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PubMed2002

Identification of neurite outgrowth promoting sites on the laminin alpha 3 chain G domain.

Laminins are expressed in specific tissues and are involved in various biological activities including promoting cell adhesion, growth, migration, neurite outgrowth, and differentiation. The laminin alpha3 chain is mainly located in the skin and is also expressed in the floor plate of the developing neural tube. Previously, we showed that the human laminin alpha3 chain LG4 module binds to syndecan-2/4, a membrane-associated proteoglycan, and promotes human fibroblast adhesion. Here, we have evaluated the neurite outgrowth activity of the laminin alpha3 chain LG4 and LG5 modules. Three overlapping recombinant proteins, which contained LG4 and/or LG5 modules of the human laminin alpha3 chain, were prepared using a mammalian cell expression system. Two proteins, rec-alpha3LG4-5 and rec-alpha3LG4, promoted cell attachment and neurite outgrowth of rat pheochromocytoma PC12 cells, but rec-alpha3LG5 was inactive. Twenty-two peptides covering the entire LG4 module were synthesized and tested for cell attachment and neurite outgrowth activity to identify active sites of the LG4 module. A3G75 (KNSFMALYLSKG, alpha3 chain 1411-1422) and A3G83 (GNSTISIRAPVY, alpha3 chain 1476-1487) promoted PC12 cell attachment and neurite outgrowth. Additionally, A3G75 and A3G83 inhibited PC12 cell attachment to rec-alpha3LG4. These results suggest that the A3G75 and A3G83 sites are important for PC12 cell attachment and neurite outgrowth in the laminin alpha3 chain LG4 module. We also conjugated the A3G75 and A3G83 peptides on chitosan membranes to test their potential as bio-materials. These peptide-conjugated chitosan membranes were more active for neurite outgrowth than the peptide-coated plates. These results suggest that the A3G75- and A3G83-conjugated chitosan membranes are applicable as bio-medical materials for neural tissue repair and engineering.

Amino Acid Sequence↗

PubMed2006

The binding of the PDZ tandem of syntenin to target proteins.

PDZ domains are among the most abundant protein modules in the known genomes. Their main function is to provide scaffolds for membrane-associated protein complexes by binding to the cytosolic, C-terminal fragments of receptors, channels, and other integral membrane proteins. Here, using both heteronuclear NMR and single crystal X-ray diffraction, we show how peptides with different sequences, including those corresponding to the C-termini of syndecan, neurexin, and ephrin B, can simultaneously bind to both PDZ domains of the scaffolding protein syntenin. The PDZ2 domain binds these peptides in the canonical fashion, and an induced fit mechanism allows for the accommodation of a range of side chains in the P(0) and P(-)(2) positions. However, binding to the PDZ1 domain requires that the target peptide assume a noncanonical conformation. These data help explain how syntenin, and perhaps other PDZ-containing proteins, may preferentially bind to dimeric and clustered targets, and provide a mechanistic explanation for the previously reported cooperative ligand binding by syntenin's two PDZ domains.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

A temporospatial map of adhesive molecules in the organ of Corti of the mouse cochlea.

In the nervous system, several classes of cell-surface and extracellular matrix molecules have been implicated in processes such as neural growth, fasciculation, pathfinding, target recognition and synaptogenesis, which require cell-to-cell or cell-to-substrate binding. In the developing mouse cochlea, little is known about the types of cell-surface and extracellular matrix molecules existing along the neural growth paths or their possible roles in development. Whole mount and sectioned cochlear tissue were immunolabeled for six different adhesive molecules - neural cell adhesion molecule (NCAM), polysialic acid (PSA), neural cell adhesion molecule L1, E-cadherin, syndecan-1 and tenascin-C. A temporospatial map of adhesive molecule distribution in the basal turns of the mouse cochlea was generated. Distributions of adhesive molecules were compared to each other and to the known progress of neural development in the region. This comparison demonstrated differences in the complements of adhesive molecules between the inner and outer hair cell regions, and variations in the expressions of adhesion molecules among different types of nerve fibers. In addition, developmental changes in the adhesive environment around and beneath the outer hair cells coincided with the known timing of the appearance of morphologically defined efferent synapses. These observations raise the possibility that molecular differences at the cell surface of inner and outer hair cells are one way that ingrowing neurites distinguish different environments to determine their growth routes and synaptic partners in the cochlea. In addition these observations demonstrate the potential for differential signaling of afferent and efferent innervation by altering the microenvironments in which synapses are formed.

Animals↗

PubMedDate not supplied

Protein-bound carbohydrates on cell-surface as targets of recognition: an odyssey in understanding them.

Multidisciplinary approaches by a number of investigators have established that cell-surface carbohydrates are integral components of recognition systems regulating survival, migration, adhesion, growth and differentiation of various cells. Our own experience and contributions to this exciting field are described. We discovered Endo D as the first endoglycosidase acting on glycoproteins, found complementary specificity of two endoglycosidases (Endo D and Endo H), and applied these enzymes for glycoprotein research. Endo-beta-galactosidase C, which hydrolyzes Galalpha1-3Galbeta1-4GlcNAc xenoantigenic determinant, was later found and molecularly cloned. We also found highly branched poly-N-acetyllactosamines in early embryonic cells, and demonstrated developmentally regulated carbohydrate changes during early mammalian development. The binding site for Dolichos biflorus agglutinin was introduced as a new differentiation marker. Basigin and embigin, two related members of the immunoglobulin superfamily, a sialomucin MGC-24 and other glycoproteins were discovered as carriers of developmentally regulated carbohydrate markers. We proposed enhancement of integrin action as a function of sugar chains with Lewis X epitope, and observed a relationship between the expression of carbohydrate markers and invasive properties of human carcinoma. Midkine, a heparin-binding growth factor, was discovered more recently and its interaction with heparin and oversulfated chondroitin sulfate was elucidated. N-Acetylglucosamine-6-sulfotransferase was cloned and used to reconstitute L-selectin ligands. Gene knockout was applied to reveal in vivo function of basigin, syndecan-4 and chondroitin 6-sulfate. Throughout my research on all these subjects, I have been fortunate in obtaining unexpected observations and enjoying fruitful collaborations.

Animals↗

PubMed2001

Proteoglycans: pericellular and cell surface multireceptors that integrate external stimuli in the mammary gland.

Proteoglycans consist of a core protein and an associated glycosaminoglycan (GAG) chain of heparan sulfate, chondroitin sulfate, dermatan sulfate or keratan sulfate, which are attached to a serine residue. The core proteins of cell surface proteoglycans may be transmembrane, e.g., syndecan, or GPI-anchored, e.g., glypican. Many different cell surface and matrix proteoglycan core proteins are expressed in the mammary gland and in mammary cells in culture. The level of expression of these core proteins, the structure of their GAG chains, and their degradation are regulated by many of the effectors that control the development and function of the mammary gland. Regulatory proteins of the mammary gland that bind GAG include many growth factors and morphogens (fibroblast growth factors, hepatocyte growth factor/scatter factor, members of the midkine family, wnts), matrix proteins (collagen, fibronectin, and laminin), enzymes (lipoprotein lipase) and microbial surface proteins. Structural diversity within GAG chains ensures that each protein-GAG interaction is as specific as necessary and a number of sequences of saccharides that recognize individual proteins have been elucidated. The GAG-protein interactions serve to regulate the signal output of growth factor receptor tyrosine kinase and hence cell fate as well as the storage and diffusion of extracellular protein effectors. In addition, GAGs clearly coordinate stromal and epithelial development, and they are active participants in mediating cell-cell and cell-matrix interactions. Since a single proteoglycan, even if it carries a single GAG chain, can bind multiple proteins, proteoglycans are also likely to act as multireceptors which promote the integration of cellular signals.

Breast↗

PubMed2003

Cell membrane glycosylation mediates the adhesion, migration, and invasion of ovarian carcinoma cells.

We have previously shown that ovarian carcinoma cell adhesion to mesothelial cell monolayers and migration toward fibronectin, type IV collagen, and laminin is partially mediated by CD44, a proteoglycan known to affect the functional abilities of tumor cells. The purpose of this study was to determine the role of cell membrane glycosylation in the metastatic abilities of ovarian carcinoma cells. NIH:OVCAR5 cells were treated with glycosidases to remove carbohydrate moieties from molecules on the cells' surface. The ability of the treated cells to adhere to extracellular matrix components or mesothelial cell monolayers, migrate toward extracellular matrix proteins, and invade through Matrigel was assessed. We observed that the loss of different carbohydrate moieties resulted in altered ovarian carcinoma cell adhesion, migration, and/or invasion toward extracellular matrix components or mesothelial cell monolayers. Gene array analysis of NIH:OVCAR5 cells revealed the expression of several proteoglycans, including syndecan 4, decorin, and perlecan. In tissue samples obtained from patients, altered proteoglycan gene expression was observed in primary ovarian carcinoma tumors and secondary metastases, compared to normal ovaries. Taken together, these results suggest that ovarian carcinoma cell proteoglycans affect the cells' ability to adhere, migrate, and invade toward extracellular matrix components and mesothelial cell monolayers. Thus, the carbohydrate modifications of several proteoglycans may mediate the formation and spread of secondary tumor growth in ovarian carcinoma.

Cell Adhesion↗

PubMed1999

Expression of homing receptors and related molecules on human mast cells and basophils: a comparative analysis using multi-color flow cytometry and toluidine blue/immunofluorescence staining techniques.

Mast cells (MC) and blood basophils (Ba) are multifunctional effector cells of the immune system and accumulate in areas of ongoing disease. However, despite of similar morphology, MC and Ba differ from each other in terms of cell surface receptor expression, mediator content, and tissue distribution. In order to gain new insights into mechanisms and molecules responsible for the distribution and accumulation of MC and Ba, we have investigated expression of homing receptors on primary human MC (lung, n=28; uterus, n=17), Ba (healthy donors, n=64), the mast cell line HMC-1, and the basophil line KU-812. Expression of cell surface antigens on MC and Ba was analyzed by mAb and indirect immunofluorescence staining techniques. In addition to previous findings, Ba were found to react with mAb against the selectin-ligands sLe(x) (CD15s) and PSGL-1 (CD162), L-selectin (CD62L), beta7-integrin, the 'matrix-receptor' neurothelin (CD147), platelet-endothelial cell tetraspan antigen-3 (PETA-3=CD151), and BST-1 (CD157). Novel antigens detectable on MC (lung and uterus) were CD147, CD151, CD157 and CD49c (VLA-3alpha). By contrast, MC were not recognized by mAb to sLe(x), PSGL-1, L-selectin, or beta7 integrin. No reactivity of Ba or MC with mAb to syndecan-1 (CD138), VE-cadherin (CD144), MUC18/MCAM (CD146), MGC-24 (CD164), or ALCAM (CD166) was found. The cell lines HMC-1 and KU-812 expressed a similar profile of antigens when compared to primary cells. In summary, Ba and MC express a unique profile of homing molecules. Apparently, Ba differ from MC in expression of recognition receptors relevant for binding to endothelium and consecutive transmigration.

Antibodies, Monoclonal↗

PubMed2000

Expression and distribution of cell-surface proteoglycans in the normal Lewis rat molar periodontium.

Cell-surface proteoglycans participate in several biological functions such as cell cell and cell-matrix interactions, cell adhesion, the binding to various growth factors as co-receptors and repair. To understand better the expression and distribution of cell-surface proteoglycans in the periodontal tissues, an immunohistochemical evaluation of the normal Lewis rat molar periodontium using panels of antibodies for syndecan-1, -2, -4, glypican and betaglycan was carried out. Our results demonstrated the expression and distribution of all proteoglycans in the suprabasal gingival epithelium, soft and hard connective tissues. Both cellular and matrix localization was evident within the various periodontal compartments. The presence of these cell-surface proteoglycans indicates the potential for roles in the process of tissue homeostasis, repair or regeneration in periodontium of which each function requires further study.

Animals↗

PubMed2000

Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2.

Membrane-associated guanylate kinases (MAGUKs) contain multiple protein-binding domains that allow them to assemble specific multiprotein complexes in particular regions of the cell. CASK/LIN-2, a MAGUK required for EGF receptor localization and signalling in Caenorhabditis elegans, contains a calmodulin-dependent protein kinase-like domain followed by PDZ, SH3 and guanylate kinase-like domains. In adult rat brain, CASK is concentrated at neuronal synapses and binds to the cell-surface proteins neurexin and syndecan and the cytoplasmic proteins Mint/LIN-10 and Veli/LIN-7. Here we report that, through its guanylate kinase domain, CASK interacts with Tbr-1, a T-box transcription factor that is involved in forebrain development. CASK enters the nucleus and binds to a specific DNA sequence (the T-element) in a complex with Tbr-1. CASK acts as a coactivator of Tbr-1 to induce transcription of T-element containing genes, including reelin, a gene that is essential for cerebrocortical development. Our findings show that a MAGUK which is usually associated with cell junctions has a transcription regulation function.

Animals↗

PubMed1996

Expression of Mad, an antagonist of Myc oncoprotein function, in differentiating keratinocytes during tumorigenesis of the skin.

The Myc oncoprotein is associated with cell proliferation and is often down-regulated during cell differentiation. The related Mad transcription factor, which antagonises Myc activity, is highly expressed in epidermal keratinocytes. Mad also inhibits cell proliferation in vitro. To study Mad expression in keratinocyte proliferation and differentiation, we have analysed Mad RNA expression in regenerating and hyperproliferative epidermal lesions and epidermal tumours of varying degrees of differentiation using the RNA in situ hybridisation and RNAase protection techniques. Mad was strongly expressed in differentiating suprabasal keratinocytes in healing dermal wounds and in benign hyperproliferative conditions, but also in squamous cell carcinomas, in which the keratinocytes retain their differentiation potential. However, Mad expression was lost in palisading basal carcinoma cells and poorly differentiated squamous cell carcinomas, which lacked the epithelial differentiation marker syndecan-1. We therefore suggest that Mad expression is closely associated with epithelial cell differentiation, and that this association is retained in epithelial tumours of the skin.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1995

Receptors for fibroblast growth factors.

The recent discovery of the involvement of heparan sulfate proteoglycans (HSPG) in the activation of fibroblast growth factor receptors (FGFR) has led to an intensification of study of this field. It appears that the HSPG act as low affinity receptors to which the fibroblast growth factors (FGF) must bind in order to successfully activate the high affinity FGFR. Heparan sulfate chains consisting of alternately arranged N-acetylated or N-sulfated glucosamine and uronic acid disaccharide regions, covalently attached to a core protein are found in two major families of cell surface HSPG, the syndecans and glypicans. A high affinity bFGF binding region has been isolated from fibroblast HS. There are four basic members of the FGFR family (FGFR 1-4), as well as a wealth of splice variants. The alternative forms of the basic receptors can have altered ligand binding or signalling qualities, depending on the region of the gene which is spliced. Investigations with null FGFR, incapable of signalling, have demonstrated the requirement for FGF in the organization of mammalian tissues and in embryonic patterning. Mutation of the FGFR genes has been recognized recently in human craniosynostoses where a single base pair mutation in the FGFR gene results in skeletal malformations specific to each syndrome. One suggestion is that the interaction of the mutant FGFR with the HSPG/FGF complex somehow contributes to the disease phenotype.

Binding Sites↗

PubMed2005

Gene expression profiling of noninvasive primary urothelial tumours using microarrays.

At present, the mechanism leading to bladder cancer is still poorly understood, and our knowledge about early events in tumorigenesis is limited. This study describes the changes in gene expression occurring during the neoplastic transition from normal bladder urothelium to primary Ta tumours. Using DNA microarrays, we identified novel differentially expressed genes in Ta tumours compared to normal bladder, and genes that were altered in high-grade tumours. Among the mostly changed genes between normal bladder and Ta tumours, we found genes related to the cytoskeleton (keratin 7 and syndecan 1), and transcription (high mobility group AT-hook 1). Altered genes in high-grade tumours were related to cell cycle (cyclin-dependent kinase 4) and transcription (jun d proto-oncogene). Furthermore, we showed the presence of high keratin 7 transcript expression in bladder cancer, and Western blotting analysis revealed three major molecular isoforms of keratin 7 in the tissues. These could be detected in urine sediments from bladder tumour patients.

Cluster Analysis↗

PubMed2000

Transcriptional targeting of adenoviral gene delivery into migrating wound keratinocytes using FiRE, a growth factor-inducible regulatory element.

Impaired cutaneous wound healing is a common complication in diabetes, ischemia and venous insufficiency of lower extremities, and in long-term treatment with corticosteroids or other immunosuppressive agents. In development of gene therapy for wound repair, expression of therapeutic transgenes should be precisely targeted and controlled. Here, we describe a recombinant adenovirus RAdFiRE-EGFP, in which a growth factor inducible element (FiRE) of the murine syndecan-1 gene controls the expression of enhanced green fluorescent protein (EGFP) reporter gene. Treatment of RAdFiRE-EGFP-transduced murine epidermal keratinocytes in culture with FiRE-activating growth factor markedly enhanced the expression of EGFP. In ex vivo organ culture of wounded murine skin transduced with RAdFiRE-EGFP, the EGFP expression was specifically detected in wound margin keratinocytes, but not in intact skin. Activity of EGFP was first detected 2 days after a single application of RAdFiRE-EGFP and persisted up to 10 days. Similarly, FiRE-driven EGFP expression was detected specifically in epidermal keratinocytes in the edge of incisional wounds in murine skin transduced with RAdFiRE-EGFP. In contrast, adenovirus-mediated lacZ expression driven by CMV promoter was detected scattered in epidermal, dermal and subcutaneous layers in ex vivo and in vivo wounds, as well as in intact skin. These data demonstrate the feasibility of FiRE as a tool for transcriptional targeting of adenovirus-mediated transgene expression to cutaneous wound edge keratinocytes.

Adenoviridae↗

PubMed2004

IL-6 regulates CD44 cell surface expression on human myeloma cells.

Multiple myeloma (MM) is a progressive B-lineage neoplasia characterized by the accumulation of slow proliferative malignant plasma cells in the bone marrow compartment where the microenvironment seems to be favorable for their growth and survival. Heparan sulfate proteoglycans such as syndecan-1 and CD44 are thought to play a central role in the survival signals provided by these bone marrow survival niches, which require complex interactions between myeloma cells, extracellular matrix, stromal cells and soluble factors. In this report, we demonstrate that interleukin-6 (IL-6), the main survival and growth factor for myeloma cells, strongly increases CD44 gene expression. In addition, we show that IL-6 modulates CD44 RNA alternative splicing and induces the overexpression of all CD44 variant exons. Finally, we show that IL-6-induced CD44 cell surface molecules have a functional polarized membrane distribution. As IL-6 secretion induced from bone marrow stromal cells by myeloma cells is partly mediated through direct cell-to-cell interaction involving CD44 adhesion molecules, our findings suggest that a CD44/IL-6 amplification loop plays a crucial role in myeloma cell survival.

Alternative Splicing↗

PubMed2005

High incidence of Kaposi sarcoma-associated herpesvirus infection in HIV-related solid immunoblastic/plasmablastic diffuse large B-cell lymphoma.

Kaposi sarcoma-associated herpesvirus (KSHV) is known to be associated with two distinct lymphoproliferative disorders: primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD)/MCD-associated plasmablastic lymphoma. We here report a high incidence of KSHV infection in solid HIV-associated immunoblastic/plasmablastic non-Hodgkin's lymphomas (NHLs), in patients lacking effusions and without evidence of (prior) MCD. Within a cohort of 99 HIV-related NHLs, 10 cases were found to be KSHV positive on the basis of immunostaining for KSHV LNA-1 as well as KSHV-specific polymerase chain reaction. All but one of the tumors coexpressed Epstein-Barr virus. Interestingly, all KSHV-positive cases belonged to a distinctive subgroup of 26 diffuse large B-cell lymphomas characterized by the expression of CD138 (syndecan-1) and plasmablastic/immunoblastic morphology. These KSHV-positive lymphomas were preceded by Kaposi sarcoma in 60% of the patients and involved the gastrointestinal tract in 80%. Our results indicate that KSHV infection is not restricted to PEL and MCD; it is also common (38%) in HIV-related solid immunoblastic/plasmablastic lymphomas.

Adult↗

PubMed1999

Isolation and characterization of mammalian homologues of Caenorhabditis elegans lin-7: localization at cell-cell junctions.

In Caenorhabditis elegans, the vulval induction is mediated by the let-23 receptor tyrosine kinase (RTK)/ Ras signaling pathway. The precise localization of the let-23 RTK at the epithelial junctions is essential for the vulval induction, and requires three genes including lin-2, -7, and -10. The mammalian homologue of lin-2 has been identified as a protein interacting with a neuronal adhesion molecule, neurexin, and named CASK. CASK has recently been reported to interact with syndecans and an actin-binding protein, band 4.1, at epithelial and synaptic junctions, and to play central roles in the formation of cell-cell junctions. The product of C. elegans lin-7 directly interacts with let-23 RTK and localize it at epithelial junctions. Here, we report three rat homologues of lin-7 ubiquitously expressed in various tissues. These homologues are accumulated at the junctional complex region in cultured Madin-Darby canine kidney cells, and are also localized at the synaptic junctions in neurons. The mammalian homologues of lin-7 may be implicated in the formation of cell-cell junctions.

Amino Acid Sequence↗

PubMed2002

HOXD3 enhances motility and invasiveness through the TGF-beta-dependent and -independent pathways in A549 cells.

Homeobox genes regulate sets of genes that determine cellular fates in embryonic morphogenesis and maintenance of adult tissue architecture by regulating cellular motility and cell-cell interactions. Our previous studies showed that a specific member, HOXD3, when overexpressed, upregulates integrin beta3 expression in human erythroleukemia HEL cells and lung cancer A549 cells, and enhances their motility and invasiveness. We performed a microarray study of over 7075 genes to determine the mechanisms underlying the HOXD3-enhanced motility and invasiveness in A549 cells. RT-PCR-based tracking gene analyses highlighted a set of TGF-beta-upregulated genes, which included matrix metalloproteinase-2, syndecan-1, CD44, and TGF-beta-induced 68 kDa protein. Exogenous TGF-beta also caused this pattern of upregulation in A549 cells and enhanced their migratory and invasive activity, confirming the involvement of TGF-beta signaling. However, HOXD3 reduced the expression of TGF-beta-independent genes coding for desmosomal components such as desmoglein, desmoplakin and plakoglobin which are known to suppress tumor invasion and metastasis. These results suggest that HOXD3 enhances the invasive and metastatic potential of cancer cells through the TGF-beta-dependent and -independent pathways.

Cell Movement↗

PubMed2005

Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells.

A hallmark of plasma cells is the expression of syndecan-1, which has major functions in epithelial cells, in particular as the coreceptor of heparin-binding growth factors. We previously found that heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a growth factor for malignant plasma cells. As amphiregulin (AREG) is another heparin-binding factor of the EGF family, we investigated its role in multiple myeloma (MM). Using Affymetrix DNA microarrays, we show here that the AREG gene was expressed by purified primary myeloma cells from 65 patients and that the expression was higher than in normal bone marrow (BM) plasma cells or plasmablastic cells. AREG stimulated IL-6 production and growth of BM stromal cells. Using real-time reverse transcriptase-polymerase chain reaction, we found that MM cells expressed ErbB receptors and that AREG promoted their growth. Furthermore, PD169540 (a pan-ErbB inhibitor) and IRESSA (an ErbB1-specific inhibitor) induced apoptosis of primary myeloma cells from 10/14 and 4/14 patients, respectively, and there was a synergistic effect with dexamethasone. Altogether, our data provide strong evidence that AREG plays an important role in the biology of MM and emphasize the advantages of using ErbB inhibitors, which might target myeloma cells as well as the tumor environment.

Amphiregulin↗