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PubMed2005

An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior.

Dopamine plays an important role in the etiology of schizophrenia, and D2 class dopamine receptors are the best-established target of antipsychotic drugs. Here we show that D2 class-receptor-mediated Akt regulation involves the formation of signaling complexes containing beta-arrestin 2, PP2A, and Akt. beta-arrestin 2 deficiency in mice results in reduction of dopamine-dependent behaviors, loss of Akt regulation by dopamine in the striatum, and disruption of the dopamine-dependent interaction of Akt with its negative regulator, protein phosphatase 2A. Importantly, canonical cAMP-mediated dopamine-receptor signaling is not inhibited in the absence of beta-arrestin 2. These results demonstrate that, apart from its classical function in receptor desensitization, beta-arrestin 2 also acts as a signaling intermediate through a kinase/phosphatase scaffold. Furthermore, this function of beta-arrestin 2 is important for the expression of dopamine-associated behaviors, thus implicating beta-arrestin 2 as a positive mediator of dopaminergic synaptic transmission and a potential pharmacological target for dopamine-related psychiatric disorders.

Animals↗
PubMed1982

Immune complex-mediated lung injury produced by horseradish peroxidase (HRP) and anti-HRP antibodies in rats.

Horseradish peroxidase (HRP) was administered intratracheally to rats with circulating autologous or heterologous anti-HRP antibodies. Intrapulmonary immune complexes containing HRP, anti-HRP antibodies, but no C3, were detected by immunofluorescence from 1 hour to 48 hours with a maximum of 6 hours after antigenic challenge. The concomitant hemorrhagic alveolitis characterized by fibrin deposits and infiltration by polymorphs and macrophages was also maximal after 6 hours. At the ultrastructural level, HRP was easily detected, and HRP-containing immune deposits were demonstrated along the basement membrane in subepithelial and subendothelial localization and in interstitial spaces. These findings suggest a C3 independent mechanism for lung injury mediated by immune complexes formed in situ.

Animals↗
PubMed2005

The tyrosine 974 within the LIF-R-chain of the gp130/LIF-R heteromeric receptor complex mediates negative regulation of LIF signalling.

Signalling of interleukin (IL)-6 and interleukin-11 through gp130 homodimeric receptor complexes has been analysed with respect to initiation and termination of signalling in great detail. Gp130 contains a crucial motif around tyrosine Y759, which mediates negative regulation through the feedback inhibitor SOCS3 and the protein tyrosine phosphatase SHP2. Signalling of leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), CT-1-like factor (CLC) or oncostatin M (OSM) through gp130/LIF-R is believed to be similar due to the presence of the common signal transducer gp130 within the receptor complexes utilized, but the difference in the composition of gp130/gp130-homodimers and gp130/LIF-R-heterodimers is likely to be reflected in different signalling. Here, we analysed the contribution of the LIF-R within the gp130/LIF-R complex to negative regulation mediated by SHP2 and SOCS3. We show that SHP2 contributes to the negative regulation of signalling through gp130/LIF-R complexes. The inhibitory tyrosine motifs within the cytoplasmic parts of gp130 and the LIF-R act independently. Whereas SHP2 and SOCS3 bind directly to the inhibitory motif of gp130, only SHP2 was found to bind to the corresponding inhibitory sequence of the LIF-R. This observation was further corroborated by experiments indicating that mainly gp130 contributes to the inhibition of signalling by SOCS3.

Amino Acid Motifs↗
PubMed2002

Genome-wide multilocus analysis for immune-mediated complex diseases.

In postgenomic era, searching and identification of disease genes associated with complex diseases are still one of the great challenge for dissecting human complex diseases. To improve the disease gene localization for complex diseases, a group of closely immune-mediated disease loci were overlapped on each chromosome based on previously reported genome-wide scanning data. Interestingly, five overlapping chromosomal regions (1q21, 2q33, 5q31.1-q33.1, 6p21, and 11q13) were identified by co-localizing disease loci for the following diseases: diabetes, asthma, atopic dermatitis, osteoporosis, and inflammatory bowel disease. The development of specific disease was associated with different combinations of disease loci among five overlapped chromosomal regions. Therefore, the analysis of multiple genetic loci should be considered to determine the effects of multiple genes responsible for complex diseases resulting from the influence of multiple genes.

Chromosome Mapping↗
PubMed1993

Arthritis in Mediterranean spotted fever. An immune complex mediated synovitis.

Arthromyalgia are frequent in Mediterranean spotted fever (MSF) (16-76%) but arthritis is rare. We report on a 54-year-old woman who, 1 day after suffering from fever, headache and malaise, developed a painful and swollen left knee. A maculopapular rash and the characteristic 'tache noire' skin lesion appeared 5 days later. Immune complexes were detected in serum and in the SF and normalized following improvement of clinic manifestations. These findings along with a low C3 complement level in the SF suggest that arthritis was mediated by immune complex deposits.

Antigen-Antibody Complex↗
PubMed1992

The habenular complex mediates hormonal stimulation of maternal behavior in rats.

The role of the habenular complex (Hbc) in the hormonal onset and nonhormonal maintenance of maternal behavior in rats was examined. In Experiment 1, bilateral lesions were produced in the Hbc on Gestational Day (GD) 12. On GD 16, animals were hysterectomized-ovariectomized and given estradiol benzoate (EB); they were then tested for maternal behavior 48 hr later. Hbc lesions delayed the appearance of all components of maternal behavior for several days. In Experiment 2, large Hbc lesions that were produced on Postpartum Day 4 caused only 1- or 2-day deficits in maternal behavior. These data suggest that the Hbc mediates the hormonal onset of maternal behavior. During the postpartum period, however, the importance of the Hbc for maternal behavior diminishes as the hormones of pregnancy become less important.

Animals↗
PubMed1991

Decreased expression of decay-accelerating factor on endothelial cells of immune complex-mediated vasculitic skin lesions.

Endothelial cells may be damaged directly by the membrane attack complex of complement in immune complex vasculitis of the skin. However, for endothelial cell membrane injury to occur, normal regulatory mechanisms must fail. One of the main complement regulatory proteins of endothelial cells is decay-accelerating factor, a surface protein which interferes with either the classical or alternative pathway C3 and C5 convertases. We have investigated the expression of decay-accelerating factor in 4 patients with histologically proven cutaneous immune complex vasculitis, using an immuno-electronmicroscopic technique. We demonstrated that endothelial cells of upper dermal vessels in vasculitic lesions were almost completely devoid of decay-accelerating factor. By contrast, the expression of this protein on endothelial cells in uninvolved skin of the patients was the same as in skin of healthy volunteers. As yet, the mechanism responsible for depletion of decay-accelerating factor is not clear. Absence of decay-accelerating factor may follow enzymatic release from the phosphatidylinositol anchor, proteolytic stripping from the cell membrane or a down-regulation of decay-accelerating factor synthesis. Regardless of mechanism, endothelial cell injury or death could serve a phlogistic function to facilitate complement-mediated destruction of endothelial cells for removal and repair.

Adolescent↗
PubMed1998

The LIN-2/LIN-7/LIN-10 complex mediates basolateral membrane localization of the C. elegans EGF receptor LET-23 in vulval epithelial cells.

In C. elegans, the LET-23 receptor tyrosine kinase is localized to the basolateral membranes of polarized vulval epithelial cells. lin-2, lin-7, and lin-10 are required for basolateral localization of LET-23, since LET-23 is mislocalized to the apical membrane in lin-2, lin-7, and lin-10 mutants. Yeast two-hybrid, in vitro binding, and in vivo coimmunoprecipitation experiments show that LIN-2, LIN-7, and LIN-10 form a protein complex. Furthermore, compensatory mutations in lin-7 and let-23 exhibit allele-specific suppression of apical mislocalization and signaling-defective phenotypes. These results present a mechanism for basolateral localization of LET-23 receptor tyrosine kinase by direct binding to the LIN-2/LIN-7/LIN-10 complex. Each of the binding interactions within this complex is conserved, suggesting that this complex may also mediate basolateral localization in mammals.

Animals↗
PubMed1989

Immune-complexes-mediated evasion of Plasmodium knowlesi from destruction by macrophages.

The role of immune-complexes in the evasion of Plasmodium knowlesi from destruction by macrophages was studied in vitro. Incubation of macrophages with immune-complexes, prepared either by mixing total parasite antigens soluble in culture medium with normal or immune monkey serum, or by polyethylene glycol precipitation of serum from monkeys acutely infected with P. knowlesi, significantly reduced both the pool size of the macrophages that bound parasitized erythrocytes, and the number of parasitized erythrocytes bound per macrophage. Parasitized erythrocytes with mature schizonts were invariably preferred over those containing rings. These observations appear to indicate that during P. knowlesi infection in rhesus monkeys, immune-complexes may inhibit the binding of parasitized erythrocytes with mononuclear phagocytes and thus may enable them to evade the destructive mechanisms mounted by the host.

Animals↗
PubMed2002

Protein complexes mediate signalling in plant responses to hormones, light, sucrose and pathogens.

Living organisms use complex pathways of signal perception and transduction to respond to stimuli in their environments. In plants, putative signal transduction components have been identified through mutant screens and comparative analysis of genome sequences of model eukaryotes. Several pieces in a large series of puzzles have now been identified and a current challenge is to determine how these pieces interconnect. Functional analysis of the encoded proteins has necessitated a change from genetic to biochemical approaches. In recent years, the application of techniques such as two-hybrid screening and epitope tagging has facilitated the study of protein-protein interactions and has increased our understanding of cellular signalling mechanisms. One focus of present research is the ubiquitin/proteasome-mediated degradation of proteins. Increasing evidence suggests this is a control common to many plant signalling pathways including development and responsiveness to hormones, light and sucrose. A central challenge in the study of plant disease resistance has been to identify protein complexes that contain host defence proteins and pathogenicity factors. In this review we summarize the latest developments in these areas where the existence of protein complexes has been demonstrated to be of fundamental importance in plant signalling.

Bacteria↗
PubMed2006

The Cdc34/SCF ubiquitination complex mediates Saccharomyces cerevisiae cell wall integrity.

To identify novel functions for the Cdc34/SCF ubiquitination complex, we analyzed genomewide transcriptional profiles of cdc53-1 and cdc34-2 Saccharomyces cerevisiae mutants. This analysis revealed altered expression for several gene families, including genes involved in the regulation of cell wall organization and biosynthesis. This led us to uncover a role for the Cdc34/SCF complex in the regulation of cell wall integrity. In support of this, cdc53-1 and cdc34-2 mutants exhibit phenotypes characteristic of cell wall integrity mutants, such as SDS sensitivity and temperature-sensitive suppression by osmotic stabilizers. Examination of these mutants revealed defects in their induction of Slt2 phosphorylation, indicating defects in Pkc1-Slt2 MAPK signaling. Consistent with this, synthetic genetic interactions were observed between the genes encoding the Cdc34/SCF complex and key components of the Pck1-Slt2 MAPK pathway. Further analysis revealed that Cdc34/SCF mutants have reduced levels of active Rho1, suggesting that these defects stem from the deregulated activity of the Rho1 GTPase. Altering the activity of Rho1 via manipulation of the Rho1-GAPs LRG1 or SAC7 affected Cdc34/SCF mutant growth. Strikingly, however, deletion of LRG1 rescued the growth defects associated with Cdc34/SCF mutants, whereas deletion of SAC7 enhanced these defects. Given the differential roles that these GAPs play in the regulation of Rho1, these observations indicate the importance of coordinating Cdc34/SCF activity with specific Rho1 functions.

Anaphase-Promoting Complex-Cyclosome↗
PubMed1990

The complement SC5b-9 complex mediates cell adhesion through a vitronectin receptor.

Adhesion of cells to the terminal complement complex of C5b through C9 containing the serum S-protein (SC5b-9) was investigated using a microtiter plate attachment assay with L8 myoblast indicator cells. The skeletal muscle-derived L8 myoblasts bound and spread on substratum coated with SC5b-9, and with the vitronectin/S-protein component of SC5b-9. The myoblasts did not adhere to substratum coated with collagen, laminin, or fibronectin. The cell attachment was blocked by antibody to vitronectin/S-protein, whereas antibody to the other components C5, C6, C7, C8, or C9 had minimal effect. The cells were not bound to free vitronectin because attachment activity was removed by adsorption with an anti-C6 antibody column. The L8 cell attachment was dependent on divalent cations, was blocked by synthetic peptides containing the amino acid sequence Arg-Gly-Asp, and was inhibited by antivitronectin receptor antibody. These results indicate that cells adhere to the SC5b-9 complex through interaction of the vitronectin component with an integrin vitronectin receptor. Cell attachment to terminal C complexes could be used for leukocyte adherence and migration during inflammation, and also for attachment of tissue cells during regeneration after disease or traumatic injury.

Animals↗
PubMed2003

Haematopoietic lineage cell-specific protein 1 (HS1) promotes actin-related protein (Arp) 2/3 complex-mediated actin polymerization.

HS1 (haematopoietic lineage cell-specific gene protein 1), a prominent substrate of intracellular protein tyrosine kinases in haematopoietic cells, is implicated in the immune response to extracellular stimuli and in cell differentiation induced by cytokines. Although HS1 contains a 37-amino acid tandem repeat motif and a C-terminal Src homology 3 domain and is closely related to the cortical-actin-associated protein cortactin, it lacks the fourth repeat that has been shown to be essential for cortactin binding to filamentous actin (F-actin). In this study, we examined the possible role of HS1 in the regulation of the actin cytoskeleton. Immunofluorescent staining demonstrated that HS1 co-localizes in the cytoplasm of cells with actin-related protein (Arp) 2/3 complex, the primary component of the cellular machinery responsible for de novo actin assembly. Furthermore, recombinant HS1 binds directly to Arp2/3 complex with an equilibrium dissociation constant (K(d)) of 880 nM. Although HS1 is a modest F-actin-binding protein with a K(d) of 400 nM, it increases the rate of the actin assembly mediated by Arp2/3 complex, and promotes the formation of branched actin filaments induced by Arp2/3 complex and a constitutively activated peptide of N-WASP (neural Wiskott-Aldrich syndrome protein). Our data suggest that HS1, like cortactin, plays an important role in the modulation of actin assembly.

Actin-Related Protein 2↗
PubMed1995

The MIM complex mediates preprotein translocation across the mitochondrial inner membrane and couples it to the mt-Hsp70/ATP driving system.

We have identified a complex in mitochondria that functions as a part of the preprotein import machinery of the inner membrane (MIM complex). Two known components, MIM23 and MIM17, and two novel components, MIM33 and MIM14, were found as constituents of this complex. In the presence of a translocating chain, the outer membrane import machinery (MOM complex) and the MIM complex form translocation contact sites. On the matrix side, the MIM complex is associated with the mt-Hsp70-MIM44 system. We propose a structure of the import machinery in which the MIM complex constitutes a proteinaceous channel that accepts preproteins from the MOM complex, facilitates their reversible transmembrane movement, and mediates unidirectional transport by linkage to the ATP-dependent mt-Hsp70-MIM44 system.

Adenosine Triphosphate↗
PubMed2005

Transmembrane interaction mediates complex formation between peptidase homologues and Kv4 channels.

An asthma-related peptidase homologue (DPP10) may act as an auxiliary subunit of Kv4 channels, similar to DPPX. Here we show that DPP10 preferentially binds to Kv4 channel proteins to increase current density and alter channel gating. DPP10 also forms complexes by themselves and with DPPX in the absence of Kv4 channels. DPP10 mRNA is abundantly expressed in nodose and dorsal root ganglia, suggesting that DPP10 participates in controlling airway reactivity and mechanosensation. The region from the N-terminus to the end of the transmembrane of DPP10 mediates its association with the channel, whereas the S1-S2 portion of the channel is sufficient for complex formation. This N-terminal portion of DPP10 also confers all the gating effects produced by the peptidase homologue. Thus, interaction between transmembranes of DPP10/DPPX and Kv4 channel mediates functional complex formation. We call this protein DPPY, instead of DPP10, because of its revealed role as a Kv4 channel regulator.

Alternative Splicing↗
PubMed2001

Direct evidence for a ruthenium(IV) oxo complex-mediated oxidation of a hydroxamic acid in the presence of phosphine oxide donors.

Ruthenium(II) complexes can be used to oxidise N-Boc hydroxylamine the the presence of tert-butylhydroperoxide to the corresponding nitroso dienophile, which is trapped using cyclohexa-1,3-diene as the hetero-Diels-Alder adduct; direct evidence has been obtained for the intervention of a triphenylphosphine oxide-stabilised ruthenium(IV) oxocomplex as the catalytically active species.

Journal Article↗
PubMed2004

Countercurrent distribution of two distinct SNARE complexes mediating transport within the Golgi stack.

Genetic and biochemical evidence has established that a SNARE complex consisting of syntaxin 5 (Sed5)-mYkt6 (Ykt6)-GOS28 (Gos1)-GS15 (Sft1) is required for transport of proteins across the Golgi stack in animals (yeast). We have utilized quantitative immunogold labeling to establish the cis-trans distribution of the v-SNARE GS15 and the t-SNARE subunits GOS28 and syntaxin 5. Whereas the distribution of the t-SNARE is nearly even across the Golgi stack from the cis to the trans side, the v-SNARE GS15 is present in a gradient of increasing concentration toward the trans face of the stack. This contrasts with a second distinct SNARE complex, also required for intra-Golgi transport, consisting of syntaxin 5 (Sed5)-membrin (Bos1)-ERS24 (Sec22)-rBet1 (Bet1), whose v-(rBet1) and t-SNARE subunits (membrin and ERS24), progressively decrease in concentration toward the trans face. Transport within the stack therefore appears to utilize countercurrent gradients of two Golgi SNAREpins and may involve a mechanism akin to homotypic fusion.

Animals↗
PubMed1989

Immune complex mediated activation of the classical complement pathway.

The activation of classical C pathway by immune complexes depends on the binding and activation of C1, the first component of C. The Ig in the complex must be of the right class and in the right configuration to accomplish the conversion of precursor (zymogen) C1s to C1s, the active enzyme, whose substrates are C4 and C2. The primary question discussed in this paper is evidence that indicates that epitope distribution and density is a major factor in controlling the configuration of antibodies which in turn controls the activation of bound C1. This evidence confirms earlier findings that binding of C1 is a necessary but not sufficient condition for activating C1.

Animals↗