Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Surfactant protein C (SP-C) is a small lipopeptide of which the main part consists of a typical valyl-rich transmembrane domain. The protein is expressed as a propeptide (proSP-C) which is processed and sorted via the regulated secretory pathway to the lamellar body, where mature SP-C is stored before secretion into the alveolar space. In this study we investigated the identity of the compartment to which proSP-C is sorted in cells that do not have a regulated secretory pathway, such as CHO cells. By electron microscopy we determined that proSP-C was localized in an uncommon membrane compartment with very regular morphology, which was not present in control cells. This membrane compartment is not influenced by the palmitoylation of proSP-C and is probably derived from the endoplasmic reticulum. However, proSP-C chimeras with artificial transmembrane domains induced a membrane compartment with a different morphology. Therefore we propose that the typical amino acid sequence of the transmembrane domain of proSP-C plays a role in membrane formation and morphology, which may be relevant under physiological conditions.
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PMID:The transmembrane domain of surfactant protein C precursor determines the morphology of the induced membrane compartment in CHO cells. 1286 96

Surfactant protein C (SP-C) is a lung-specific protein that is synthesized as a 21-kDa integral membrane propeptide (pro-SP-C) and proteolytically processed to a 3.7-kDa secretory product. Previous studies have shown that palmitoylation of pro-SP-C is dependent on two N-terminal juxtamembrane positively charged residues. We hypothesized that these residues influence modification of pro-SP-C by directing transmembrane orientation. Double substitution mutation of these juxtaposed residues from positive to neutral charged species resulted in complete reversal of transmembrane orientation of pro-SP-C and total abrogation of post-translational processing. Mutation of a single residue resulted in mixed orientation. Protein trafficking studies in A549 cells showed that while the double mutant was retained in the endoplasmic reticulum, single mutants produced a mixed pattern of both endoplasmic reticulum (double mutant-like) and vesicular (wild type-like) expression. Our study demonstrates the crucial role juxtamembrane positively charged residues play in establishing membrane topology and their influence on the trafficking and processing of pro-SP-C. Moreover this study provides a likely precedent for a mechanism in disorders associated with mutations in the membrane-flanking region of integral membrane proteins.
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PMID:Processing of surfactant protein C requires a type II transmembrane topology directed by juxtamembrane positively charged residues. 1293 1

Surfactant Protein C (SP-C) is a secreted transmembrane protein that is exclusively expressed by alveolar type II epithelial cells of the lung. SP-C associates with surfactant lipids to reduce surface tension within the alveolus, maintaining lung volume at end expiration. Mutations in the gene encoding SP-C (SFTPC) have recently been linked to chronic lung disease in children and adults. The goal of this study was to determine whether a disease-linked mutation in SFTPC causes lung disease in transgenic mice. The SFTPC mutation, designated g.1728 G --> A, results in the deletion of exon4, generating a truncated form of SP-C (SP-C(Deltaexon4)). cDNA encoding SP-C(Deltaexon4) was constitutively expressed in type II epithelial cells of transgenic mice. Viable F0 transgene-positive mice were not generated after two separate rounds of pronuclear injections. Histological analysis of lung tissue harvested from embryonic day 17.5 F0 transgene-positive fetuses revealed that SP-C(Deltaexon4) caused a dose-dependent disruption in branching morphogenesis of the lung associated with epithelial cell cytotoxicity. Transient expression of SP-C(Deltaexon4) in isolated type II epithelial cells or HEK293 cells resulted in incomplete processing of the mutant proprotein, a dose-dependent increase in BiP transcription, trapping of the proprotein in the endoplasmic reticulum, and rapid degradation via a proteasome-dependent pathway. Taken together, these data suggest that the g.1728 G --> A mutation causes misfolding of the SP-C proprotein with subsequent induction of the unfolded protein response and endoplasmic reticulum-associated degradation pathways ultimately resulting in disrupted lung morphogenesis.
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PMID:Expression of a human surfactant protein C mutation associated with interstitial lung disease disrupts lung development in transgenic mice. 1452 80

Glucose-regulated protein 94 (GRP94/gp96), the endoplasmic reticulum heat shock protein 90 paralog, elicits both innate and adaptive immune responses. Regarding the former, GRP94/gp96 stimulates APC cytokine expression and dendritic cell maturation. The adaptive component of GRP94/gp96 function reflects a proposed peptide-binding activity and, consequently, a role for native GRP94/gp96-peptide complexes in cross-presentation. It is by this mechanism that tumor-derived GRP94/gp96 is thought to suppress tumor growth and metastasis. Recent data have demonstrated that GRP94/gp96-elicited innate immune responses can be sufficient to suppress tumor growth and metastasis. However, the immunological processes activated in response to tumor Ag-negative sources of GRP94/gp96 are currently unknown. We have examined the in vivo immunological response to nontumor sources of GRP94/gp96 and report that administration of syngeneic GRP94/gp96- or GRP94/gp96-N-terminal domain-secreting KBALB fibroblasts to BALB/c mice stimulates CD11b(+) and CD11c(+) APC function and promotes bystander activation of CD4(+) T cell Th1 cytokine production. Only modest activation of CD8(+) T cell or NK cell cytolytic function was observed. The GRP94/gp96-dependent induction of CD4(+) T cell cytokine production was markedly inhibited by carrageenan, indicating an essential role for APC in this response. These results identify the bystander activation of CD4(+) T lymphocytes as a previously unappreciated immunological consequence of GRP94/gp96 administration and demonstrate that GRP94/gp96-elicited alterations in the in vivo cytokine environment influence the development of CD4(+) T cell effector functions, independently of its proposed function as a peptide chaperone.
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PMID:Glucose-regulated protein 94/glycoprotein 96 elicits bystander activation of CD4+ T cell Th1 cytokine production in vivo. 1503 32

Proteins that fail to attain their correct three-dimensional structure are retained in the endoplasmic reticulum (ER) and eventually degraded within the cells. We investigated the degradation of mutant proteins, using naturally occurring protein C (PC) mutants (Arg178Gln and Cys331Arg) which lead to congenital deficiencies. Chinese hamster ovary (CHO) cells were transfected with normal or mutant expression vectors. The introduction of mutation at Asn329 of an unusual sequence Asn-X-Cys for N-linked glycosylation revealed that the mutation at Cys331, which may preclude a formation of disulfide bond with Cys345, resulted in no addition of N-linked oligosaccharides at Asn329. PC mutants with 4 glycosylation sites were gradually glycosylated in the ER, and the fourth glycosylation site is less accessible for glycosylation as reported for PC in plasma. The half lives of PC178 and PC331 mutants were about 5 and 4 h, respectively. PC mutants were degraded, but the degradation was inhibited by inhibitors for proteasome. Mannose trimming of N-linked oligosaccharides after glucose removal targeted PC mutants for degradation by proteasomes. And also the inhibition of glucose trimming immediately led to mannose trimming, resulting in the accelerated degradation of PC mutants. These degradations were inhibited by mannosidase I inhibitor, kifunensine. These results indicate that the initiation of mannose trimming by mannosidase I leads to the proteasomemediated degradation of glucose-trimmed or untrimmed PC mutants.
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PMID:Gradually glycosylated protein C mutants (Arg178Gln and Cys331Arg) are degraded by proteasome after mannose trimming. 1558 35

Cell-based vaccines consisting of invariant chain-negative tumor cells transfected with syngeneic MHC class II (MHC II) and costimulatory molecule genes are prophylactic and therapeutic agents for the treatment of murine primary and metastatic cancers. Vaccine efficacy is due to direct presentation of endogenously synthesized, MHC II-restricted tumor peptides to CD4+ T cells. Because the vaccine cells lack invariant chain, we have hypothesized that, unlike professional APC, the peptide-binding groove of newly synthesized MHC II molecules may be accessible to peptides, allowing newly synthesized MHC II molecules to bind peptides that have been generated in the proteasome and transported into the endoplasmic reticulum via the TAP complex. To test this hypothesis, we have compared the Ag presentation activity of multiple clones of TAP-negative and TAP-positive tumor cells transfected with I-Ak genes and the model Ag hen egg white lysozyme targeted to the endoplasmic reticulum or cytoplasm. Absence of TAP does not diminish Ag presentation of three hen egg white lysozyme epitopes. Likewise, cells treated with proteasomal and autophagy inhibitors are as effective APC as untreated cells. In contrast, drugs that block endosome function significantly inhibit Ag presentation. Coculture experiments demonstrate that the vaccine cells do not release endogenously synthesized molecules that are subsequently endocytosed and processed in endosomal compartments. Collectively, these data indicate that vaccine cell presentation of MHC II-restricted endogenously synthesized epitopes occurs via a mechanism independent of the proteasome and TAP complex, and uses a pathway that overlaps with the classical endosomal pathway for presentation of exogenously synthesized molecules.
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PMID:Presentation of endogenously synthesized MHC class II-restricted epitopes by MHC class II cancer vaccines is independent of transporter associated with Ag processing and the proteasome. 1569 7

In the attempt to develop a pre-embedding immunoelectron microscopic method with improved ultrastructral morphology, we examined an antigen retrieval (AR) method using citraconic anhydride, and compared the effects of glutaraldehyde fixation with routine paraformaldehyde fixation in the pre-embedding immunoelectron microscopic method with reference to the localization of surfactant-associated pro-protein C (proSP-C) in the lung. The glutaraldehyde-fixed tissues were immunostained after AR in 0.05% citraconic anhydride solution, pH 7.4, at 98 degrees C for 60 min. In routine pre-embedding immunoelectron microscopic method using paraformaldehyde fixation, proSP-C positive products were distributed sporadically in the type II alveolar epithelial cells. In glutaraldehyde-fixed tissues without the AR method, proSP-C products were not detected, however after AR in citraconic anhydride proSP-C positive products were distributed specifically, in rough endoplasmic reticulum membranes, Golgi complex membranes, multivesicular bodies and osmiophilic lamellar bodies. The positive proSP-C products also showed lattice-like structures in the alveoli. Thus, the present AR method provides successful pre-embedding immunoelectron microscopy of glutaraldehyde-fixed tissues.
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PMID:A new antigen retrieval method using citraconic anhydride for immunoelectron microscopy: localization of surfactant pro-protein C (proSP-C) in the type II alveolar epithelial cells. 1590 96

Diverse functions of 14-3-3 proteins are directly coupled to their ability to interact with targeted peptide substrates. RSX(pS/pT)XP and RXPhiX(pS/pT)XP are two canonical consensus binding motifs for 14-3-3 proteins representing the two common binding modes, modes I and II, between 14-3-3 and internal peptides. Using a genetic selection, we have screened a random peptide library and identified a group of C-terminal motifs, termed SWTY, capable of overriding an endoplasmic reticulum localization signal and redirecting membrane proteins to cell surface. Here we report that the C-terminal SWTY motif, although different from mode I and II consensus, binds tightly to 14-3-3 proteins with a dissociation constant (K(D)) of 0.17 microM, comparable with that of internal canonical binding peptides. We show that all residues but proline in -SWTX-COOH are compatible for the interaction and surface expression. Because SWTY-like sequences have been found in native proteins, these results support a broad significance of 14-3-3 interaction with protein C termini. The C-terminal binding consensus, mode III, represents an expansion of the repertoire of 14-3-3-targeted sequences.
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PMID:C-terminal recognition by 14-3-3 proteins for surface expression of membrane receptors. 1612 35

Dendritic cells (DC), uniquely among APC, express an open/empty conformation of MHC class II (MHC-II) proteins (correctly folded molecules lacking bound peptides). Generation and trafficking of empty HLA-DR during DC differentiation are investigated here. HLA-DR did not fold as an empty molecule in the endoplasmic reticulum/trans-Golgi network, did not derived from MHC/Ii complexes trafficking to the cell surface, but was generated after invariant chain degradation within lysosomal-like MHC-II rich compartments (MIIC). In pre-DC, generated from monocytes cultured in the presence of GM-CSF, Lamp-1(+)MHC-II(+) compartments are predominantly electron dense and, in these cells, empty MHC-II molecules accounts for as much as 20% of total surface HLA-DR. In immature DC, generated in presence of GM-CSF and IL-4, empty HLA-DR reside in multilamellar MIIC, but are scarcely observed at the cell surface. Thus, the morphology/composition of lysosomal MIIC at different DC maturational stages appear important for surface egression or intracellular retention of empty HLA-DR. Ag loading can be achieved for the fraction of empty HLA-DR present in the "peptide-receptive" form. Finally, in vivo, APC-expressing surface empty HLA-DR were found in T cell areas of secondary lymphoid organs.
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PMID:Conformational variation of surface class II MHC proteins during myeloid dendritic cell differentiation accompanies structural changes in lysosomal MIIC. 1621 May 95

Calcium homeostasis of the endoplasmic reticulum (ER) is involved in intracellular signaling pathways and is implicated in major cell functions such as cell growth, differentiation, protein synthesis and apoptosis. The accumulation of calcium in the ER is performed by specific sarco/endoplasmic reticulum calcium transport ATPases (SERCA iso-enzymes). The expression of biochemically distinct SERCA isoforms is cell type dependent and developmentally regulated. This review summarizes pertinent data about the modulation of the expression of SERCA enzymes during the differentiation of normal and tumor cells. These data support the implication of SERCA pumps and especially SERCA3 in the differentiation program of cancer and leukemia cells. During the multi-step process of colon carcinogenesis, the decrease of SERCA3 expression seems to be linked to enhanced APC/ss-catenin/TCF4 signaling and deficient Sp1-like factor-dependent transcription.
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PMID:[Expression of SERCA pumps during cell differentiation and tumorigenesis: application to colonic carcinogenesis]. 1712 48


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