patch-clamp experiments demonstrated that LK intake decreased the probability finding SK channels and channel activity defined by NP(o) (a product of channel number and open probability) in the CCD of both rat and mouse kidneys. Also, LK intake significantly stimulated the production of superoxide anions in the renal cortex and outer medulla in both rats and mice and increased superoxide level in the rat CCD. Moreover, LK intake augments the phosphorylation of p38 and ERK MAPK, the expression of c-Src and tyrosine phosphorylation of ROMK channels. However, treatment of animals with tempol abolished the effect of LK intake on MAPK and c-Src and increased ROMK channel activity in comparing with those of nontreated rats on a LK diet. Inhibiting p38 and ERK with SB202190 and PD98059 significantly stimulated SK in the CCD in rats on a LK diet. In addition, inhibition of PTK with herbimycin A activated SK channels in the CCD from rats on a LK diet. We conclude that LK intake stimulates the generation of superoxide anion and related products and that MAPK and Src family PTK play a physiological role in inhibiting apical K channels in the principal cells in response to LK intake.
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PMID:Decrease in dietary K intake stimulates the generation of superoxide anions in the kidney and inhibits K secretory channels in the CCD. 2035 31

Mutations in the PKHD1 gene result in autosomal recessive polycystic kidney disease (ARPKD) in humans. To determine the molecular mechanism of the cystogenesis in ARPKD, we recently generated a mouse model for ARPKD that carries a targeted mutation in the mouse orthologue of human PKHD1. The homozygous mutant mice display hepatorenal cysts whose phenotypes are similar to those of human ARPKD patients. By littermates of this mouse, we developed two immortalized renal collecting duct cell lines with Pkhd1 and two without. Under nonpermissive culture conditions, the Pkhd1(-/-) renal cells displayed aberrant cell-cell contacts and tubulomorphogenesis. The Pkhd1(-/-) cells also showed significantly reduced cell proliferation and elevated apoptosis. To validate this finding in vivo, we examined proliferation and apoptosis in the kidneys of Pkhd1(-/-) mice and their wildtype littermates. Using proliferation (PCNA and Histone-3) and apoptosis (TUNEL and caspase-3) markers, similar results were obtained in the Pkhd1(-/-) kidney tissues as in the cells. To identify the molecular basis of these findings, we analyzed the effect of Pkhd1 loss on multiple putative signaling regulators. We demonstrated that the loss of Pkhd1 disrupts multiple major phosphorylations of focal adhesion kinase (FAK), and these disruptions either inhibit the Ras/C-Raf pathways to suppress MEK/ERK activity and ultimately reduce cell proliferation, or suppress PDK1/AKT to upregulate Bax/caspase-9/caspase-3 and promote apoptosis. Our findings indicate that apoptosis may be a major player in the cyst formation in ARPKD, which may lead to new therapeutic strategies for human ARPKD.
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PMID:Cystogenesis in ARPKD results from increased apoptosis in collecting duct epithelial cells of Pkhd1 mutant kidneys. 2087 7

Members of the epidermal growth factor (EGF) family bind to ErbB (EGFR) family receptors which play an important role in the regulation of various fundamental cell processes including cell proliferation and differentiation. The normal rodent kidney has been shown to express at least three members of the ErbB receptor family and is a major site of EGF ligand synthesis. Polycystic kidney disease (PKD) is a group of diseases caused by mutations in single genes and is characterized by enlarged kidneys due to the formation of multiple cysts in both kidneys. Tubule cells proliferate, causing segmental dilation, in association with the abnormal deposition of several proteins. One of the first abnormalities described in cell biological studies of PKD pathogenesis was the abnormal mislocalization of the EGFR in cyst lining epithelial cells. The kidney collecting duct (CD) is predominantly an absorptive epithelium where electrogenic Na(+) entry is mediated by the epithelial Na(+) channel (ENaC). ENaC-mediated sodium absorption represents an important ion transport pathway in the CD that might be involved in the development of PKD. A role for EGF in the regulation of ENaC-mediated sodium absorption has been proposed. However, several investigations have reported contradictory results indicating opposite effects of EGF and its related factors on ENaC activity and sodium transport. Recent advances in understanding how proteins in the EGF family regulate the proliferation and sodium transport in normal and PKD epithelial cells are discussed here. This article is part of a Special Issue entitled: Polycystic Kidney Disease.
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PMID:Epidermal growth factor-mediated proliferation and sodium transport in normal and PKD epithelial cells. 2095 42

Renal cell carcinoma (RCC) accounts for approximately 3% of all new cancer diagnosis every year. RCC arises from the renal epithelium and represents 85% of all kidney tumors. According to histology, these neoplasms are divided into the following types: clear cell, papillary, chromophobe, oncocytoma, collecting duct, and unclassified. Approximately, 75% of RCCs are of the clear cell type and in recent years, there have been substantial advances in the understanding of its molecular biology leading to the development of effective treatments. However, there is still an area of uncertainty with regard to non-clear cell histologies. Scarce studies have been conducted testing different drugs in this patient population. Thus, most of the evidence comes from small phase II trials, retrospective analysis, or expanded access programs. Recent insights in the molecular basis of these tumors have opened a promising research field. Molecules targeting mammalian target of rapamycin, epidermal growth factor receptor, c-MET, vascular endothelial growth factor, and platelet-derived growth factor are among some of the promising drugs tested in this setting. This article reviews the mechanisms of disease on RCC and summarizes treatment options with a particular focus on patients with non-clear cell tumors.
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PMID:Non-clear cell advanced kidney cancer: is there a gold standard? 2117 5

Renal epithelial cell primary cilia act as mechanosensors in response to changes in luminal fluid flow. To determine the role of cilia bending in the mechanosensory function of cilia, we performed proteomic analysis of collecting duct cell lines with or without cilia that were kept stationary or rotated to stimulate cilia bending. Expression of the Raf-1 kinase inhibitor protein (RKIP), an inhibitor of the MAPK pathway, was significantly elevated in rotated cilia (+) cells. This was compared with RKIP levels in cilia (-) cells that were stationary or rotated as well as in cilia (+) cells that were stationary. This result was confirmed in cilia knockout adult mice that had lower renal RKIP levels compared with adult mice with cilia. Downstream of RKIP, expression of phosphorylated ERK was decreased only in cells that had cilia and were subjected to constant cilia bending. Furthermore, elevated RKIP levels were associated with reduced cell proliferation. Blockade of PKC abrogated ciliary bending-induced increases in RKIP. In summary, we found that ciliary movement may help control the expression of the Raf-1 kinase inhibitor protein and thus maintain cell differentiation. In terms of polycystic kidney disease, loss of cilia and therefore sensitivity to flow may lead to reduced RKIP levels, activation of the MAPK pathway, and contribute to the formation of cysts.
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PMID:Cilia movement regulates expression of the Raf-1 kinase inhibitor protein. 2134 75


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