L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth

Neural cell adhesion molecules (CAMs) of the immunoglobulin superfamily engage in multiple neuronal interactions that influence cell migration, axonal and dendritic projection, and synaptic targeting. Their downstream signal transduction events specify whether a cell moves or projects axons and dendrites to targets in the brain. Many of the diverse functions of CAMs are brought about through homophilic and heterophilic interactions with other cell surface receptors. An emerging concept is that CAMs act as coreceptors to assist in intracellular signal transduction, and to provide cytoskeletal linkage necessary for cell and growth cone motility. Here we will focus on new discoveries that have revealed novel coreceptor functions for the best-understood CAMs--L1, CHL1, and NCAM--important for neuronal migration and axon guidance. We will also discuss how dysregulation of CAMs may also bear on neuropsychiatric disease and cancer.     

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     

Tumor cell/endothelial cell tight contact upregulates endothelial adhesion molecule expression mediated by NFκB: Differential role of the shear stress

Cancer metastasis is a multistep process involving cell-cell interactions, but little is known about the adhesive interactions and signaling events during extravasation of tumor cells (TCs). In this study, cell adhesion molecule (CAM) expression was investigated using an in vitro assay, in which TCs were seeded onto an endothelial cell (ECs) monolayer and cocultured during 5 h. Flow cytometry, confocal microscopy as well as western blot analysis indicated that endothelial ICAM-1 (Inter Cellular Adhesion Molecule-1), VCAM-1 (Vascular Adhesion Molecule-1) and E-selectin were up-regulated after TC-EC coculture, whereas no change was observed for CAMs expression in tumor cells. This increased CAMs expression required tight contact between TCs and ECs. Incubation of ECs with the pyrrolidine-dithiocarbamate NFκB inhibitor prior to coculture, fully prevented coculture-induced expression of endothelial CAMs. Using specific blocking antibodies we showed an implication of ICAM-1 and VCAM-1 for TCs extravasation and VCAM-1 for adhesion. Moreover, fluid flow experiments revealed that high shear stress totally abolished coculture-induced as well as TNFα-induced CAMs over-expression. This study suggests that TCs could act as a potent inflammatory stimulus on ECs by inducing CAMs expression via NFκB activation, and that this action can be modulated by shear stress.     

Activation of EGF receptor kinase by L1-mediated homophilic cell interactions

Neural cell adhesion molecules (CAMs) are important players during neurogenesis and neurite outgrowth as well as axonal fasciculation and pathfinding. Some of these developmental processes entail the activation of cellular signaling cascades. Pharmacological and genetic evidence indicates that the neurite outgrowth-promoting activity of L1-type CAMs is at least in part mediated by the stimulation of neuronal receptor tyrosine kinases (RTKs), especially FGF and EGF receptors. It has long been suspected that neural CAMs might physically interact with RTKs, but their activation by specific cell adhesion events has not been directly demonstrated. Here we report that gain-of-function conditions of the Drosophila L1-type CAM Neuroglian result in profound sensory axon pathfinding defects in the developing Drosophila wing. This phenotype can be suppressed by decreasing the normal gene dosage of the Drosophila EGF receptor gene. Furthermore, in Drosophila S2 cells, cell adhesion mediated by human L1-CAM results in the specific activation of human EGF tyrosine kinase at cell contact sites and EGF receptors engage in a physical interaction with L1-CAM molecules. Thus L1-type CAMs are able to promote the adhesion-dependent activation of EGF receptor signaling in vitro and in vivo.     

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.     

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.     

Cell Adhesion as a Basis of Pattern in Embryonic Development

The development of the modern methodologies of cell biologyin the fifties and sixties and of molecular biology in the seventiesand eighties has led to a reductionist view of embryonic developmentthat centers on the cell and the gene as the functional unitsof development. The functional units in most inductive and morphogeneticprocesses in the embryo are not single cells, however, but ratherare collectives of interacting cells that give rise to the tissuesand organs. Can these methodological developments reconcilea molecular analysis with the fact that form arises epigeneticallyfrom the increasing number of embryonic cells during development?To answer this question one must link genetic regulation tomechanochemical processes that coordinate cell division, cellmovement and cell death. Recent studies of cell adhesion suggestthat one such link is provided by cell adhesion molecules (CAMs)that mediate cell-cell binding. These studies suggest that CAMsare involved in defining cell collectives and their bordersas they interact during inductive events in morphogenesis. AlthoughCAMs cannot be considered the "cause" of induction, they playkey roles among the complex causal chains of inductive interactionsinvolving hormones and growth-factors, extracellular matrixcomponents and cellular receptors. We provide here a brief summaryof modern developments in the field centered about the functionof CAMs in morphogenesis and using recent experimental resultsin the developing feather as a paradigmatic example.     

Constitutive internalization of constitutively active agiotensin II AT(1A) receptor mutants is blocked by inverse agonists.

As constitutively active mutants (CAMs) mimic an active conformation, they can be used to characterize the process of G protein-coupled receptor activation. Here, we used CAMs to study the link between activation and internalization of the angiotensin II AT(1A) receptor. The cellular localization of fluorescently tagged N111A, I245T, and L305Q mutants was determined by confocal microscopy. In the absence of ligand, CAMs were mostly located in intracellular vesicles, whereas the wild-type AT(1A) was found at the cell surface. After 2 h incubation with inverse agonist, losartan, CAMs were translocated to the plasma membrane. Similar observations were made in H295, a human adrenocortical cell line which expresses physiologically the AT(1) receptor. This phenomenon, which was not dependent on protein synthesis and the pharmacology and kinetics of which were similar to the recycling of the wild-type receptor, was called "externalization". After externalization and losartan removal, the L305Q CAM underwent rapid ligand-independent endocytosis, with the same kinetics and temperature sensitivity as the angiotensin II-induced internalization of the wild-type AT(1A). Moreover, the addition of a second mutation known to block internalization (Delta 329 truncation) prevented intracellular localization of the CAM. These data show that AT(1A) CAMs are constitutively and permanently internalized and recycled. This mechanism is different from the down-regulation observed for CAMs of other G protein-coupled receptors and thus defines a new paradigm for the cellular regulation of CAMs.     

Role of E-cadherin and other cell adhesion molecules in survival and differentiation of human pluripotent stem cells

The survival, proliferation, self-renewal and differentiation of human pluripotent stem cells (hPSCs, including human embryonic stem cells and human induced pluripotent stem cells) involve a number of processes that require cell-cell and cell-matrix interactions. The cell adhesion molecules (CAMs), a group of cell surface proteins play a pivotal role in mediating such interactions. Recent studies have provided insights into the essential roles and mechanisms of CAMs in the regulation of hPSC fate decisions. Here, we review the latest research progress in this field and focus on how E-cadherin and several other important CAMs including classic cadherins, Ig-superfamily CAMs, integrins and heparin sulfate proteoglycans control survival and differentiation of hPSCs     

Role of E-cadherin and other cell adhesion molecules in survival and differentiation of human pluripotent stem cells

The survival, proliferation, self-renewal and differentiation of human pluripotent stem cells (hPSCs, including human embryonic stem cells and human induced pluripotent stem cells) involve a number of processes that require cell-cell and cell-matrix interactions. The cell adhesion molecules (CAMs), a group of cell surface proteins play a pivotal role in mediating such interactions. Recent studies have provided insights into the essential roles and mechanisms of CAMs in the regulation of hPSC fate decisions. Here, we review the latest research progress in this field and focus on how E-cadherin and several other important CAMs including classic cadherins, Ig-superfamily CAMs, integrins and heparin sulfate proteoglycans control survival and differentiation of hPSCs     

The role of the cytoskeleton in cellular adhesion molecule expression in tumor necrosis factor-stimulated endothelial cells

Leukocyte infiltration is a hallmark of the atherosclerotic lesion. These cells are captured by cellular adhesion molecules (CAMs), including vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), platelet-endothelial cell adhesion molecule (PECAM), and E-selectin, on endothelial cells (EC). We examined the role of the actin cytoskeleton in tumor necrosis factor-alpha (TNF-alpha)-induced translocation of CAMs to the cell surface. Human aortic EC were grown on 96-well plates and an ELISA was used to assess surface expression of the CAMs. TNF-alpha increased VCAM-1, ICAM-1, and E-selectin by 4 h but had no affect on the expression of PECAM. A functioning actin cytoskeleton was important for VCAM-1 and ICAM-1 expression as both cytochalasin D, an actin filament disruptor, and jasplakinolide, an actin filament stabilizer, attenuated the expression of these CAMs. These compounds were ineffective in altering E-selectin surface expression. Myosin light chains are phosphorylated in response to TNF-alpha and this appears to be regulated by Rho kinase instead of myosin light chain kinase. However, the Rho kinase inhibitor, Y27632, had no affect on TNF-alpha-induced CAM expression. ML-7, a myosin light chain kinase inhibitor, had a modest inhibitory effect on the translocation of VCAM-1 but not on ICAM-1 or E-selectin. These data suggest that the surface expression of VCAM-1 and ICAM-1 is dependent on cycling of the actin cytoskeleton. Nevertheless, modulation of actin filaments via myosin light chain phosphorylation is not necessary. The regulation of E-selectin surface expression differs from that of the other CAMs.     

Differential effects of NgCAM and N-cadherin on the development of axons and dendrites by cultured hippocampal neurons

A fundamental step in neuronal development is the acquisition of a polarized form, with distinct axons and dendrites. Although the ability to develop a polarized form appears to be largely an intrinsic property of neurons, it can be influenced by environmental cues. For example, in cell cultures substrate and diffusible factors can enhance and orient axonal development. In this study we examine the effects of growth on each of two cell adhesion molecules (CAMs), NgCAM and N-cadherin, on the development of polarity by cultured hippocampal neurons. We find that although the same pattern of development occurs on control substrates and the CAMs, the CAMs greatly accelerate the rate and extent of development of axons—axons form sooner and grow longer on the CAMs than on the control substrate. In contrast, the CAMs have opposite effects on dendritic development—N-cadherin enhances, but NgCAM reduces dendritic growth compared to control. These results provide further evidence that the development of polarity is largely determined by a cell-autonomous program, but that environmental cues can independently regulate axonal and dendritic growth.     

In vivo invasion of modified chorioallantoic membrane by tumor cells: the role of cell surface-bound urokinase

The ability of the chick embryo chorioallantoic membrane (CAM) to withstand invasion by tumor cells can be intentionally compromised by altering its morphological integrity. Using a newly developed quantitative assay of invasion we showed that intact CAMs were completely resistant to invasion by tumor cells, wounded CAMs did not pose a barrier to penetration, and CAMs that were wounded and then allowed to reseal displayed partial susceptibility to invasion. The invasion of resealed CAMs required catalytically active plasminogen activator (PA) of the urokinase type (uPA); the invasive efficiency of tumor cells was reduced by 75% when tumor uPA activity or tumor uPA production was inhibited. The invasive ability of human tumor cells, which have surface uPA receptors but which do not produce the enzyme, could be augmented by saturating their receptors with exogenous uPA. The mere stimulation of either uPA or tissue plasminogen activator production, in absence of binding to cell receptors, did not result in an enhancement of invasiveness. These findings suggest that the increased invasive potential of tumor cells is correlated with cell surface-associated proteolytic activity stemming from the interaction between uPA and its surface receptor.     

Adhesion molecules from the diatom Phaeodactylum tricornutum (Bacillariophyceae): genomic identification by amino‐acid profiling and in vivo analysis

Cell adhesion molecules (CAMs) are important in prokaryotes and eukaryotes for cell–cell and cell–substratum interactions. The characteristics of adhesive proteins in the model diatom Phaeodactylum tricornutum were investigated by bioinformatic analysis and in vivo characterization. Bioinformatic analysis of the protein coding potential of the P. tricornutum genome used an amino‐acid profile that we developed as a new system to identify uncharacterized or novel CAMs. Putative diatom CAMs were identified and seven were characterized in vivo, by generation of transgenic diatom lines overexpressing genes encoding C‐terminal yellow fluorescent protein (YFP) fusion proteins. Three of these selected genes encode proteins with weak similarity to characterized proteins, a c‐type lectin and two fasciclins, whereas the others are novel. The resultant cell lines were investigated for alterations in their adhesive ability. Whole cell‐substratum adhesion strength was measured in a fully turbulent flow chamber, while atomic force microscopy was used to quantify the relative frequency of adhesion, as well as the length and strength of single molecules in the secreted mucilage. Finally, quartz crystal microbalance analysis characterized the visco‐elastic properties and interaction of the mucilage–substratum interface. These combined studies revealed a range of phenotypes affecting adhesion, and led to the identification of candidate proteins involved in diatom adhesion. In summary, our study has for the first time combined bioinformatics and molecular physiological studies to provide new insights into diatom adhesive molecules.     

Adhesion molecule signalling: not always a sticky business

The signalling activity of cell adhesion molecules (CAMs) such as cadherins, immunoglobulin-like CAMs or integrins has long been considered to be a direct consequence of their adhesive properties. However, there are physiological and pathological processes that reduce or even abrogate the adhesive properties of CAMs, such as cleavage, conformational changes, mutations and shedding. In some cases these 'adhesion deficient' CAMs still retain signalling properties through their cytoplasmic domains and/or their mutated or truncated extracellular domains. The ability of CAMs to activate signal transduction cascades in the absence of cell adhesion significantly extends their range of biological activities.     

Embigin,a developmentally expressed member of the immunoglobulin super family,is also expressed during regression of prostate and mammary gland

Cell adhesion molecules (CAMs) are intimately involved in a variety of cellular processes, including development, cell growth, apoptosis, and differentiation. Interaction of CAMs with components of the extracellular matrix (ECM), growth factors, and other CAMs provides an intricate regulatory mechanism for a diverse range of cellular responses. Embigin is a developmentally expressed protein that is a member of the immunoglobulin superfamily (IgSF) class of CAMs. We have identified embigin as a gene expressed during tissue regression in rat prostate and lactating mammary gland following hormonal ablation. In the absence of the appropriate hormone, the secretory epithelial cells of these two tissues undergo successive waves of apoptotic cell death co-incident with extensive reorganization of the surviving tissue. Using Northern analysis, in situ hybridization analysis, RT-PCR, and Western analysis, we have characterized the expression of embigin mRNA and protein in both regressing prostate and mammary gland. During development of the prostate gland, increased expression of embigin is correlated with the appearance of highly organized lumenal and ductal structures. Embigin is also expressed in a variety of adult tissues including heart, liver, lung, and brain. Zoo-blot analysis with the rat embigin cDNA indicates that embigin homologs exist in species as diverse as Homo sapiens and Drosophila melanogaster, suggesting that it has been highly conserved during evolution. Embigin protein is expressed at readily detectable levels in a variety of prostate and mammary cancer cell lines, and in some cell lines the expression of embigin appears to be down-regulated in the presence of ECM. Our data have led us to propose a model in which embigin functions as a regulator of cell/ECM interactions during development and in the homeostasis of normal adult tissues. Dev. Genet. 21:268–278, 1997. © 1997 Wiley-Liss, Inc.     

Protein Kinase C regulates the complex between cell membrane molecules in ovarian cancer

The interactions between the integrated complex array of integral and peripheral cell adhesion molecules (CAMs) are tightly controlled by kinases such as Protein Kinase C (PKC) in response to changes in external or internal forces and/or signaling. Focusing on the complex of EpCAM-claudin-tetraspanin-driven ovarian cancer, we described a sequence of events by which role of PKCs located in the tetraspanin enriched microdomains affected on the interactions and performed immunoprecipitations in PKC activator and inhibitors-treated ovarian cancer cells and xenograft ovarian cancer mouse models. Activated PKC isoforms associated with tetraspanins and induced detectable changes in the claudin phosphorylation state. These results suggest that PKC targets claudin-4 ad -7. Phosphorylation, especially by PKC δ and η of claudins was important for the interactions between claudin-4, -7 and EpCAM. These results represent the direct evidence that phosphorylation of claudins by PKCs functions in the EpCAM-claudin-tetraspanin complex formation to allow these complexes to operate in ovarian cancer progression and metastasis in vitro and in vivo.     

突触细胞黏附分子在应激中作用的研究进展

突触细胞黏附分子是一类介导突触前、后膜结构和功能互作的膜表面糖蛋白,可以动态调节突触活动和可塑性,其表达与功能受到环境因素调控。突触细胞黏附分子亦是应激反应重要的效应分子之一,可介导应激对认知和情绪的不良影响。本文综述近年来突触细胞黏附分子在应激中作用的研究进展,旨在为应激相关障碍的分子机制研究和药物研发提供思路。