Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of increased and disorganized bone turnover. Genetic factors are important in the pathogenesis of PDB, and in previous studies, we and others identified a locus for familial PDB by genome-wide search on 5q35-qter (PDB3). The gene encoding sequestosome 1 (SQSTM1/p62) maps to within the PDB3 critical region, and recent studies have identified a proline-leucine amino acid change at codon 392 of SQSTM1 (P392L) in French-Canadian patients with PDB. We conducted mutation screening of positional candidate genes in the PDB3 locus in patients with PDB, and also identified mutations in the gene encoding SQSTM1 as a common cause of familial and sporadic PDB. Three different mutations were found, all affecting the highly conserved ubiquitin-binding domain. The most common mutation was the P392L change in exon 8, which was found in 13 of 68 families (19.1%). Another mutation-a T insertion that introduces a stop codon at position 396 in exon 8-was found in four (5.8%) families. A third mutation affecting the splice donor site in intron 7 was found in one (1.5%) family. The P392L mutation was also found in 15 of 168 (8.9%) of patients with sporadic PDB and 0 of 160 of age- and sex-matched controls (P<0.0001). These studies confirm that mutations affecting the ubiquitin-binding domain of SQSTM1 are a common cause of familial and sporadic Paget's disease of bone.
Hum Mol Genet 2002 Oct 15
PMID:Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. 1237 63

Recent results showed the critical role of the mammalian p62-atypical protein kinase C (aPKC) complex in the activation of NF-kappaB in response to different stimuli. Here we demonstrate using the RNA interference technique on Schneider cells that the Drosophila aPKC (DaPKC) is required for the stimulation of the Toll-signaling pathway, which activates the NF-kappaB homologues Dif and Dorsal. However, DaPKC does not appear to be important for the other Drosophila NF-kappaB signaling cascade, which activates the NF-kappaB homologue Relish in response to lipopolysaccharides. Interestingly, DaPKC functions downstream of the nuclear translocation of Dorsal or Dif, controlling the transcriptional activity of the Drosomycin promoter. We also show that the Drosophila Ref(2)P protein is the homologue of mammalian p62 as it binds to DaPKC, its overexpression is sufficient to activate the Drosomycin but not the Attacin promoter, and its depletion severely impairs Toll signaling. Collectively, these results demonstrate the conservation of the p62-aPKC complex for the control of innate immunity signal transduction in Drosophila melanogaster.
Mol Cell Biol 2002 Dec
PMID:The Drosophila atypical protein kinase C-ref(2)p complex constitutes a conserved module for signaling in the toll pathway. 1244 95

Maximal activation of NADPH oxidase requires formation of a complex between the p40(phox) and p67(phox) subunits via association of their PB1 domains. We have determined the crystal structure of the p40(phox)/p67(phox) PB1 heterodimer, which reveals that both domains have a beta grasp topology and that they bind in a front-to-back arrangement through conserved electrostatic interactions between an acidic OPCA motif on p40(phox) and basic residues in p67(phox). The structure enabled us to identify residues critical for heterodimerization among other members of the PB1 domain family, including the atypical protein kinase C zeta (PKC zeta) and its partners Par6 and p62 (ZIP, sequestosome). Both Par6 and p62 use their basic "back" to interact with the OPCA motif on the "front" of the PKC zeta. Besides heterodimeric interactions, some PB1 domains, like the p62 PB1, can make homotypic front-to-back arrays.
Mol Cell 2003 Jul
PMID:PB1 domain-mediated heterodimerization in NADPH oxidase and signaling complexes of atypical protein kinase C with Par6 and p62. 1288 91

Splicing of the Saccharomyces cerevisiae mitochondrial DNA group II intron aI2 depends on the intron-encoded 62-kDa reverse transcriptase-maturase protein (p62). In wild-type strains, p62 remains associated with the excised intron lariat RNA in ribonucleoprotein (RNP) particles that are essential for intron homing. Studies of a bacterial group II intron showed that the DIVa substructure of intron domain IV is a high-affinity binding site for its maturase. Here we first present in vitro evidence extending that conclusion to aI2. Then, experiments with aI2 DIVa mutant strains show that the binding of p62 to DIVa is not essential for aI2 splicing in vivo but is essential for homing. Because aI2 splicing in the DIVa mutant strains remains maturase dependent, splicing must rely on other RNA-protein contacts. The p62 that accumulates in the mutant strains has reverse transcriptase activity, but fractionation experiments at high and low salt concentrations show that it associates more weakly than the wild-type protein with endogenous mitochondrial RNAs, and that phenotype probably explains the homing defect. Replacing the DIVa of aI2 with that of the closely related intron aI1 improves in vivo splicing but not homing, indicating that DIVa contributes to the specificity of the maturase-RNA interaction needed for homing.
Mol Cell Biol 2003 Dec
PMID:The DIVa maturase binding site in the yeast group II intron aI2 is essential for intron homing but not for in vivo splicing. 1461 20

The nuclear transport of the internalised naER is influenced by a 58 kDa protein, p58, that appears to recognize the nuclear localization signals on the naER. At the nuclear pore complex the naER-p58 complex binds to a 62 kDa protein, p62; p58 recognizes p62 in this interaction. It is further observed that p62 gets 'docked' at a 66 kDa nuclear pore complex protein, npcp66. The nuclear entry of naER is an ATP-dependent process. An ATP-dependent biphasic nuclear entry of naER, has been observed. It is possible that the docking of p58-naER complex at the nuclear pore complex and the eventual nuclear entry of naER following its dissociation from the p58 are influenced by two different ranges in the concentration of ATP. In this process, it appears that, the nuclear entry requires an additional quantum of energy, provided by the hydrolysed ATP, in contrast to the energy requirement associated with, the nuclear 'docking' event.
Mol Cell Biochem 2004 Apr
PMID:Proteins which mediate the nuclear entry of goat uterine non activated estrogen receptor (naER) following naER internalization from the plasma membrane. 1512 17

The nuclear envelope (NE) is one of many intracellular targets of the autoimmune response in patients with autoimmune liver disease, systemic lupus erythematosus, and related conditions. In eukaryotic organisms the NE consists of five interconnected regions: an outer nuclear membrane (ONM) that is continuous with the endoplasmic reticulum, an intermembrane or perinuclear space, an inner nuclear membrane (INM) with a unique set of integral membrane proteins, the underlying nuclear lamina, and the pore domains that are regions where the ONM and INM come together. The pore domains are sites of regulated continuity between the cytoplasm and nucleus that are occupied by supramolecular structures, termed nuclear pore complexes (NPCs). Human autoantibodies identified to date bind to specific components in three of the five NE compartments. Autoantigen targets include the lamins A, B, and C of the nuclear lamina, gp210, p62 complex proteins, Nup153, and Tpr within the NPC, and LBR, MAN1, LAP1, and LAP2 that are integral proteins of the INM. Autoantibodies to these NE targets have been shown to be correlated with various autoimmune diseases such as primary biliary cirrhosis, other autoimmune liver diseases and systemic rheumatic diseases. Now that the proteome of the NE is more clearly defined, other autoantibodies to components in this cell compartment are likely to be defined.
J Mol Med (Berl) 2004 Jul
PMID:Autoantigens of the nuclear pore complex. 1517 62

The human general transcription factor TFIIH is involved in both transcription and DNA repair. We have identified a structural domain in the core subunit of TFIIH, p62, which is absolutely required for DNA repair activity through the nucleotide excision repair pathway. Using coimmunoprecipitation experiments, we showed that this activity involves the interaction between the N-terminal domain of p62 and the 3' endonuclease XPG, a major component of the nucleotide excision repair machinery. Furthermore, we reconstituted a functional TFIIH particle with a mutant of p62 lacking the N-terminal domain, showing that this domain is not required for assembly of the TFIIH complex and basal transcription. We solved its three-dimensional structure and found an unpredicted pleckstrin homology and phosphotyrosine binding (PH/PTB) domain, uncovering a new class of activity for this fold.
Nat Struct Mol Biol 2004 Jul
PMID:TFIIH contains a PH domain involved in DNA nucleotide excision repair. 1522 Oct 21

1. Exposure of PC12 cells to nerve growth factor (NGF) induces an early tyrosine phosphorylation of many proteins, a number of which is still unidentified. Although NGF is known to bind to and activate the receptor tyrosine kinase TrkA, many downstream targets of NGF signaling may be possibly phosphorylated by nonreceptor tyrosine kinases such as c-Src and focal adhesion kinase (FAK). 2. In the present study, exposure of TrkA-overexpressing PC12 cells to NGF is found to cause a rapid and sustained loss in the recovery of a subpopulation of nominally active FAK (i.e., being autophosphorylated on the positive site of regulation). 3. Consistent with the possibility that NGF induces the proteolysis of FAK via recruitment of Src family kinases, the use of various phosphorylation site-specific anti-FAK antibodies revealed an NGF-inducible and PP1-sensitive accumulation of a putative fragment (i.e., p62) of FAK. Significantly, the mitogenic epidermal growth factor (EGF) failed to induce the downregulation of FAK and the accumulation of tyrosine phosphorylated p62. Such differential response of FAK to NGF and EGF may shape the specificity by which these growth factors control the status of cell-matrix adhesion and the adhesion-driven signaling.
Cell Mol Neurobiol 2004 Jun
PMID:Nerve growth factor (NGF) induces a rapid and sustained downregulation of the focal adhesion kinase (FAK). 1520 25

Herein, we demonstrate that the ubiquitin-associated (UBA) domain of sequestosome 1/p62 displays a preference for binding K63-polyubiquitinated substrates. Furthermore, the UBA domain of p62 was necessary for aggregate sequestration and cell survival. However, the inhibition of proteasome function compromised survival in cells with aggregates. Mutational analysis of the UBA domain reveals that the conserved hydrophobic patch MGF as well as the conserved leucine in helix 2 are necessary for binding polyubiquitinated proteins and for sequestration-aggregate formation. We report that p62 interacts with the proteasome by pull-down assay, coimmunoprecipitation, and colocalization. Depletion of p62 levels results in an inhibition of ubiquitin proteasome-mediated degradation and an accumulation of ubiquitinated proteins. Altogether, our results support the hypothesis that p62 may act as a critical ubiquitin chain-targeting factor that shuttles substrates for proteasomal degradation.
Mol Cell Biol 2004 Sep
PMID:Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. 1534 68

p62 is a scaffolding protein that binds to polyubiquitin. It is involved in the degradation of proteins by the proteasome. To determine if p62 is critical in the development of Mallory bodies (MBs), primary culture hepatocytes from drug-primed mice were studied and the results were compared with normal hepatocytes. Gene-specific gripNA (gp62) was added to the medium of the primary cultures of the hepatocytes to inhibit the expression of p62. Overexpression of p62 was achieved by transfecting the hepatocytes with a plasmid containing green fluorescent protein (GFP) fused p62 (p62-GFP). Gp62 dramatically inhibited MB formation by 94% in drug-primed hepatocytes. The cells transfected with gp62 had decreased protein levels of p62, ubiquitin (Ub), and cytokeratin 8 (CK8). Overexpression of p62 accelerated and enhanced MB formation by 339% in drug-primed hepatocytes. Overexpression of p62 in normal mouse hepatocytes induced MB-like aggresomes that were stained by Ub but not by CK8. The results indicate that p62 is involved in the mechanism of MB formation.
Exp Mol Pathol 2004 Dec
PMID:p62 is involved in the mechanism of Mallory body formation. 1550 32


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