Cell-CAM 105-an adhesive cell surface glycoprotein

Summary Cell recognition and adhesion are important events in embryonic development as well as in adult physiology. In recent years several cell adhesion molecules (CAMs), that mediate adhesive interactions between vertebrate cells, have been identified and characterized. These CAMs are in general cell surface-associated high molecular weight glycoproteins. Two groups of CAMs have been classified: primary CAMs, that appear early in development; secondary CAMs, that become expressed later and with a more restricted tissue distribution. One example of a secondary CAM is cellCAM 105. This glycoprotein was originally identified in rat hepatocytes, and was shown to be involved in the reaggregation of freshly isolated hepatocytesin vitro. Physico-chemical studies on pure cellCAM 105 have demonstrated that it has adhesive properties and can bind to itself in a homophilic, calcium-independent reaction. Immunochemical and immunohistochemical investigations have shown that cellCAM 105 occurs in liver, several epithelia, vessel endothelia, platelets and polymorphonuclear leukocytes, and that it is expressed primarily in terminally differentiated cells or cells that are undergoing terminal differentiation. Available information suggests that cellCAM 105 has different functions in different cell types, and that the common functional denominator might be membrane-membrane binding. Recent data indicate that cellCAM 105 is a calmodulin-binding protein, suggesting that cellCAM-mediated cell binding could be involved in transmembrane signalling.Abbreviation CAM cell adhesion molecule     

The Receptor for Advanced Glycation End-Products (RAGE) Is Only Present in Mammals,and Belongs to a Family of Cell Adhesion Molecules (CAMs)

The human receptor for advanced glycation endproducts (RAGE) is a multiligand cell surface protein belonging to the immunoglobulin superfamily, and is involved in inflammatory and immune responses. Most importantly, RAGE is considered a receptor for HMGB1 and several S100 proteins, which are Damage-Associated Molecular Pattern molecules (DAMPs) released during tissue damage. In this study we show that the Ager gene coding for RAGE first appeared in mammals, and is closely related to other genes coding for cell adhesion molecules (CAMs) such as ALCAM, BCAM and MCAM that appeared earlier during metazoan evolution. RAGE is expressed at very low levels in most cells, but when expressed at high levels, it mediates cell adhesion to extracellular matrix components and to other cells through homophilic interactions. Our results suggest that RAGE evolved from a family of CAMs, and might still act as an adhesion molecule, in particular in the lung where it is highly expressed or under pathological conditions characterized by an increase of its protein levels.     

Significance of cell adhesion molecules, CD56/NCAM in particular, in human tumor growth and spreading

Cell adhesion molecules (CAM) represent a large group of cell surface protein moieties with distinctive biological functions. In physiological terms they ascertain cell to cell contact such as cell cohesion of epithelia, condition cell migration and transmigration via biological membranes such as blood vessel walls, provide means for homing cells in a new microenvironment etc. These features of CAM are exploited by tumor cells to grow and spread in a tumor bearing host. CD56/N-CAM antigen is 140 kD isoform of neural cell adhesion molecule. N-CAM belongs to the large Ig superfamily of CAMs. CD56 can be traced at various sites, including nervous tissue, neuro-muscular junctions, neuroendocrine and endocrine organs. It is well known as a differentiation antigen of natural killer (NK) cells. Its role and function are far from clear, but its adhesion properties are evident in cell-cell (homophilic) interactions. CD56 has been, however, demonstrated the cells various human malignancies. Tumors of the nervous system such as neuroblastoma, are well known to express this marker. Malignant lymphomas of T-NK cell origin bear CD56, as well as multiple myeloma, melanoma and some cancers of epithelial origin. These data suggest that CD56/N-CAM antigen is, in some unknown manner involved in tumor biology.     

Expression of the cell adhesion molecule E-cadherin by the human bone marrow stromal cells and its probable role in CD34(+) stem cell adhesion.

Bone marrow stroma is the physical basis of the haematopoietic microenvironment and regulates several key features of stem cell proliferation and differentiation. It plays a crucial role in maintaining haematopoietic homeostasis. Earlier studies have shown that this is achieved through interactions with the extracellular matrix and specific molecules called the cell adhesion molecules (CAMs). In this paper, we show that E-cadherin, a cell adhesion molecule which plays a crucial role in cell-cell aggregation during development, is also present in the bone marrow stroma. The expression of the CAM can also be demonstrated on a subset of CD34(+)stem cells. Stromal expression of E-cadherin is decreased when treated with lymphokine mixture, phytohaemagglutinin-treated-leukocyte-conditioned medium (PHA-LCM). This is the reverse of ICAM-I expression, which increases with PHA-LCM treatment. E-cadherin shows homotypic and homophilic interaction and its presence on a subset of CD34(+)cells leads to speculation on whether this CAM has a role in adherence of primitive stem cells to the marrow stroma.     

cDNAs of cell adhesion molecules of different specificity induce changes in cell shape and border formation in cultured S180 cells

The liver cell adhesion molecule (L-CAM) and N-cadherin or adherens junction-specific CAM (A-CAM) are structurally related cell surface glycoproteins that mediate calcium-dependent adhesion in different tissues. We have isolated and characterized a full-length cDNA clone for chicken N-cadherin and used this clone to transfect S180 mouse sarcoma cells that do not normally express N-cadherin. The transfected cells (S180cadN cells) expressed N-cadherin on their surfaces and resembled S180 cells transfected with L-CAM (S180L cells) in that at confluence they formed an epithelioid sheet and displayed a large increase in the number of adherens and gap junctions. In addition, N-cadherin in S180cadN cells, like L-CAM in S180L cells, accumulated at cellular boundaries where it was colocalized with cortical actin. In S180L cells and S180cadN cells, L-CAM and N-cadherin were seen at sites of adherens junctions but were not restricted to these areas. Adhesion mediated by either CAM was inhibited by treatment with cytochalasin D that disrupted the actin network of the transfected cells. Despite their known structural similarities, there was no evidence of interaction between L-CAM and N-cadherin. Doubly transfected cells (S180L/cadN) also formed epithelioid sheets. In these cells, both N-cadherin and L-CAM colocalized at areas of cell contact and the presence of antibodies to both CAMs was required to disrupt the sheets of cells. Studies using divalent antibodies to localize each CAM at the cell surface or to perturb their distributions indicated that in the same cell there were no interactions between L-CAM and N-cadherin molecules. These data suggest that the Ca(++)-dependent CAMs are likely to play a critical role in the maintenance of epithelial structures and support a model for the segregation of CAM mediated binding. They also provide further support for the so-called precedence hypothesis that proposes that expression and homophilic binding of CAMs are necessary for formation of junctional structures in epithelia.     

The CEACAM1 N-terminal Ig domain mediates cis- and trans-binding and is essential for allosteric rearrangements of CEACAM1 microclusters

Cell adhesion molecules (CAMs) sense the extracellular microenvironment and transmit signals to the intracellular compartment. In this investigation, we addressed the mechanism of signal generation by ectodomains of single-pass transmembrane homophilic CAMs. We analyzed the structure and homophilic interactions of carcinoembryonic antigen (CEA)–related CAM 1 (CEACAM1), which regulates cell proliferation, apoptosis, motility, morphogenesis, and microbial responses. Soluble and membrane-attached CEACAM1 ectodomains were investigated by surface plasmon resonance–based biosensor analysis, molecular electron tomography, and chemical cross-linking. The CEACAM1 ectodomain, which is composed of four glycosylated immunoglobulin-like (Ig) domains, is highly flexible and participates in both antiparallel (trans) and parallel (cis) homophilic binding. Membrane-attached CEACAM1 ectodomains form microclusters in which all four Ig domains participate. Trans-binding between the N-terminal Ig domains increases formation of CEACAM1 cis-dimers and changes CEACAM1 interactions within the microclusters. These data suggest that CEACAM1 transmembrane signaling is initiated by adhesion-regulated changes of cis-interactions that are transmitted to the inner phase of the plasma membrane.     

Critical and optimal Ig domains for promotion of neurite outgrowth by L1/Ng‐CAM

Mammalian L1 and avian Ng‐CAM are homologous neural cell adhesion molecules (CAMs) that promote neurite outgrowth and cell adhesion in most neurons. Previous attempts to map these activities to discrete regions in the CAMs have suggested the involvement of a variety of different domains. However, these studies mainly used bacterially expressed proteins that were much less active on a molar basis than the native molecules. To define regions that are critical for maximal neurite outgrowth, we constructed and tested a panel of eukaryotically expressed proteins containing various extracellular segments of human L1 (hL1) or Ng‐CAM. Our results indicate that Ig domains 1–4 of hL1 are critical for homophilic binding and neurite outgrowth; however this segment is less potent than the entire extracellular region. Optimal neurite outgrowth activity was seen with proteins containing all six Ig domains of hL1 or Ng‐CAM. The adhesive properties of hL1 fragments correlated tightly with their neurite outgrowth activities, suggesting that these two processes are closely linked. These results suggest that Ig domains 1–4 form a structural cassette responsible for hL1 homophilic binding, while Ig domains 1–6 represent a functional region for optimal promotion of neurite outgrowth in vitro and possibly in vivo. © 2000 John Wiley & Sons, Inc. J Neurobiol 42: 287–302, 2000     

神经粘附分子CHL1在神经系统中的研究进展

粘附分子通过介导细胞间相互作用发挥其在发育、再生和突触修饰等方面的重要作用.神经细胞粘附分子CHL1(close homologue of L1)是近年发现的粘附分子,属于粘附分子免疫球蛋白超家族,集中表达于神经系统,通过亲异性作用(heterophilic interaction)介导细胞与细胞、细胞与胞外基质的相互作用,进而参与神经系统的发育、轴突的生长、迁移及导向等过程.     

Physiology and pathophysiology of selectins, integrins, and IgSF cell adhesion molecules focusing on inflammation. A paradigm model on infectious endocarditis

The development of adhesion bonds, either among cells or among cells and components of the extracellular matrix, is a crucial process. These interactions are mediated by some molecules collectively known as adhesion molecules (CAMs). CAMs are ubiquitously expressed proteins playing a central role in controlling cell migration, proliferation, survival, and apoptosis. Besides their key function in physiological maintenance of tissue integrity, CAMs play an eminent role in various pathological processes such as cardiovascular disorders, atherogenesis, atherosclerotic plaque progression and regulation of the inflammatory response. CAMs such as selectins, integrins, and immunoglobulin superfamily take part in interactions between leukocyte and vascular endothelium (leukocyte rolling, arrest, firm adhesion, migration). Experimental data and pathologic observations support the assumption that pathogenic microorganisms attach to vascular endothelial cells or sites of vascular injury initiating intravascular infections. In this review a paradigm focusing on cell adhesion molecules pathophysiology and infective endocarditis development is given.     

The mechanism of axon growth

Cell adhesion molecules (CAMs) are not just an inert glue that mediates static cell-cell and cell-extracellular matrix (ECM) adhesion; instead, their adhesivity is dynamically controlled to enable a cell to migrate through complex environmental situations. Furthermore, cell migration requires distinct levels of CAM adhesivity in various subcellular regions. Recent studies on L1, a CAM in the immunoglobulin superfamily, demonstrate that cell adhesion can be spatially regulated by the polarized internalization and recycling of CAMs. This article examines the molecular mechanism of axon growth, with a particular focus on the role of L1 trafficking in the polarized adhesion and migration of neuronal growth cones.     

Physiology and Pathophysiology of Selectins,Integrins, and IgSf Cell Adhesion Molecules Focusing on Inflammation. A Paradigm Model on Infectious Endocarditis

Abstract

The development of adhesion bonds, either among cells or among cells and components of the extracellular matrix, is a crucial process. These interactions are mediated by some molecules collectively known as adhesion molecules (CAMs). CAMs are ubiquitously expressed proteins playing a central role in controlling cell migration, proliferation, survival, and apoptosis. Besides their key function in physiological maintenance of tissue integrity, CAMs play an eminent role in various pathological processes such as cardiovascular disorders, atherogenesis, atherosclerotic plaque progression and regulation of the inflammatory response. CAMs such as selectins, integrins, and immunoglobulin superfamily take part in interactions between leukocyte and vascular endothelium (leukocyte rolling, arrest, firm adhesion, migration). Experimental data and pathologic observations support the assumption that pathogenic microorganisms attach to vascular endothelial cells or sites of vascular injury initiating intravascular infections. In this review a paradigm focusing on cell adhesion molecules pathophysiology and infective endocarditis development is given.     

The mechanism of axon growth: what we have learned from the cell adhesion molecule L1

Cell adhesion molecules (CAMs) are not just an inert glue that mediates static cell-cell and cell-extracellular matrix (ECM) adhesion; instead, their adhesivity is dynamically controlled to enable a cell to migrate through complex environmental situations. Furthermore, cell migration requires distinct levels of CAM adhesivity in various subcellular regions. Recent studies on L1, a CAM in the immunoglobulin superfamily, demonstrate that cell adhesion can be spatially regulated by the polarized internalization and recycling of CAMs. This article examines the molecular mechanism of axon growth, with a particular focus on the role of L1 trafficking in the polarized adhesion and migration of neuronal growth cones.     

Calcium-dependent cell adhesion molecules

The adhesive function of Ca2(+)-dependent CAMS has in the past been studied only indirectly, mainly using immunological techniques. The molecular cloning and information about the primary structure of several CAMs has been an important step in a more detailed molecular analysis. If there is a homophilic interaction between CAMs of neighbouring cells, an important question concerns the specificity of each CAM-mediated adhesiveness. Has each CAM a unique specificity and can this specificity be linked to a defined amino acid sequence? It will be important to elucidate the molecular mechanism of how each CAM interacts with the other. The experiments of Volk et al. (1987) suggest that an interaction of two different CAMs can occur. Since during development a given cell can express more than one CAM such an heterophilic interaction could play some regulatory role. Alternative splicing mechanisms or different protein forms during development or on different cell types have not yet been observed for Ca2(+)-dependent CAMs. However, uvomorulin is assumed to have a slightly different function during development and in adult tissues. During development uvomorulin is involved in the condensation, the pattern formation, and the sorting out of cells. In these processes the uvomorulin-mediated adhesiveness should be controlled, since cells reorganize and migrate during development. For the maintenance of the histoarchitecture in adult tissues uvomorulin might act more as a glue. This argues for the existence of mechanisms to regulate the strength of adhesiveness, and the cytoplasmic domain might be involved in these processes. The association of the cytoplasmic domain of uvomorulin with catenins could be an important observation in this respect.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of cell adhesion molecules in the progression of colorectal cancer and the development of liver metastasis

Cell adhesion molecules (CAMs) play a significant role in the metastatic potential of colorectal cancer and thus mediate the prognosis of this common malignancy. The downregulation of cadherins and catenins facilitates tumour cell detachment from the primary site, while the expression of selectins, integrins and members of the immunoglobulin superfamily may support neoplastic progression, intravasation and malignant cell attachment to foreign tissue, leading to the development of metastases. The liver is the main host organ of colorectal metastatic lesions. The process of hepatic invasion originates in the sinusoids, where non-parenchymal cells interact with metastasising ones, through the expression of numerous CAMs, following complex molecular pathways. Concurrently, the selective expression of cell adhesion molecules on different organs and endothelia, in conjunction with the presence of dissimilar adhesion ligands on various colorectal cancer cell lines, suggest that CAMs may also mediate the selection of the host organ, for the development of distant colorectal metastases.     

Approaches in extracellular matrix engineering for determination of adhesion molecule mediated single cell function

The native extracellular matrix (ECM) and the cells that comprise human tissues are together engaged in a complex relationship; cells alter the composition and structure of the ECM to regulate the material and biologic properties of the surrounding environment while the composition and structure of the ECM modulates cellular processes that maintain healthy tissue and repair diseased tissue. This reciprocal relationship occurs via cell adhesion molecules (CAMs) such as integrins, selectins, cadherins and IgSF adhesion molecules. To study these cell-ECM interactions, researchers use two-dimensional substrates or three-dimensional matrices composed of native proteins or bioactive peptide sequences to study single cell function. While two-dimensional substrates provide valuable information about cell-ECM interactions, three-dimensional matrices more closely mimic the native ECM; cells cultured in three-dimensional matrices have demonstrated greater cell movement and increased integrin expression when compared to cells cultured on two-dimensional substrates. In this article we review a number of cellular processes (adhesion, motility, phagocytosis, differentiation and survival) and examine the cell adhesion molecules and ECM proteins (or bioactive peptide sequences) that mediate cell functionality.     

Structure and Functions of Classical Cadherins

Cadherins are a family of membrane receptors that mediate calcium-dependent homophilic cell–cell adhesion. Cadherins play a key role in the regulation of organ and tissue development during embryogenesis. In adult organisms, these proteins are responsible for formation of stable cell–cell junctions and maintenance of normal tissue structure. Disruption in expression or function of cadherins may cause uncontrolled cell migration and proliferation during tumor development. This review focuses on the structure and physiological functions of classical cadherins.     

Crystal Structure of the cis-Dimer of Nectin-1: implications for the architecture of cell-cell junctions

In multicellular organisms, cells are interconnected by cell adhesion molecules. Nectins are immunoglobulin (Ig)-like cell adhesion molecules that mediate homotypic and heterotypic cell-cell adhesion, playing key roles in tissue organization. To mediate cell-cell adhesion, nectin molecules dimerize in cis on the surface of the same cell, followed by trans-dimerization of the cis-dimers between the neighboring cells. Previous cell biological studies deduced that the first Ig-like domain of nectin and the second Ig-like domain are involved in trans-dimerization and cis-dimerization, respectively. However, to understand better the steps involved in nectin adhesion, the structural basis for the dimerization of nectin must be determined. In this study, we determined the first crystal structure of the entire extracellular region of nectin-1. In the crystal, nectin-1 formed a V-shaped homophilic dimer through the first Ig-like domain. Structure-based site-directed mutagenesis of the first Ig-like domain identified four essential residues that are involved in the homophilic dimerization. Upon mutating the four residues, nectin-1 significantly decreased cis-dimerization on the surface of cultured cells and abolished the homophilic and heterophilic adhesion activities. These results indicate that, in contrast with the previous notion, our structure represents a cis-dimer. Thus, our findings clearly reveal the structural basis for the cis-dimerization of nectins through the first Ig-like domains.     

Cell autonomy of DSCAM function in retinal development

Cell adhesion molecules (CAMs) provide identifying cues by which neural architecture is sculpted. The Down Syndrome Cell Adhesion Molecule (DSCAM) is required for many neurodevelopmental processes in different species and also has several potential mechanisms of activity, including homophilic adhesion, homophilic repulsion and heterophilic interactions. In the mouse retina, Dscam is expressed in many, but not all neuronal subtypes. Mutations in Dscam cause the fasciculation of dendrites of neighboring homotypic neurons, indicating a role in self-avoidance among cells of a given type, a disruption of the non-random patterning of their cell bodies, and a decrease in developmental cell death in affected cell populations. In order to address how DSCAM facilitates retinal pattering, we developed a conditional allele of Dscam to use alongside existing Dscam mutant mouse strains. Conditional deletion of Dscam reproduces cell spacing, cell number and dendrite arborization defects. Inducible deletion of Dscam and retinal ganglion cell depletion in Brn3b mutant retinas both indicate that these DSCAM-mediated phenotypes can occur independently. In chimeric retinas, in which wild type and Dscam mutant cells are comingled, Dscam mutant cells entangle adjacent wild type cells of the same type, as if both cells were lacking Dscam, consistent with DSCAM-dependent cell spacing and neurite arborization being mediated through homophilic binding cell-to-cell. Deletion of Dscam in specific cell types causes cell-type-autonomous cell body spacing defects, indicating that DSCAM mediates arborization and spacing by acting within given cell types. We also examine the cell autonomy of DSCAM in laminar stratification and find that laminar disorganization can be caused in a non-cell autonomous fashion. Finally, we find Dscam dosage-dependent defects in developmental cell death and amacrine cell spacing, relevant to the increased cell death and other disorders observed in Down syndrome mouse models and human patients, in which Dscam is present in three copies.     

The role of cell adhesion molecule in cancer progression and its application in cancer therapy

Multiple and diverse cell adhesion molecules take part in intercellular and cell-extracellular matrix interactions of cancer. Cancer progression is a multi-step process in which some adhesion molecules play a pivotal role in the development of recurrent, invasive, and distant metastasis. A growing body of evidence indicates that alterations in the adhesion properties of neoplastic cells play a pivotal role in the development and progression of cancer. Loss of intercellular adhesion and the desquamation of cells from the underlying lamina propria allows malignant cells to escape from their site of origin, degrade the extracellular matrix, acquire a more motile and invasion phenotype, and finally, invade and metastasize. In addition to participating in tumor invasiveness and metastasis, adhesion molecules regulate or significantly contribute to a variety of functions including signal transduction, cell growth, differentiation, site-specific gene expression, morphogenesis, immunologic function, cell motility, wound healing, and inflammation. Cell adhesion molecule (CAM), a diverse system of transmembrane glycoproteins has been identified that mediates the cell-cell and cell-extracellular matrix adhesion and also serves as the receptor for different kinds of virus. We summarize recent progress regarding the role of CAM, particularly, immunoglobulin-CAMs and cadherins in the progression of cancer and discuss the potential application of CAMs in the development of cancer therapy mainly on urogenital cancer.