Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

S100 proteins are calcium-responsive signaling proteins that are overexpressed in cancer and inflammatory diseases. They act by forming complexes with target proteins to modify target protein function. Identifying S100 intracellular distribution, site of action, and protein targets are important goals. S100A7 (psoriasin) is an important member of this family that is markedly overexpressed in psoriatic keratinocytes; however, its role in disease progression is poorly understood. In this study, we express S100A7 in normal keratinocytes as a means to study S100A7 function. We show that S100A7 is present in the cytosol and in BiP/GRP78-positive (endoplasmic reticulum) tubular structures. When cells are challenged with elevated intracellular calcium, cytoplasmic S100A7 redistributes to alpha-actinin- and paxillin-positive peripheral structures that contact the substrate surface. Epidermal fatty acid binding protein is also overexpressed in psoriasis, and is a putative target of S100A7 in keratinocytes. To study this interaction, we coexpressed S100A7 and epidermal fatty acid binding protein. These studies indicate that S100A7 and epidermal fatty acid binding protein colocalize in the cytoplasm in untreated cultures, and localize in peripheral structures in response to calcium challenge. In addition, S100A7 expression appears to stabilize epidermal fatty acid binding protein level, and vice versa. Moreover, the proteins can be coprecipitated in the presence of bifunctional cross-linker, suggesting that they are part of a common complex. The colocalization with alpha-actinin and paxillin suggests that S100A7 and epidermal fatty acid binding protein colocalize in focal adhesion-like structures following calcium treatment.
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PMID:S100A7 (psoriasin) interacts with epidermal fatty acid binding protein and localizes in focal adhesion-like structures in cultured keratinocytes. 1283 73

The endoplasmic reticulum (ER) possesses the structural and functional features expected of an organelle that supports the integration and coordination of major cellular processes. Ca(2+) sequestered within the ER sustains lumenal protein processing while providing a reservoir of the cation to support stimulus-response coupling in the cytosol. Release of ER Ca(2+) sufficient to impair protein processing promotes ER stress and signals the "unfolded protein response" (UPR). The association of the UPR with an acute suppression of mRNA translational initiation and a longer term up-regulation of ER chaperones and partial translational recovery is discussed. Regulatory sites in mRNA translation and the mechanisms responsible for the early and later phases of the UPR are reviewed. The regulatory significance of GRP78/BiP, a multifunctional, broad-specificity ER chaperone, in the coordination of ER protein processing with mRNA translation during acute and chronic ER stress is addressed. The relationship of ER stress to protein misfolding in the cytoplasm is examined. Translational alterations in embryonic cardiomyocytes during treatments with various Ca(2+)-mobilizing, growth-promoting stimuli are described. The importance of ER Ca(2+) stores, ER chaperones, and cytosolic-free Ca(2+) in translational control and growth promotion by these stimuli is assessed. Some perspectives are provided regarding Ca(2+) as an integrating factor in the generation or diversion of metabolic energy. Circumstances impacting upon cellular adaptability during exposure to growth stimuli or during stressful conditions that require rapid adjustments in ATP for continued viability are considered.
Cell Calcium
PMID:Calcium dynamics and endoplasmic reticular function in the regulation of protein synthesis: implications for cell growth and adaptability. 1290 81

Loss-of-function mutations in RET cause abnormal development of the enteric nervous system, a congenital condition known as Hirschsprung disease. Hirschsprung mutations in the extracellular domain of RET (RETECD) affect processing in the endoplasmic reticulum (ER) and prevent RET expression at the cell surface. We have investigated the processing and function of a series of Hirschsprung disease mutations affecting different biochemical properties of the RETECD. All mutations examined prevented the maturation of RETECD in the ER and abolished its ability to interact with the GDNF/GFRalpha1 ligand complex, indicating defects in protein folding. Immature forms of RETECD accumulating intracellularly associated with the ER chaperone Grp78/BiP and showed different degrees of protein ubiquitination. Maturation of RETECD mutants, including those deficient in Ca2+ binding and disulfide bridge formation, could be rescued by allowing protein expression to proceed at 30 degrees C, a condition known to facilitate protein folding. Several of the mutants produced at 30 degrees C regained their ability to bind to the GDNF/GFRalpha1 complex comparable to wild-type, demonstrating that the mutations affected RETECD folding but not function. Analysis of autonomous folding subunits in the RETECD indicated an intrinsic propensity to misfolding in three N-terminal cadherin-like domains, CLD1-3, which also concentrate the majority of Hirschsprung mutations affecting the RETECD. In agreement with this, expression and maturation of these subdomains was specifically improved at 30 degrees C, identifying them as temperature-sensitive determinants in RETECD. Intriguingly, while production of human and mouse RETECD was suboptimal at 37 degrees C compared with 30 degrees C, expression of Xenopus RETECD was higher at 37 degrees C, a non-physiological temperature for amphibians. The intrinsic susceptibility to misfolding of mammalian RETECD may be the result of a trade-off that helps to avoid an increased incidence of tumors, at the expense of a greater vulnerability to Hirschsprung disease.
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PMID:Intrinsic susceptibility to misfolding of a hot-spot for Hirschsprung disease mutations in the ectodomain of RET. 1291 70

A constitutively active form of At-ACA8, a plasma membrane Ca(2+)-ATPase from Arabidopsis thaliana (L.) Heynh., from which the first 74 amino acids containing the calmodulin-binding domain (delta74- At-ACA8) had been deleted, was expressed in Saccharomyces cerevisiae strain K616, which lacks the main endogenous active Ca(2+) transport systems. Delta74- At-ACA8 complemented the K616 phenotype, making it able to grow in a calcium-depleted medium. Delta74- At-ACA8 protein, which co-migrated with the endoplasmic reticulum marker BiP in a sucrose-density gradient, catalyzed MgATP-dependent Ca(2+) uptake and Ca(2+)-dependent MgATP hydrolysis, and retained the biochemical characteristics of the native plant plasma membrane Ca(2+)-ATPase (low specificity for nucleoside triphosphate, high sensitivity to inhibition by the fluorescein derivatives erythrosin B and eosin Y), thus confirming that it is correctly folded and functional. Substitution of the (794)HE residues (numbers refer to full-length At-ACA8) following the highly conserved TGDG(TV)NDP(AS)L motif in the cytoplasmic headpiece with two lysine residues generated an hyperactive protein, with a catalytic activity 2-fold higher than that of delta74- At-ACA8. The (794)HE-->KK mutant was also about 6-fold more sensitive than delta74- At-ACA8 to inhibition by vanadate, indicating that the mutation determines an increase in the proportion of enzyme in the E(2) state during the catalytic cycle.
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PMID:Functional expression in yeast of an N-deleted form of At-ACA8, a plasma membrane Ca(2+)-ATPase of Arabidopsis thaliana, and characterization of a hyperactive mutant. 1464 21

GM1-ganglioside (GM1) is a major sialoglycolipid of neuronal membranes that, among other functions, modulates calcium homeostasis. Excessive accumulation of GM1 due to deficiency of lysosomal beta-galactosidase (beta-gal) characterizes the neurodegenerative disease GM1-gangliosidosis, but whether the accumulation of GM1 is directly responsible for CNS pathogenesis was unknown. Here we demonstrate that activation of an unfolded protein response (UPR) associated with the upregulation of BiP and CHOP and the activation of JNK2 and caspase-12 leads to neuronal apoptosis in the mouse model of GM1-gangliosidosis. GM1 loading of wild-type neurospheres recapitulated the phenotype of beta-gal-/- cells and activated this pathway by depleting ER calcium stores, which ultimately culminated in apoptosis. Activation of UPR pathways did not occur in mice double deficient for beta-gal and ganglioside synthase, beta-gal-/-/GalNAcT-/-, which do not accumulate GM1. These findings suggest that the UPR can be induced by accumulation of the sialoglycolipid GM1 and this causes a novel mechanism of neuronal apoptosis.
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PMID:GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis. 1535 Feb 19

Recent studies have suggested that neuronal death in Alzheimer's disease (AD) or ischemia could arise from dysfunction of the endoplasmic reticulum (ER). Inhibition of protein glycosylation, perturbation of calcium homeostasis, and reduction of disulfide bonds provoke accumulation of unfolded protein in the ER, and are called 'ER stress'. Normal cells respond to ER stress by increasing transcription of genes encoding ER-resident chaperones such as GRP78/BiP, to facilitate protein folding or by suppressing the mRNA translation to synthesize proteins. These systems are termed the unfolded protein response (UPR). Familial Alzheimer's disease-linked presenilin-1 (PS1) mutation downregulates the unfolded protein response and leads to vulnerability to ER stress. The mechanisms by which mutant PS1 affects the ER stress response are attributed to the inhibited activation of ER stress transducers such as IRE1, PERK and ATF6. On the other hand, in sporadic Alzheimer's disease (sAD), we found the aberrant splicing isoform (PS2V), generated by exon 5 skipping of the Presenilin-2 (PS2) gene transcript, responsible for induction of high mobility group A1a protein (HMGA1a). The PS2V also downregulates the signaling pathway of the UPR, in a similar fashion to that reported for mutants of PS1 linked to familial AD. It was clarified what molecules related to cell death are activated in the case of AD and we discovered that caspase-4 plays a key role in ER stress-induced apoptosis. Caspase-4 also seems to act upstream of the beta-amyloid-induced ER stress pathway, suggesting that activation of caspase-4 might mediate neuronal cell death in AD.
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PMID:Induction of neuronal death by ER stress in Alzheimer's disease. 1536 92

The endoplasmic reticulum (ER) is a command center of the cell that is second only to the nucleus in terms of the breadth of its influence on other organelles and activities. It is a major site of protein synthesis, contains the cellular calcium stores that are an essential component of many signaling pathways, and is the proximal site of a signal transduction cascade that responds to cellular stress conditions and serves to maintain homeostasis of the cell. All eucaryotic cells possess an ER, which can comprise nearly 50% of the membranes of a cell. Its functions can be divided into those that occur on the cytosolic side of the membrane (where protein translation and signal transduction cascades occur) and the luminal space (where most other ER functions take place). Our studies during the past several years have revealed that the ER molecular chaperone BiP is a master regulator of ER function. It is responsible for maintaining the permeability barrier of the ER during protein translocation, directing protein folding and assembly, targeting misfolded proteins for retrograde translocation so they can be degraded by the proteasome, contributing to ER calcium stores, and sensing conditions of stress in this organelle, to activate the mammalian unfolded protein response.
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PMID:The ER function BiP is a master regulator of ER function. 1554 29

Sarcolipin (SLN) and phospholamban (PLN) are effective inhibitors of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA). These homologous proteins differ at their N and C termini: the C-terminal Met-Leu-Leu in PLN is replaced by Arg-Ser-Tyr-Gln-Tyr in SLN. The role of the C-terminal sequence of SLN tagged N-terminally with the FLAG epitope (NF-SLN) in endoplasmic reticulum (ER) retention was investigated by transfecting human embryonic kidney-293 cells with cDNAs encoding NF-SLN or a series of NF-SLN mutants in which C-terminal amino acids were deleted progressively. Immunofluorescence and immunoblotting of transfected cells by using anti-FLAG antibodies indicated that NF-SLN and PLN tagged at its N terminus with the FLAG epitope, even when overexpressed, were restricted to the ER. However, C-terminal truncation deletions of SLN, which lacked RSYQY, were not localized to ER and did not inhibit Ca(2+)-dependent Ca2+ uptake by SERCA. The shortest deletion constructs, NF-SLN 1-22 and NF-SLN 1-23, did not express stable protein products. However, all NF-SLN cDNA constructs, including NF-SLN 1-22 and NF-SLN 1-23, were expressed stably and localized to the ER when they were coexpressed with SERCA2a. These results show that NF-SLN subcellular distribution depends on SERCA coexpression and on its luminal, C-terminal RSYQY sequence. By using immunoprecipitation and MS, glucose-regulated protein 78/BiP and glucose-regulated protein 94 were identified as proteins that interact with NF-SLN through the RSYQY sequence. Thus, in the absence of SERCA, retention of NF-SLN in the ER is mediated through its association with other components through the C-terminal RSYQY sequence.
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PMID:Sarcolipin retention in the endoplasmic reticulum depends on its C-terminal RSYQY sequence and its interaction with sarco(endo)plasmic Ca(2+)-ATPases. 1555 94

Hippocalcin is a neuronal calcium binding protein, but its physiological function in brain is unknown. We show here that hippocampal neurons from hippocalcin-deficient mice are more vulnerable to degeneration, particularly using thapsigargin, elevating intracellular calcium. Caspase-12 was activated in neurons lacking hippocalcin, while calpain was unchanged. Neuronal viability was accompanied by endoplasmic reticulum (ER) stress and a change in the relative induction of the ER chaperone, BiP/GRP78. Neuronal apoptosis inhibitor protein (NAIP), known to interact with hippocalcin, was not altered, but hippocampal neurons from gene-deleted mice were more sensitive to excitotoxicity caused by kainic acid. In addition, an age-dependent increase in neurodegeneration occurred in the gene-deleted mice, showing that hippocalcin contributes to neuronal viability during aging.
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PMID:Hippocalcin protects against caspase-12-induced and age-dependent neuronal degeneration. 1560 44

The endoplasmic reticulum (ER) is the major intracellular membrane system. The ER is essential for protein and lipid biosynthesis, transport of proteins along the secretory pathway, and calcium storage. Here, we describe our investigations into the dynamics and regulation of the ER in the early Caenorhabditis elegans embryo. Using a GFP fusion to the ER-resident signal peptidase SP12, we observed the morphological transitions of the ER through fertilization and the early cell-cycles in living embryos. These transitions were tightly coordinated with the division cycle: upon onset of mitosis, the ER formed structured sheets that redispersed at the initiation of cleavage. Although microtubules were not required for the transition of the ER between these different states, the actin cytoskeleton facilitated the dispersal of the ER at the end of mitosis. The ER had an asymmetric distribution in the early embryo, which was dependent on the establishment of polarity by the PAR proteins. The small GTPase ARF-1 played an essential role in the ER dynamics, although this function appeared to be unrelated to the role of ARF-1 in vesicular traffic. In addition, the ER-resident heat shock protein BiP and a homologue of the AAA ATPase Cdc48/p97 were found to be crucial for the ER transitions. Both proteins have been implicated in homotypic ER membrane fusion. We provide evidence that homotypic membrane fusion is required to form the sheet structure in the early embryo.
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PMID:Involvement of the actin cytoskeleton and homotypic membrane fusion in ER dynamics in Caenorhabditis elegans. 1571 56


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