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:2.7.13.3 (histidine kinase)
2,405 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sln1p is a plasma membrane-localized two-component histidine kinase that functions as an osmotic stress sensor in Saccharomyces cerevisiae. Changes in osmotic pressure modulate Sln1p kinase activity, which, together with Ypd1p, a phosphorelay intermediate, changes the phosphorylation status of two response regulators, Ssk1p and Skn7p. Ssk1p controls the activity of the HOG1 mitogen-activated protein kinase pathway. Skn7p is a nuclearly localized transcription factor that regulates genes involved in cell wall integrity and other processes. Subcellular compartmentalization may therefore play an important role in eukaryotic two-component pathway regulation. We have studied the subcellular localization of SLN1 pathway components and find that Ypd1p is a dynamic protein with a role in shuttling the osmotic stress signal from Sln1p to Ssk1p in the cytosol and to Skn7p in the nucleus. The need to translocate the signal into different intracellular compartments contributes a spatial dimension to eukaryotic two-component pathways compared to the prototypical two-component pathways of prokaryotes.
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PMID:Saccharomyces cerevisiae histidine phosphotransferase Ypd1p shuttles between the nucleus and cytoplasm for SLN1-dependent phosphorylation of Ssk1p and Skn7p. 1466 64

The two-component histidine kinase Chk1p of Candida albicans has been implicated in the regulation of cell wall biosynthesis. Deletion of CHK1 results in avirulence that in part may be due to the increased sensitivity of mutant strains to polymorphonuclear leukocytes. The mutant also does not adhere to human oesophageal tissue in vitro, probably as a consequence of its altered cell wall. In the current study, a CHK1 promoter-lacZ reporter (CHK1prlacZ) construct was expressed in wild-type C. albicans strain CAI4 and in two-component signal transduction mutants to determine the effect of environmental stress conditions on the regulation of CHK1 and the co-regulatory activities among these proteins. It is shown that lacZ expression varied according to the type of growth conditions and incubation time; expression was also influenced by the strain background. lacZ expression in CAI4 was greater at 37 degrees C and at a pH of 3.5 and in the presence of 4 mM H2O2, 0.1 mM menadione, 10 % serum or 1.5 M NaCl compared to cells grown at 30 or 42 degrees C. The increases in expression were time-dependent and not observed until cells were incubated for 120 min in these conditions (P < 0.05). As a correlate of the increase in transcription of CHK1-lacZ in the presence of H2O2, the chk1 mutant was more sensitive than wild-type and revertant cells to H2O2 in vitro. In addition to strain CAI4, we also measured CHK1p-lacZ reporter activity of mutants deleted in genes encoding other two-component proteins such as the response regulator gene SSK1, the histidine kinases, SLN1 and NIK1, and the HOG1 MAP kinase. Of these proteins, Ssk1p and Sln1p are presumed to mediate phosphotransfer to the HOG1 [hyperosmotic glycerol] MAP kinase pathway during oxidative and perhaps osmotic stress in C. albicans. Compared to strain CAI4, lacZ reporter activity increased significantly in the ssk1 mutant under all growth conditions after a 10 and 120 min incubation (P < 0.0001). lacZ expression in the ssk1 mutant was less at 42 degrees C compared to all other growth conditions (P < 0.05). Furthermore, lacZ reporter activity also increased in the hog1 mutant of C. albicans. These data suggest that SSK1 and HOG1 indirectly or directly negatively regulate CHK1 under most growth conditions tested. In the sln1 mutant, downregulation of CHK1 was observed in all growth conditions compared to strain CAI4 (P < 0.05), while regulation of lacZ in the nik1 mutant was similar to strain CAI4 except when cells were incubated in the presence of 4 mM H2O2 for 120 min (P < 0.05). Western blot analysis was used to determine the role of Chk1p in phosphorylation of Hog1p under oxidative or osmotic stress. It was found that Hog1p was phosphorylated in the chk1 mutant similar to wild-type CAF2-1 cells, although the temporal events of phosphorylation differed slightly in mutant cells. These results show that transcription of CHK1, as measured by the lacZ reporter assay, is statistically increased when cells are exposed to several types of stress or when incubated in 10 % serum in a mutant-specific background and at a specific time point. Of importance, our data also suggest that lacZ expression is indirectly or directly regulated by the HOG1 MAP kinase pathway, although a determination of its position in this pathway or in a cross-talking pathway awaits additional studies.
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PMID:Studies on the regulation of the two-component histidine kinase gene CHK1 in Candida albicans using the heterologous lacZ reporter gene. 1547 Jan 10

Yeast Sln1p is an osmotic stress sensor with histidine kinase activity. Modulation of Sln1 kinase activity in response to changes in the osmotic environment regulates the activity of the osmotic response mitogen-activated protein kinase pathway and the activity of the Skn7p transcription factor, both important for adaptation to changing osmotic stress conditions. Many aspects of Sln1 function, such as how kinase activity is regulated to allow a rapid response to the continually changing osmotic environment, are not understood. To gain insight into Sln1p function, we conducted a two-hybrid screen to identify interactors. Mog1p, a protein that interacts with the yeast Ran1 homolog, Gsp1p, was identified in this screen. The interaction with Mog1p was characterized in vitro, and its importance was assessed in vivo. mog1 mutants exhibit defects in SLN1-SKN7 signal transduction and mislocalization of the Skn7p transcription factor. The requirement for Mog1p in normal localization of Skn7p to the nucleus does not fully account for the mog1-related defects in SLN1-SKN7 signal transduction, raising the possibility that Mog1p may play a role in Skn7 binding and activation of osmotic response genes.
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PMID:Role for the Ran binding protein, Mog1p, in Saccharomyces cerevisiae SLN1-SKN7 signal transduction. 1559 Aug 28

The structural simplicity of the plant hormone ethylene contrasts with its dramatic effects in various developmental processes, as well as in the cellular processes that ethylene initiates in response to a diversity of environmental signals. A single well-conserved signaling cascade mediates this broad spectrum of responses. Ethylene is perceived by a family of two-component histidine kinase receptors that become inactivated upon ethylene binding. In the absence of the hormone, the receptors activate CTR1, a negative regulator of ethylene responses. Sequence similarity between CTR1 and the Raf protein kinases implies involvement of a mitogen-activated protein kinase cascade in this signaling pathway. The protein EIN2 acts downstream of CTR1 and the possible kinase cascade. Although the biochemical function of EIN2 is not understood, its critical role is manifested by the complete ethylene insensitivity of EIN2 loss-of-function mutants. Downstream of EIN2, a family of plant-specific EIN3-like transcription factors mediate ethylene responses. The regulation of EIN3 stability by ethylene is accomplished by F-box-containing proteins that participate in the formation of a SKP1/cullin/F-box complex that targets proteins for degradation by the proteasome. A large number of ethylene-regulated genes have been identified, including the APETALA2 domain-containing transcription factor genes ERF1 and EDF1 to 4, which suggests the participation of a transcriptional cascade in the ethylene response. The differential regulation of some components of this complex nuclear cascade by other signaling pathways provides a possible mechanism for interaction and signal integration. As new points of intersection with other pathways and additional participants in the pathway are identified, the Connections Map will be updated to include this new information.
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PMID:Ethylene signaling pathway. 1578 79

Genome sequencing analyses revealed that Aspergillus nidulans has orthologous genes to all those of the high-osmolarity glycerol (HOG) response mitogen-activated protein kinase (MAPK) pathway of Saccharomyces cerevisiae. A. nidulans mutant strains lacking sskA, sskB, pbsB, or hogA, encoding proteins orthologous to the yeast Ssk1p response regulator, Ssk2p/Ssk22p MAPKKKs, Pbs2p MAPKK and Hog1p MAPK, respectively, showed growth inhibition under high osmolarity, and HogA MAPK in these mutants was not phosphorylated under osmotic or oxidative stress. Thus, activation of the A. nidulans HOG (AnHOG) pathway depends solely on the two-component signalling system, and MAPKK activation mechanisms in the AnHOG pathway differ from those in the yeast HOG pathway, where Pbs2p is activated by two branches, Sln1p and Sho1p. Expression of pbsB complemented the high-osmolarity sensitivity of yeast pbs2Delta, and the complementation depended on Ssk2p/Ssk22p, but not on Sho1p. Pbs2p requires its Pro-rich motif for binding to the Src-homology3 (SH3) domain of Sho1p, but PbsB lacks a typical Pro-rich motif. However, a PbsB mutant (PbsB(Pro)) with the yeast Pro-rich motif was activated by the Sho1p branch in yeast. In contrast, HogA in sskADelta expressing PbsB(Pro) was not phosphorylated under osmotic stress, suggesting that A. nidulans ShoA, orthologous to yeast Sho1p, is not involved in osmoresponsive activation of the AnHOG pathway. We also found that besides HogA, PbsB can activate another Hog1p MAPK orthologue, MpkC, in A. nidulans, although mpkC is dispensable in osmoadaptation. In this study, we discuss the differences between the AnHOG and the yeast HOG pathways.
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PMID:Aspergillus nidulans HOG pathway is activated only by two-component signalling pathway in response to osmotic stress. 1588 18

We previously reported that the group III histidine kinase Dic1p in the maize pathogen Cochliobolus heterostrophus is involved in resistance to dicarboximide and phenylpyrrole fungicides and in osmotic adaptation. In addition, exposure to the phenylpyrrole fungicide fludioxonil led to improper activation of Hog1-type mitogen-activated protein kinases (MAPKs) in some phytopathogenic fungi, including C. heterostrophus. Here we report, for the first time, the relationship between the group III histidine kinase and Hog1-related MAPK: group III histidine kinase is a positive regulator of Hog1-related MAPK in filamentous fungi. The phosphorylation pattern of C. heterostrophus BmHog1p (Hog1-type MAPK) was analyzed in wild-type and dic1-deficient strains by Western blotting. In the wild-type strain, phosphorylated BmHog1p was detected after exposure to both iprodione and fludioxonil at a concentration of 1 microg/ml. In the dic1-deficient strains, phosphorylated BmHog1p was not detected after exposure to 10 microg/ml of the fungicides. In response to osmotic stress (0.4 M KCl), a trace of phosphorylated BmHog1p was found in the dic1-deficient strains, whereas the band representing active BmHog1p was clearly detected in the wild-type strain. Similar results were obtained for Neurospora crassa Os-2p MAPK phosphorylation in the mutant of the group III histidine kinase gene os-1. These results indicate that group III histidine kinase positively regulates the activation of Hog1-type MAPKs in filamentous fungi. Notably, the Hog1-type MAPKs were activated at high fungicide (100 microg/ml) and osmotic stress (0.8 M KCl) levels in the histidine kinase mutants of both fungi, suggesting that another signaling pathway activates Hog1-type MAPKs in these conditions.
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PMID:Group III histidine kinase is a positive regulator of Hog1-type mitogen-activated protein kinase in filamentous fungi. 1627 49

The molecular mechanisms that enable yeast cells to detect and transmit cold signals and their physiological significance in the adaptive response to low temperatures are unknown. Here, we have demonstrated that the MAPK Hog1p is specifically activated in response to cold. Phosphorylation of Hog1p was dependent on Pbs2p, the MAPK kinase (MAPKK) of the high osmolarity glycerol (HOG) pathway, and Ssk1p, the response regulator of the two-component system Sln1p-Ypd1p. However, Sho1p was not required. Interestingly, phosphorylation of Hog1p was stimulated at 30 degrees C in cells exposed to the membrane rigidifier agent dimethyl sulfoxide. Moreover, Hog1p activation occurred specifically through the Sln1 branch. This suggests that Sln1p monitors changes in membrane fluidity caused by cold. Quite remarkably, activation of Hog1p at low temperatures affected the transcriptional response to cold shock. Indeed, the absence of Hog1p impaired the cold-instigated expression of genes for trehalose- and glycerol-synthesizing enzymes and small chaperones. Moreover, a downward transfer to 12 or 4 degrees C stimulated the overproduction of glycerol in a Hog1p-dependent manner. However, hog1Delta mutant cells showed no growth defects at 12 degrees C as compared with the wild type. On the contrary, deletion of HOG1 or GPD1 decreased tolerance to freezing of wild-type cells preincubated at a low temperature, whereas no differences could be detected in cells shifted directly from 30 to -20 degrees C. Thus, exposure to low temperatures triggered a Hog1p-dependent accumulation of glycerol, which is essential for freeze protection.
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PMID:A downshift in temperature activates the high osmolarity glycerol (HOG) pathway, which determines freeze tolerance in Saccharomyces cerevisiae. 1637 51

PTEN tumor suppressor gene failure in ras(Ha)-activated skin carcinogenesis was investigated by mating exon 5 floxed-PTEN (Delta5PTEN) mice to HK1.ras mice that expressed a RU486-inducible cre recombinase (K14.creP). PTEN inactivation in K14.cre/PTEN(flx/flx) keratinocytes resulted in epidermal hyperplasia/hyperkeratosis and novel 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted papillomas, whereas HK1.ras/K14.cre/PTEN(flx/flx) cohorts displayed a rapid onset of papillomatogenesis due to a synergism of increased AKT activity and extracellular signal-regulated kinase (ERK) elevation. High 5-bromo-4-deoxyuridine labeling in Delta5PTEN papillomas showed that a second promotion mechanism centered on failures in cell cycle control. Elevated cyclin D1 was associated with both HK1.ras/ERK- and Delta5PTEN-mediated AKT signaling, whereas cyclin E2 overexpression seemed dependent on PTEN loss. Spontaneous HK1.ras/Delta5PTEN malignant conversion was rare, whereas TPA promotion resulted in conversion with high frequency. On comparison with all previous HK1.ras carcinomas, such TPA-induced carcinomas expressed atypical retention of keratin K1 and lack of K13, a unique marker profile exhibited by TPA-induced K14.cre/PTEN(flx/flx) papillomas that also lacked endogenous c-ras(Ha) activation. Moreover, in all PTEN-null tumors, levels of ras(Ha)-associated total ERK protein became reduced, whereas phosphorylated ERK and cyclin D1 were lowered in late-stage papillomas returning to elevated levels, alongside increased cyclin E2 expression, in TPA-derived carcinomas. Thus, during early papillomatogenesis, PTEN loss promotes ras(Ha) initiation via elevation of AKT activity and synergistic failures in cyclin regulation. However, in progression, reduced ras(Ha)-associated ERK protein and activity, increased Delta5PTEN-associated cyclin E2 expression, and unique K1/K13 profiles following TPA treatment suggest that PTEN loss, rather than ras(Ha) activation, gives rise to a population of cells with greater malignant potential.
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PMID:PTEN loss promotes rasHa-mediated papillomatogenesis via dual up-regulation of AKT activity and cell cycle deregulation but malignant conversion proceeds via PTEN-associated pathways. 1645 83

Methylglyoxal (MG) is a typical 2-oxoaldehyde derived from glycolysis. We have recently found that MG activates transcription factors such as Yap1 and Msn2, and triggers a Hog1 mitogen-activated protein kinase cascade in Saccharomyces cerevisiae. Regarding the activation of Hog1 by MG, we found that Sln1, an osmosensor possessing histidine kinase activity, functions as a sensor of MG (Maeta, K., Izawa, S., and Inoue, Y. (2005) J. Biol. Chem. 280, 253-260). To gain further insight into the role of MG as a signal initiator, here we analyze the response of Schizosaccharomyces pombe to extracellular MG. Spc1, a stress-activated protein kinase (SAPK), was phosphorylated following the treatment with MG. No phosphorylation was observed in a wis1Delta mutant. The His-to-Asp phosphorelay system consisting of three histidine kinases (Phk1, Phk2, and Phk3), a phosphorelay protein (Spy1), and a response regulator (Mcs4) exists upstream of the Spc1-SAPK pathway. The phosphorylation of Spc1 following MG treatment was observed in phk1Deltaphk2Deltaphk3Delta and spy1Delta cells, but not in mcs4Delta cells. These results suggest that S. pombe has an alternative module(s) that directs the MG signal to the SAPK pathway via Mcs4. Additionally, we found that the transcription factor Pap1 is concentrated in the nucleus in response to MG, independent of the Spc1-SAPK pathway.
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PMID:Methylglyoxal as a signal initiator for activation of the stress-activated protein kinase cascade in the fission yeast Schizosaccharomyces pombe. 1646 60

Signal transduction pathways play crucial roles in cellular adaptation to environmental changes. In this study, we employed comparative genomics to analyse the high osmolarity glycerol pathway in fungi. This system contains several signalling modules that are used throughout eukaryotic evolution, such as a mitogen-activated protein kinase and a phosphorelay module. Here we describe the identification of pathway components in 20 fungal species. Although certain proteins proved difficult to identify due to low sequence conservation, a main limitation was incomplete, low coverage genomic sequences and fragmentary genome annotation. Still, the pathway was readily reconstructed in each species, and its architecture could be compared. The most striking difference concerned the Sho1 branch, which frequently does not appear to activate the Hog1 MAPK module, although its components are conserved in all but one species. In addition, two species lacked apparent orthologues for the Sln1 osmosensing histidine kinase. All information gathered has been compiled in an MS Excel sheet, which also contains interactive visualisation tools. In addition to primary sequence analysis, we employed analysis of protein size conservation. Protein size appears to be conserved largely independently from primary sequence and thus provides an additional tool for functional analysis and orthologue identification.
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PMID:Comparative genomics of the HOG-signalling system in fungi. 1646 42


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