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PubMedDate not supplied

Cystic diseases of the kidney: role of adhesion molecules in normal and abnormal tubulogenesis.

This short review summarizes some information concerning what is known about matrix adhesion molecules, focal adhesion proteins, and cell-cell adhesion molecules in normal renal development and cystic diseases of the kidney. The focus is on human nephrogenesis and disease, but utilizes critical information gained from genetically manipulated mouse models. Interestingly, a significant role for the human PKD-1-encoded gene product, polycystin-1, has been found in cell-matrix interactions via integrins during development, and mutations lead to autosomal dominant polycystic kidney disease (ADPKD). Recent studies on human ADPKD have implicated polycystin-1 in the formation of multiprotein complexes containing focal adhesion proteins at the basal cell surface of the normal ureteric bud. Further evidence of a critical role of cell-matrix interactions via focal adhesion complex formation is provided by the development of renal cystic disease in tensin knockout mice.

Animals↗

PubMedDate not supplied

Diversity of G protein-coupled receptor signaling pathways to ERK/MAP kinase.

One of the most intriguing examples of cross talk between signaling systems is the interrelationship between G protein-coupled receptor and growth factor receptor pathways leading to activation of the ERK/MAP kinase phosphorylation cascade. This review focuses on the mechanism of this cross talk, denoting primarily signaling components known to occur in the G protein-coupled receptor branch of the MAP kinase pathways in neural cells. Recent evidence is presented on the existence of a plethora of pathways, due to the multiplicity of G protein-coupled receptors, their differential interaction with heterotrimeric G protein isoforms, various effectors and second messengers. In light of this rich diversity, the review will discuss different points of convergence of G protein-coupled receptor and growth factor receptor pathways that may feature a requirement for growth factor receptor transactivation, receptor internalization and scaffolds to assemble receptor, adaptor and anchoring proteins into multiprotein complexes.

Animals↗

PubMed2002

Role of the PDZ scaffolding protein in tubule cells in maintenance of polarised function.

Polarized tubule epithelial cell functions are dependent on correct delivery of effector proteins to the target apical or basolateral plasma membrane and associated cortical cytoskeleton. PDZ (Postsynaptic density protein 95/Drosophila Disks large/Zona occludens-1) domain-containing proteins have been identified as playing a critical role in membrane trafficking and sorting of ion transporters, receptors and other signalling proteins. These scaffolding proteins coordinate the assembly of functional plasma membrane multiprotein complexes, through PDZ domain binding to a consensus amino acid motif within the carboxyl-terminus of target proteins. The organization of these proteins into submembranous complexes may facilitate downstream signalling. Although several epithelial PDZ proteins that bind to a number of important mammalian proteins have been isolated, in many cases the significance of these interactions is unclear. However, the epithelial PDZ domain-containing Na(+)/H(+) exchanger regulatory factor tethers the Na(+)/H(+) exchanger and cystic fibrosis transmembrane regulator Cl(-) channel within an apical plasma membrane signalling complex, and has been shown to regulate the activity of these proteins. This article reviews the current evidence that supports a central role for the PDZ protein in the regulation of polarized tubule cell functions, such as vectorial solute transport.

Animals↗

PubMed2006

Gamma-secretase modulation with Abeta42-lowering nonsteroidal anti-inflammatory drugs and derived compounds.

The amyloid-beta (Abeta) peptides and specifically the highly amyloidogenic isoform Abeta42 appear to be key agents in the pathogenesis of familial and sporadic forms of Alzheimer's disease (AD). The final step in the generation of Abeta from the amyloid precursor protein is catalyzed by the multiprotein complex gamma-secretase, which constitutes a prime drug target for prevention and therapy of the disease. However, highly potent gamma-secretase inhibitors that block formation of all Abeta peptides have provoked troubling side effects in preclinical animal models of AD. This toxicity can be readily explained by the promiscuous substrate specificity of gamma-secretase and its essential role in the NOTCH signaling pathway. For that reason and because of the crucial role of Abeta42 in the pathogenesis of the disease, selective inhibition of Abeta42 production would seem to be a more promising alternative to complete inhibition of gamma-secretase activity. This theoretical concept has edged much closer to clinical reality with the surprising finding that certain nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, and derived compounds display preferential Abeta42-lowering activity. In contrast to gamma-secretase inhibitors, these gamma-secretase modulators effectively suppress Abeta42 production while sparing processing of NOTCH and other gamma-secretase substrates. Although not fully resolved on the molecular level, the mechanism of action of Abeta42-lowering NSAIDs is independent of cyclooxygenase inhibition and most likely involves direct interaction with components of the gamma-secretase complex or its substrates. Current efforts to improve the pharmacological shortcomings of available gamma-secretase modulators will hopefully lead to the development of clinically useful Abeta42-lowering compounds in the near future.

Alzheimer Disease↗

PubMed1992

A sequence-specific DNA-binding protein recognising a GA-rich element cooperates with Oct-1 at the herpes simplex virus type 1 IE3 promoter.

Herpes simplex virus immediate early (IE) gene transcription is regulated via the upstream TAATGARAT motif and involves the recruitment of the ubiquitous octamer-binding protein Oct-1 and a component of the virion Vmw65 into a multiprotein complex termed the immediate early complex (IEC). An upstream GA-rich element (GA-RE) has been postulated to mediate a response to Vmw65 independent of TAATGARAT. We have studied IEC formation in gel shift assays using DNA fragments containing these sequence elements from the HSV-1 IE gene 3 promoter in different combinations. The results show that a factor which footprints to the GA-RE cooperates with Oct-1 to increase IEC levels on a TAATGARAT motif located 5 bp 5' to the GA-RE. The factor alone is unable to promote IEC formation. We were unable to demonstrate any effect of this factor on a TAATGARAT motif located 16 bp from the GA-RE, suggesting that this effect is not universal for all TAATGARAT motifs.

Base Composition↗

PubMed1996

Regulation of tissue factor gene expression in human monocytic and endothelial cells.

Tissue factor (TF) is inducibly expressed within the vasculature by monocytes and endothelial cells. Transcriptional activation of the TF gene in these two cell types by bacterial lipopolysaccharide (LPS) or cytokines appears to be regulated by a common mechanism. Functional studies identified a 56-bp LPS response element which contains two AP-1 sites and a kappaB site. Assembly of a multiprotein complex composed of Fos-Jun and c-Rel-p65 heterodimers is required to induce TF gene transcription. Inhibiting proteolytic degradation of IkappaBalpha prevents nuclear translocation of c-Rel-p65 heterodimers and blocks inducible TF expression in monocytic and endothelial cells.

Base Sequence↗

PubMed2003

Organelle proteomics: implications for subcellular fractionation in proteomics.

Functional proteome analysis is not restricted to the sequence information but includes the broad spectrum of structural modifications and quantitative changes of proteins to which they are subjected in different tissues and cell organelles and during the development of an organism. Cell biology has provided the means required for the analysis of the composition and properties of purified cellular elements. Subcellular fractionation is an approach universal across all cell types and tissues, including cardiac and vascular system. Subcellular fractionation and proteomics form an ideal partnership when it comes to enrichment and analysis of intracellular organelles and low abundant multiprotein complexes. Subcellular fractionation is a flexible and adjustable approach resulting in reduced sample complexity and is most efficiently combined with high-resolution 2D gel/mass spectrometry analysis as well as with gel-independent techniques. In this study we introduce state of the art subcellular fractionation techniques and discuss their suitability, advantages, and limitations for proteomics research.

Animals↗

PubMed2005

H11 kinase prevents myocardial infarction by preemptive preconditioning of the heart.

Ischemic preconditioning confers powerful protection against myocardial infarction through pre-emptive activation of survival signaling pathways, but it remains difficult to apply to patients with ischemic heart disease, and its effects are transient. Promoting a sustained activation of preconditioning mechanisms in vivo would represent a novel approach of cardioprotection. We tested the role of the protein H11 kinase (H11K), which accumulates by 4- to 6-fold in myocardium of patients with chronic ischemic heart disease and in experimental models of ischemia. This increased expression was quantitatively reproduced in cardiac myocytes using a transgenic (TG) mouse model. After 45 minutes of coronary artery occlusion and reperfusion, hearts from TG mice showed an 82+/-5% reduction in infarct size compared with wild-type (WT), which was similar to the 84+/-4% reduction of infarct size observed in WT after a protocol of ischemic preconditioning. Hearts from TG mice showed significant activation of survival kinases participating in preconditioning, including Akt and the 5'AMP-activated protein kinase (AMPK). H11K directly binds to both Akt and AMPK and promotes their nuclear translocation and their association in a multiprotein complex, which results in a stimulation of survival mechanisms in cytosol and nucleus, including inhibition of proapoptotic effectors (glycogen synthase kinase-3beta, Bad, and Foxo), activation of antiapoptotic effectors (protein kinase Cepsilon, endothelial and inducible NO synthase isoforms, and heat shock protein 70), increased expression of the hypoxia-inducible factor-1alpha, and genomic switch to glucose utilization. Therefore, activation of survival pathways by H11K preemptively triggers the antiapoptotic and metabolic response to ischemia and is sufficient to confer cardioprotection in vivo equally potent to preconditioning.

AMP-Activated Protein Kinases↗

PubMed2006

Single supramolecule spectroscopy of natural and alkaline-treated chlorosomes from green sulfur photosynthetic bacteria.

Fluorescence emission properties of intact and alkaline-treated chlorosomes containing bacteriochlorophyll(BChl)-c, d, and e, which were isolated from four species of green sulfur photosynthetic bacteria, were successfully studied at the single-unit level using a total internal reflection fluorescence microscope. Single intact chlorosomes containing BChl-c from Chlorobium (Chl.) tepidum exhibited heterogeneous emission bands of BChl-c self-aggregates. In contrast, fluorescence spectra of chlorosomal BChl self-aggregates in single intact chlorosomes from the other three Chlorobium species were less heterogeneous than those from Chi. tepidum. Removal of energy-accepting BChl-a/protein complexes called baseplates from the intact chlorosomes by treatments with alkaline media hardly changed spectral shapes of BChl aggregates and their peak distributions at the single-chlorosome level. The similarity of spectral properties at the single-unit level between intact and alkaline-treated chlorosomes of four Chlorobium species clearly indicated that the removal of base-plates from intact chlorosomes by the alkaline-treatment did not affect BChl self-aggregates inside single chlorosomes.

Alkalies↗

PubMed2003

Pinin/DRS/memA interacts with SRp75, SRm300 and SRrp130 in corneal epithelial cells.

PURPOSE: Pinin (Pnn/DRS/memA) is a cell-adhesion-related and nuclear protein that has been identified as central in the establishment and maintenance of corneal epithelial cell-cell adhesion. To begin the elucidation of the role of Pnn within the nucleus of corneal epithelial cells, this study was undertaken to identify the proteins that bind to Pnn. METHODS: Yeast two-hybrid analyses were performed. A human cDNA library in the pGAD-10 vector and C-terminal region of human Pnn (465-717) in a pAS2-1 vector were cotransformed into the PJ69-4A yeast strain, containing the lacZ, HIS3, and ADE2 reporter genes. To dissect domains of Pnn responsible for mediating the interaction with the identified proteins, PNN fragments were ligated with the DNA-binding domain of the pAS2-1 vector. Human corneal epithelial cells (HCE-T, RCB1384) and HEK-293 cells were cotransfected with mammalian expression vectors containing Pnn with identified interacting partners and subsequently immunostained and immunoblotted to determine expressed and endogenous proteins. RESULTS: Pnn colocalized and copurified with serine-arginine (SR) proteins. Three SR-rich proteins were identified that interact with the C-terminus of Pnn: SRp75 and SRm300, known components of spliceosome machinery, and a novel 130-kDa nuclear protein, SRrp130. All of these proteins colocalized and coimmunoprecipitated with one another and exhibited speckled nuclear distribution that aligned with components of the pre-mRNA splicing machinery. The cDNA for SRrp130 encoded a protein of 805 amino acid residues and contained multiple arginine-serine (RS) repeats but had no RNA recognition motif. Analysis of the Pnn motifs using two-hybrid system assays demonstrated that the polyserine/RS motif within Pnn plays a central but not exclusive role in mediating molecular interactions with identified SR-rich proteins. CONCLUSIONS: The results suggest that Pnn and SR-rich proteins may be part of a multiprotein complex within the nucleus and may be involved in pre-mRNA processing.

Amino Acid Sequence↗

PubMed2003

Cellular localization of the MPP4 protein in the mammalian retina.

PURPOSE: Membrane protein, palmitoylated (MPP)-4 is a novel retina-specific member of the p55-like subfamily of membrane-associated guanylate kinases (MAGUKs). MAGUKs are known to act as scaffolding molecules for multiprotein complexes at specialized regions of the plasma membrane. The goal of this study was to characterize the MPP4 protein and to determine its location in the mammalian retina. METHODS: RT-PCR and 5' and 3' rapid amplification of cDNA ends (RACE) techniques were used to isolate and sequence the full-length bovine MPP4 cDNA. Polyclonal antisera against the bovine MPP4 protein were generated in rabbits immunized with synthetic peptides. Affinity-purified anti-MPP4 antibodies were used to investigate the properties and distribution of MPP4 in retina and transfected 293-Ebna cells by Western blot analysis and immunofluorescence microscopy. RESULTS: The full-length bovine MPP4 cDNA encodes a putative bovine MPP4 protein of 640 amino acids with a predicted molecular mass of 72.9 kDa. Affinity-purified anti-MPP4 antibodies specifically detected the MPP4 protein in extracts from retina and 293-Ebna cells transfected with the MPP4 cDNA. Immunofluorescence analyses revealed that both the bovine and porcine MPP4 proteins are localized in the connecting cilia and synaptic terminals of cone and rod photoreceptors. In addition, postsynaptic structures in the outer plexiform layer and three distinct bands in the inner plexiform layer were MPP4-positive. In porcine but not bovine retina, a subclass of cone bipolar cells were labeled with anti-MPP4. CONCLUSIONS: The concurrent presence of MPP4 in connecting cilia and synaptic structures suggests that MPP4 plays a role at membrane-cytoskeleton interfaces in distinct structural and functional compartments of bovine and porcine retinas. This work provides the basis for further investigations into the function of MPP4 as a retinal scaffolding molecule and its possible role in retinal disease.

Animals↗

PubMed2002

Formation of protein kinase C(epsilon)-Lck signaling modules confers cardioprotection.

The epsilon isoform of protein kinase C (PKCepsilon) is a member of the PKC family of serine/threonine kinases and plays a critical role in protection against ischemic injury in multiple organs. Functional proteomic analyses of PKCepsilon signaling show that this isozyme forms multiprotein complexes in the heart; however, the precise signaling mechanisms whereby PKCepsilon orchestrates cardioprotection are poorly understood. Here we report that Lck, a member of the Src family of tyrosine kinases, forms a functional signaling module with PKCepsilon. In cardiac cells, PKCepsilon interacts with, phosphorylates, and activates Lck. In vivo studies showed that cardioprotection elicited either by cardiac-specific transgenic activation of PKCepsilon or by ischemic preconditioning enhances the formation of PKCepsilon-Lck modules. Disruption of these modules, via ablation of the Lck gene, abrogated the infarct-sparing effects of these two forms of cardioprotection, indicating that the formation of PKCepsilon-Lck signaling modules is required for the manifestation of a cardioprotective phenotype. These findings demonstrate, for the first time to our knowledge, that the assembly of a module (PKCepsilon-Lck) is an obligatory step in the signal transduction that results in a specific phenotype. Thus, PKCepsilon-Lck modules may serve as novel therapeutic targets for the prevention of ischemic injury.

Animals↗

PubMed2001

Pattern of expression of cyclin T1 in human tissues.

Cyclin T1 was recently identified, together with cdk9 (previously named PITALRE), as part of the TAK multiprotein complex, a co-factor targeted by the human immunodeficiency virus Type 1 (HIV-1) protein named Tat, suggesting a role for this complex in transcription elongation. Although studies on mRNA and protein expression have shown that cyclin T1 is ubiquitous in adult human tissues, no data have yet been reported regarding the expression of this protein in different cell lineages. Using a polyclonal antiserum raised against cyclin T1, we investigated the pattern of expression of this protein in adult human tissues by immunohistochemistry. Cyclin T1 was expressed ubiquitously, although different levels of expression were found in various organs. Some specialized tissues, such as blood, lymphoid tissues, and cells of connective tissue origin, showed high cyclin T1 expression. These specific expression patterns are only partially justified by some well-known specialized functions of cyclin T1 in certain cell types, such as its involvement in peripheral blood lymphocytes and monocyte differentiation. The high expression level found in other tissues suggests new possible roles for cyclin T1 in cell types other than those of lymphoid tissue.

Adult↗

PubMed2006

NALP3: a key player in caspase-1 activation.

The NLR (NACHT-LRR) family of proteins have been implicated in the regulation of immune responses and cell death pathways. Some NLR family members can form multiprotein complexes, called inflammasomes, involved in the activation of pro-inflammatory caspases. Mutations in the NALP3/CIAS1/cryopyrin gene, a member of the NLR family, are linked to three auto-inflammatory disorders: Muckle-Wells syndrome, familial cold auto-inflammatory syndrome and neonatal-onset multisystem inflammatory disease. NALP3 along with the adaptor molecule ASC activates caspase-1 in response to a wide variety of stimuli. Here we review recent findings on the biology of NALP3 suggesting that it has functions beyond that of pathogen recognition.

Animals↗

PubMed2004

CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin.

Tetraspanins are thought to facilitate the formation of multiprotein complexes at cell surfaces, but evidence illuminating the biologic importance of this role is sparse. Tetraspanin CD151 forms very stable laminin-binding complexes with integrins alpha3beta1 and alpha6beta1 in kidney and alpha3beta1 and alpha6beta4 in skin. It is encoded by a gene at the same position on chromosome 11p15.5 as the MER2 blood group gene. We show that CD151 expresses the MER2 blood group antigen and is located on erythrocytes. We examined CD151 in 3 MER2-negative patients (2 are sibs) of Indian Jewish origin with end-stage kidney disease. In addition to hereditary nephritis the sibs have sensorineural deafness, pretibial epidermolysis bullosa, and beta-thalassemia minor. The 3 patients are homozygous for a single nucleotide insertion (G383) in exon 5 of CD151, causing a frameshift and premature stop signal at codon 140. The resultant truncated protein would lack its integrin-binding domain. We conclude that CD151 is essential for the proper assembly of the glomerular and tubular basement membrane in kidney, has functional significance in the skin, is probably a component of the inner ear, and could play a role in erythropoiesis.

Antigens, CD↗

PubMed2006

The transcription factors Scl and Lmo2 act together during development of the hemangioblast in zebrafish.

The transcription factors Scl and Lmo2 are crucial for development of all blood. An important early requirement for Scl in endothelial development has also been revealed recently in zebrafish embryos, supporting previous findings in scl(-/-) embryoid bodies. Scl depletion culminates most notably in failure of dorsal aorta formation, potentially revealing a role in the formation of hemogenic endothelium. We now present evidence that the requirements for Lmo2 in zebrafish embryos are essentially the same as for Scl. The expression of important hematopoietic regulators is lost, reduced, or delayed, panendothelial gene expression is down-regulated, and aorta-specific marker expression is lost. The close similarity of the phenotypes for Scl and Lmo2 suggest that they perform these early functions in hemangioblast development within a multiprotein complex, as shown for erythropoiesis. Consistent with this, we find that scl morphants cannot be rescued by a non-Lmo2-binding form of Scl but can be rescued by non-DNA-binding forms, suggesting tethering to target genes through DNA-binding partners linked via Lmo2. Interestingly, unlike other hematopoietic regulators, the Scl/Lmo2 complex does not appear to autoregulate, as neither gene's expression is affected by depletion of the other. Thus, expression of these critical regulators is dependent on continued expression of upstream regulators, which may include cell-extrinsic signals.

Adaptor Proteins, Signal Transducing↗

PubMed2003

GA-binding protein (GABP) and Sp1 are required, along with retinoid receptors, to mediate retinoic acid responsiveness of CD18 (beta 2 leukocyte integrin): a novel mechanism of transcriptional regulation in myeloid cells.

CD18 (beta(2) leukocyte integrin) is transcriptionally regulated in myeloid cells, but the mechanisms that increase its expression in response to retinoic acid (RA) have not been defined. The CD18 promoter was activated by RA treatment in stably transfected U937 myeloid cells. We identified a retinoic acid response element (RARE) that lies nearly 900 nucleotides upstream of the CD18 transcriptional start site that was bound by the RA receptors, retinoic acid receptor (RAR) and retinoic X receptor (RXR). This RARE accounted for one half of the RA responsiveness of CD18. However, unexpectedly, one half of the dynamic response to RA was mediated by the 96-nucleotide CD18 minimal promoter, which lacks a recognizable RARE. Binding sites for the ets transcription factor, GA-binding protein (GABP), and Sp1 were required for full RA responsiveness of both the CD18 minimal promoter and the full-length promoter. The ets sites conferred RA responsiveness on an otherwise unresponsive heterologous promoter, and RA responsiveness was directly related to the number of ets sites. The transcriptional coactivator p300/CBP physically interacted with GABP in vivo, and p300 increased the responsiveness of the CD18 promoter to RA. These studies demonstrate a novel role for non-RAR transcription factors in mediating RA activation in myeloid cells. They support the concept that transcription factors other than RARs are required for RA-activated gene expression. We hypothesize that a multiprotein complex--an enhanceosome--that includes GABP, other transcription factors, and coactivators, dynamically regulates CD18 expression in myeloid cells.

Binding Sites↗

PubMed2005

Prediction of a common structural scaffold for proteasome lid, COP9-signalosome and eIF3 complexes.

BACKGROUND: The 'lid' subcomplex of the 26S proteasome and the COP9 signalosome (CSN complex) share a common architecture consisting of six subunits harbouring a so-called PCI domain (proteasome, CSN, eIF3) at their C-terminus, plus two subunits containing MPN domains (Mpr1/Pad1 N-terminal). The translation initiation complex eIF3 also contains PCI- and MPN-domain proteins, but seems to deviate from the 6+2 stoichiometry. Initially, the PCI domain was defined as the region of detectable sequence similarity between the components mentioned above. RESULTS: During an exhaustive bioinformatical analysis of proteasome components, we detected multiple instances of tetratrico-peptide repeats (TPR) in the N-terminal region of most PCI proteins, suggesting that their homology is not restricted to the PCI domain. We also detected a previously unrecognized PCI domain in the eIF3 component eIF3k, a protein whose 3D-structure has been determined recently. By using profile-guided alignment techniques, we show that the structural elements found in eIF3k are most likely conserved in all PCI proteins, resulting in a structural model for the canonical PCI domain. CONCLUSION: Our model predicts that the homology domain PCI is not a true domain in the structural sense but rather consists of two subdomains: a C-terminal 'winged helix' domain with a key role in PCI:PCI interaction, preceded by a helical repeat region. The TPR-like repeats detected in the N-terminal region of PCI proteins most likely form an uninterrupted extension of the repeats found within the PCI domain boundaries. This model allows an interpretation of several puzzling experimental results.

Algorithms↗