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PubMed2005

Adhesion signaling by a novel mitotic substrate of src kinases.

Src kinases are activated and relocalize to the cytoplasm during mitosis, but their mitotic function has remained elusive. We describe here a novel mitotic substrate of src kinases. Trask (transmembrane and associated with src kinases) is a 140 kDa type I transmembrane glycoprotein unrelated to currently known protein families. Src kinases phosphorylate Trask in vitro and mediate its mitotic hyperphosphorylation in vivo. Trask associates with both yes and src, is localized to the cell membrane during interphase, and undergoes cytoplasmic relocalization during mitosis. Overexpression of Trask leads to cell rounding and a loss of adhesion phenotype. Consistent with a function in cell adhesion, Trask interacts with a number of adhesion and matrix proteins including cadherins, syndecans, and the membrane-type serine protease 1 (MT-SP1), and is proteolytically cleaved by MT-SP1. Trask is unique among cell adhesion molecules in that it is under cell cycle regulation and thus links src kinases with the mitotic regulation of cell adhesion. This suggests a potential pathway by which hyperactive src kinases in tumors can deregulate adhesion signaling and mediate the metastatic phenotype.

Amino Acid Sequence↗

PubMed2006

Oncogenic HRAS suppresses clusterin expression through promoter hypermethylation.

Silencing of gene expression by methylation of CpG islands in regulatory elements is frequently observed in cancer. However, an influence of the most common oncogenic signalling pathways onto DNA methylation has not yet been investigated thoroughly. To address this issue, we identified genes suppressed in HRAS-transformed rat fibroblasts but upregulated after treatment with the demethylating agent 5-Aza-2-deoxycytidine and with the MEK1,2 inhibitor U0126. Analysis of gene expression by microarray and Northern blot analysis revealed the MEK/ERK target genes clusterin, matrix metalloproteinase 2 (Mmp2), peptidylpropyl isomerase C-associated protein, syndecan 4, Timp2 and Thbs1 to be repressed in the HRAS-transformed FE-8 cells in a MEK/ERK- and methylation-dependent manner. Hypermethylation of putative regulatory elements in HRAS-transformed cells as compared to immortalized fibroblasts was detected within a CpG island 14.5 kb upstream of clusterin, within the clusterin promoter and within a CpG island of the Mmp2 promoter by bisulphite sequencing. Furthermore, hypermethylation of the clusterin promoter was observed 10 days after induction of HRAS in immortalized rat fibroblasts and a clear correlation between reduced clusterin expression and hypermethlyation could also be observed in distinct rat tissues. These results suggest that silencing of individual genes by DNA methylation is controlled by oncogenic signalling pathways, yet the mechanisms responsible for initial target gene suppression are variable.

Animals↗

PubMed2006

MicroRNAs and the hallmarks of cancer.

It has become clear that particular microRNAs (miRNAs) function either as tumour suppressors or oncogenes, whose loss or overexpression, respectively, has diagnostic and prognostic significance. In several cases, miRNAs have been shown to affect target genes that are involved in the control of cell proliferation and apoptosis. However, malignant tumours display additional traits beyond the acquisition of enhanced growth potential and decreased cell death. Malignant disease is associated with altered tumour-host interactions leading to sustained angiogenesis and the ability to invade and metastasize. It is possible that miRNAs may act as master regulators of these aspects of tumour biology. Bioinformatic analysis of putative miRNA binding sites has indicated several novel potential gene targets of cancer-associated miRNAs that function in aspects of cell adhesion, neovascularization and tissue invasion. Among others, we speculate that miRNAs may find new roles in the regulation of E-cadherin, integrin alphavbeta3, hypoxia-inducible factor-1alpha, syndecan-1, lysyl oxidase, adamalysin metalloproteinase-17, tissue inhibitors of metalloproteinase-3, c-Met and CXCR-4 that underpin the tissue architectural changes associated with malignancy.

Animals↗

PubMed2003

A synthetic peptide from the heparin-binding domain III (repeats III4-5) of fibronectin promotes stress-fibre and focal-adhesion formation in melanoma cells.

Cell adhesion to fibronectin results in formation of actin stress fibres and focal adhesions. In fibroblasts, this response requires two co-operative signals provided by interactions of the RGD sequence with alpha5beta1 integrin and the heparin-binding domain II (Hep II) domain with syndecan-4. Within Hep II, this activity was mapped to repeat III13 and to the peptide FN-C/H-V(WQPPRARITGY, repeat III14). We previously described that the synthetic heparin-binding peptide/III5 (HBP/III5) (WTPPRAQITGYRLTVGLTRR, repeat III5) binds heparin and mediates cell adhesion via chondroitin sulphate proteoglycans. We have now studied whether HBP/III5 co-operates with alpha5beta1 and drives a full cytoskeletal response in melanoma cells. SKMEL-178 cells attached and spread on the RGD-containing FNIII7-FNIII10 (FNIII7-10) fragment, but did not form stress fibres or focal adhesions. Co-immobilization of HBP/III5 with FNIII7-10 or adding soluble HBP/III5 to cells prespread on FNIII7-10, effectively induced these structures. Cell transfection with dominant-negative N19RhoA, a member of the small GTPase family, abolished the HBP/III5 effect. Both chondroitinase and heparitinase diminished focal adhesions, indicating that both types of proteoglycans bound HBP/III5 in melanoma cells. We have mapped the active sequence of HBP/III5 to YRLTVGLTRR, which is a novel sequence in fibronectin with focal-adhesion-promoting activity. The last two arginine (R) residues of this sequence are required for activity, since their replacement by alanine completely abrogated the HBP/III5 cytoskeletal effect. Moreover, this sequence is also active in the context of large fibronectin fragments. Our results establish that the Hep III region provides co-operative signals to alpha5beta1 for the progression of the cytoskeletal response and that these include activation of RhoA.

Amino Acid Sequence↗

PubMed2006

Primary attachment of murine leukaemia virus vector mediated by particle-associated heparan sulfate proteoglycan.

Target cell entry of murine leukaemia virus vectors proceeds via primary attachment, independent of the viral envelope protein and subsequent envelope-receptor interaction. Although much attention has been paid to modifying the latter for target cell specificity, the initial binding interaction has been overlooked, despite its opposing involvement both in providing the virus available for receptor binding and in depleting free virus. As a first step towards modifying primary attachment, both to provide specificity and to enhance vector availability, we sought to determine the nature of this interaction. Following an initial screen of GAGs (glycosaminoglycans) for their ability to inhibit virus binding and transduction, we have shown that production of virus from cells in which GAG sulfation is inhibited, or treatment of virus with heparinase III, reduces both particle attachment and infection. Detection in purified virus preparations of a neo-epitope generated by heparinase III confirmed the presence of virus-associated HSPG [HS (heparan sulfate) proteoglycan], acquired from the producer cell. We propose that host-acquired cell-surface HSPG (potentially including syndecan-2) provides a means of virus attachment to target cells that precedes specific receptor interaction and membrane fusion. Inhibition of HS biosynthesis may provide a sufficiently reduced background of primary binding such that novel mechanisms of attachment, ideally with appropriate target cell specificity, can be introduced.

Animals↗

PubMed1996

Expression of extracellular matrix molecules in human mesangial cells in response to prolonged hyperglycaemia.

Post-mitotic cultures of human mesangial cells were maintained in media containing 4-30 mM D-glucose for up to 28 days. Changes in mRNA and protein levels for specific macromolecules occurred between 7 and 14 days after initiating hyperglycaemic conditions. Slot blot analysis showed 2-3-fold increases in mRNAs for collagen type I, fibronectin, versican and perlecan, whereas mRNA for decorin was increased by up to 20-fold. Levels of mRNAs for biglycan and syndecan were unaffected by hyperglycaemic culture. Reverse transcriptase PCR (RT-PCR) confirmed that decorin mRNA levels are greatly elevated and also showed increased transcription of the TGF-beta 1 gene in hyperglycaemic cultures. Western analysis and ELISA indicated accumulations of collagen types I and III, laminin and fibronectin in the cell layers and media of hyperglycaemic cultures with increasing time. Type IV collagen did not accumulate in either compartment of hyperglycaemic mesangial cell cultures. Collagen types I, III, and fibronectin did not accumulate in the cell layers of hyperglycaemic human dermal fibroblasts, indicating a cell-specific response in mesangial cultures. Decorin and versican, but not biglycan, were increased in the hyperglycaemic mesangial cell culture media. There were no apparent changes in core proteins for decorin and biglycan in fibroblast media. Transforming growth factor beta 1 (TGF-beta 1) in hyperglycaemic mesangial cell cultures increased 5-fold after 7 days, but decreased thereafter to only approx. 2-fold after 28 days. The changes in TGF-beta 1 mRNA, as detected by RT-PCR, and protein followed one another closely.

Base Sequence↗

PubMed1996

Proteoglycan synthesis in human and murine haematopoietic progenitor cell lines: isolation and characterization of a heparan sulphate proteoglycan as a major proteoglycan from the human haematopoietic cell line TF-1.

Proteoglycans of bone-marrow stromal cells and their extracellular matrix are important components of the microenvironment of haematopoietic tissues. Proteoglycans might also be involved in the interaction of haematopoietic stem and stromal cells. Recently, several studies have been reported on the proteoglycan synthesis of stromal cells, but little is known about the proteoglycan synthesis of haematopoietic stem or progenitor cells. Here we report on the isolation and characterization of proteoglycans from two haematopoietic progenitor cell lines, the murine FDCP-Mix A4 and the human TF-1 cell line. Proteoglycans were isolated from metabolically labelled cells and purified by several chromatographic steps, including anion-exchange and size-exclusion chromatography. Biochemical characterization was performed by electrophoresis or gel-filtration chromatography before and after digestion with glycosaminoglycan-specific enzymes or HNO2 treatment. Whereas FDCP-Mix A4 cells synthesize a homogeneous chondroitin 4-sulphate proteoglycan, isolation and characterization of proteoglycans from the human cell line TF-1 revealed, that TF-1 cells synthesize, in addition to a chondroitin sulphate proteoglycan, a heparan sulphate proteoglycan as major proteoglycan. For this heparan sulphate proteoglycan a core protein size of approx. 59 kDa was determined. Immunochemical analysis of this heparan sulphate proteoglycan revealed that it is not related to the syndecan family nor to glypican.

Animals↗

PubMed1997

Proteoglycan synthesis in haematopoietic cells: isolation and characterization of heparan sulphate proteoglycans expressed by the bone-marrow stromal cell line MS-5.

Proteoglycans of bone-marrow stromal cells and their extracellular matrix are important components of the haematopoietic microenvironment. Recently, several studies have indicated that they are involved in the interaction of haematopoietic stem and stromal cells. However, a detailed characterization of the heparan sulphate proteoglycans synthesized by bone-marrow stromal cells is still lacking. Here we report on the isolation and characterization of proteoglycans from the haematopoietic stromal cell line MS-5, that efficiently supports the growth and differentiation of human and murine haematopoietic progenitor cells. Biochemical characterization of purified proteoglycans revealed that the haematopoietic stromal cell line MS-5 synthesizes, in addition to chondroitin sulphate proteoglycans, several different heparan sulphate proteoglycans. Immunochemical analysis, using specific antibodies against the different members of the syndecan family, glypican, betaglycan and perlecan, showed that MS-5 cells synthesize all these different heparan sulphate proteoglycans. These data were further supported by reverse-transcriptase PCR and confirmed by sequence and Northern blot analysis. The relative abundance of the different heparan sulphate proteoglycans was estimated on the protein and mRNA levels.

Animals↗

PubMed2000

Evidence in favour of ancient octaploidy in the vertebrate genome.

Vertebrate genomes are larger than invertebrates and show evidence of extensive gene duplication, including many collinear chromosomal segments. On the basis of this intra-genomic synteny, it has been proposed that two rounds of whole genome duplication (octaploidy) occurred early in the vertebrate lineage. Recently, this early vertebrate octaploidy has been challenged on the basis of gene trees. We report new linkage groups encompassing the matrilin (MATN), syndecan (SDC), Eyes Absent (EYA), HCK kinase and SRC kinase paralogous gene quartets. In contrast to other studies, the sequence trees are weakly supportive of ancient octaploidy. It is concluded that there is no strong evidence against the octaploidy, provided that consecutive genome duplication was rapid.

Animals↗

PubMed2000

Proteoglycans and cutaneous vascular defense and repair.

Proteoglycans are hybrid molecules composed of a core protein and covalently attached glycosaminoglycan chain(s). The structure, location, and processing of these molecules enables them to encode specific information that is used in multiple physiologic processes. Endothelial cells in the skin are influenced by proteoglycans through binding interactions between glycosaminoglycans and extracellular matrix, growth factors, cytokines, adhesion receptors, enzymes, and enzyme inhibitors. In wound repair, proteoglycans such as the syndecans are induced by antimicrobial peptides and can control growth factor responsiveness. The glycosaminoglycans further signal endothelial cells to increase expression of ICAM-1 and other molecules important for leukocyte adhesion. Thus, proteoglycans represent a powerful central regulatory element in skin that influences a wide variety of events and participates in host defense and tissue repair.

Animals↗

PubMed1998

B-lymphocyte suppression in multiple myeloma is a reversible phenomenon specific to normal B-cell progenitors and plasma cell precursors.

The reduced levels of normal immunoglobulin in patients with myeloma may be due to suppression of normal B-cell differentiation. However, reports on the numbers of B cells vary, with some finding decreases consistent with immunoparesis, and others reporting expansions of phenotypically aberrant cells. We have therefore assessed the phenotype and levels of B lymphocytes in patients at presentation (n = 23), in plateau or complete remission (PB n = 42, BM n = 18), and in relapse (PB n = 17, BM n = 14), in comparison to normal individuals (n = 10). Phenotypic analysis was performed using five-parameter flow cytometry, with CD14 used to exclude monocytes where necessary. We found no evidence of a phenotypically distinctive blood or marrow B-cell population in patients with myeloma, nor of an increase in the levels of any B-cell subset. Numbers of blood CD19+ 38+ normal plasma cell precursors were significantly reduced in presentation/relapse patients, but not in patients in plateau/remission. Total CD19+ cells were significantly reduced only in patients with circulating myeloma cells, detected by IgH-PCR. In the marrow, CD19+ B cells expressing CD5, CD10, CD34, CD38, CD45(low) and Syndecan-1 were significantly decreased at presentation/relapse, but not in patients in plateau/remission. The majority of these antigens are expressed by normal B-cell progenitors, indicating that myeloma also affects the early stages of B-cell development. The suppression of progenitor cells was not restricted to B-lymphoid differentiation, as total CD34+ cells were also significantly reduced in the marrow of myeloma patients at presentation. These results indicate that, if neoplastic B cells are present in myeloma, they are low in number and have a phenotype similar to their normal counterparts. Furthermore, there is a reversible suppression of CD19+ B lymphocytes that correlates inversely with disease stage, and specifically affects the early and late stages of normal B-cell differentiation.

Adult↗

PubMed2003

Recent developments in our understanding of melanocortin system in the regulation of food intake.

Obesity has become one of the most significant public health problems facing the world today. However, the pathogenesis of obesity is multifactorial and involves the interaction of genetic and environmental factors. There is a pressing need to better understand the biochemical pathways that control energy intake and expenditure. In the last few years, a number of important signalling molecules have been identified that play important roles in obesity. One family of these molecules is the melanocortin system, which consists of several components: (1) melanocortin peptides; (2) the five seven-transmembrane G-protein coupled melanocortin receptors (MCRs); (3) the endogenous MCR antagonists, agouti and agouti-related protein; (4) the endogenous melanocortin mediators, mahogany, and syndecan. This system plays a key role in the central nervous system control of feeding behaviour and energy expenditure. This article will provide an overview of the anatomy, physiology, and molecular biology of the melanocortin system, and recent developments in our understanding of this system in obesity.

Appetite Regulation↗

PubMed1998

Antimicrobial peptides: an emerging concept in cutaneous biology.

Antimicrobial peptides are part of the host defense systems of plants, insects, fish, amphibia, birds, and mammals. These small proteins were previously thought of as an evolutionarily ancient system of immune protection with little relevance to the normal function of human skin. Recent developments have found that mammalian skin expresses these gene-encoded peptide antibiotics during inflammatory events such as wound repair, contact dermatitis, and psoriasis. The presence of these peptides in the skin forms a barrier for innate host protection against microbial pathogenesis. Furthermore, antimicrobial peptides also act on animal cells by stimulating them to change behaviors such as syndecan expression, chemotaxis, and chloride secretion. The combination of effects on host cells with antimicrobial action in a single molecule represents an efficient defense and response system against injury. Understanding the action of antimicrobial peptides in skin may yield further insight into the mechanism of innate cutaneous disease control and provide new approaches to therapy of wounds and inflammatory dermatitis.

Animals↗

PubMed2001

Anti-microbial activity and cell binding are controlled by sequence determinants in the anti-microbial peptide PR-39.

PR-39 is a member of the proline-rich group of cathelicidin peptides, a class of anti-microbial peptides found in skin and in leukocytes. In addition to their innate defense function, these proline-rich peptides influence a number of mammalian cell processes, including inflammation, development, differentiation, and metastatic transformation. To characterize the mechanism further, through which proline-rich cathelicidin peptides may exert their numerous effects, we altered various conserved peptide sequence motifs using a biologically active fragment of PR-39 [PR-39(15)] as the template: We altered the N-terminal charge of its SH3 binding motif, substituted tryptophan for a conserved intervening leucine, and modified a proline-arginine stretch (residues 10-13). These peptide variants were tested for binding known targets of PR-39 and for biologic activity in mammalian and bacterial systems. We found that the N-terminal arginines are crucial for protein binding and that modification in this domain results in loss of affinity and specificity in binding to generalized and SH3-containing targets. The N-terminal charged residues are also required for NIH 3T3 syndecan induction and anti-microbial activity. In addition, modification of more C-terminal residues eliminates anti-bacterial activity while having less of an effect on peptide interactions in mammalian cell assays. This study shows that the presence of a charged N-terminus is important for peptide activity in both mammalian and bacterial systems whereas the C-terminal alterations of PR-39(15) more definitively affect anti-bacterial activity.

3T3 Cells↗

PubMed2002

The anti-inflammatory actions of antithrombin--a review.

Leukocyte-endothelial cell interaction and microvascular perfusion failure are characteristic deteriorations of the microcirculation in endotoxaemia and are known to play a crucial role in the development of septic multiple organ dysfunction. Recent studies have indicated that antithrombin III treatment is capable of significantly ameliorating these microcirculatory disorders. Endothelial cells have important anticoagulant systems, including the heparan sulfate-antithrombin system. Antithrombin III stimulates prostacyclin generation in endothelial cells by interacting with heparan sulfate of endothelial cells and inhibits cytokine and tissue factor production in endothelial cells and monocytes. Similar mechanisms may be involved in cellular actions of antithrombin III causing desensitization of chemoattractant receptors of leukocytes by activating the heparan sulfate proteoglycan, syndecan-4. Thus, antithrombin III might be among the useful agents for treating coagulation abnormalities associated with sepsis or other inflammation because it inhibits not only coagulation but also downregulation of anticoagulant activities of endothelial cells and affects leukocyte activation.

Anti-Inflammatory Agents↗

PubMed2005

[Cellular contacts in myelinated fibers of the peripheral nervous system].

Myelination allows the fast propagation of action potentials at a low energetic cost. It provides an insulating myelin sheath regularly interrupted at nodes of Ranvier where voltage-gated Na+ channels are concentrated. In the peripheral nervous system, the normal function of myelinated fibers requires the formation of highly differentiated and organized contacts between the myelinating Schwann cells, the axons and the extracellular matrix. Some of the major molecular complexes that underlie these contacts have been identified. Compact myelin which forms the bulk of the myelin sheath results from the fusion of the Schwann cell membranes through the proteins P0, PMP22 and MBP. The basal lamina of myelinating Schwann cells contains laminin-2 which associates with the glial complex dystroglycan/DPR2/L-periaxin. Non compact myelin, found in paranodal loops, periaxonal and abaxonal regions, and Schmidt-Lanterman incisures, presents reflexive adherens junctions, tight junctions and gap junctions, which contain cadherins, claudins and connexins, respectively. Axo-glial contacts determine the formation of distinct domains on the axon, the node, the paranode, and the juxtaparanode. At the paranodes, the glial membrane is tightly attached to the axolemma by septate-like junctions. Paranodal and juxtaparanodal axoglial complexes comprise an axonal transmembrane protein of the NCP family associated in cis and in trans with cell adhesion molecules of the immunoglobulin superfamily (IgSF-CAM). At nodes, axonal complexes are composed of Na+ channels and IgSF-CAMs. Schwann cell microvilli, which loosely cover the node, contain ERM proteins and the proteoglycans syndecan-3 and -4. The fundamental role of the cellular contacts in the normal function of myelinated fibers has been supported by rodent models and the detection of genetic alterations in patients with peripheral demyelinating neuropathies such as Charcot-Marie-Tooth diseases. Understanding more precisely their molecular basis now appears essential as a requisite step to further examine their involvement in the pathogenesis of peripheral neuropathies in general.

Animals↗

PubMed1998

Morphometrical and immunopathological dissection of the hepatic Schistosoma haematobium granuloma in the murine host.

This paper presents the results of a study aimed at identifying the immunopathological and morphometrical characteristics of liver granulomas induced by the parasite Schistosoma haematobium. The OF1 mouse is a susceptible host for experimental infection with the Egyptian NAMRU-3 strain of S. haematobium. Formation of liver granulomas started after 13-14 weeks of infection. These hepatic granulomas reached a maximum volume after 20 weeks of infection (MGV: 1.82 +/- 0.15 x 10(7) micron 3) and regressed thereafter (1.55 +/- 0.16 x 10(7) micron 3 after 24 weeks). Strong cellular upregulation of the adhesion molecules ICAM-1, LFA-1, syndecan-1, VLA-4, but not VLA-6 is seen, both in acute and chronic granulomas. Finally, pathological differences exist between hepatic S. mansoni and S. haematobium granulomas particularly at the level of extracellular matrix deposition. S. haematobium induced peri-ovular deposition of mainly fibronectin and to a lesser extent type I and IV collagen.

Animals↗

PubMedDate not supplied

Subcellular localization of PP5/TFPI-2 in human placenta: a possible role of PP5/TFPI-2 as an anti-coagulant on the surface of syncytiotrophoblasts.

Placental protein 5 (PP5)/tissue factor pathway inhibitor-2 (TFPI-2), a serine proteinase inhibitor, is homologous to tissue factor pathway inhibitor (TFPI) and commonly found in peripheral blood of pregnant woman. Although TFPI is well known to be synthesized primarily in endothelium and to play an important role in regulation of the extrinsic pathway of blood coagulation, the function of PP5/TFPI-2 remains unclear. Our previous report demonstrated that PP5/TFPI-2 expression is ubiquitous and extremely high in growing placental tissue. Using newly generated polyclonal anti-PP5/TFPI-2 antibody, and by immunohistochemistry and immunoelectromicroscopy, we examined precise localization of PP5/TFPI-2 in placenta especially in syncytiotrophoblasts, which had been shown to produce PP5/TFPI-2 mRNA by our previous study using in situ hybridization. Immunoelectromicroscopy revealed PP5/TFPI-2 localizing on the surface of the microvilli and the membrane of endoplasmic reticulum of syncytiotrophoblasts. To confirm the cell surface association of PP5/TFPI-2, placental villi were incubated with heparin and resultant soluble fraction was analysed by Western blotting. Heparin liberating PP5/TFPI-2 from villi suggested that PP5/TFPI-2 might be retained on the microvilli surface through the binding to membrane-anchored proteoglycans such as glypican and/or syndecan family members. We also examined the relationship between the presence of cell layer of syncytiotrophoblasts and the coagulation using clinical specimens, and revealed that the fibrin depositions were specifically observed on the regions lacking syncytiotrophoblasts cell layer in placental villi. Therefore, it is likely that during pregnancy PP5/TFPI-2 may be retained on the surface of placental villi via proteoglycans, and may play an important role to maintain intervillous blood flow and the patency of microvasculature in feto-maternal blood system mediated by the inhibition of serine proteinases involved in the blood coagulation.

Adult↗