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Leukocyte extravasation is one of the essential and first steps during the initiation of inflammation. Therefore, a better understanding of the key molecules that regulate this process may help to develop novel therapeutics for treatment of inflammation-based diseases such as atherosclerosis or rheumatoid arthritis. The endothelial adhesion molecules ICAM-1 and VCAM-1 are known as the central mediators of leukocyte adhesion to and transmigration across the endothelium. Engagement of these molecules by their leukocyte integrin receptors initiates the activation of several signaling pathways within both leukocytes and endothelium. Several of such events have been described to occur during transendothelial migration of all leukocyte subsets, whereas other mechanisms are known only for a single leukocyte subset. Here, we summarize current knowledge on regulatory mechanisms of leukocyte extravasation from a leukocyte and endothelial point of view, respectively. Specifically, we will focus on highlighting common and unique mechanisms that specific leukocyte subsets exploit to succeed in crossing endothelial monolayers.

The heterophilic synaptic adhesion molecules neuroligins and neurexins are essential for establishing and maintaining neuronal circuits by modulating the formation and maturation of synapses. The neuroligin-neurexin adhesion is Ca 2+ -dependent and regulated by alternative splicing. We report a structure of the complex at a resolution of 2.4 Å between the mouse neuroligin-1 (NL1) cholinesterase-like domain and the mouse neurexin-1β (NX1β) LNS (laminin, neurexin and sex hormone–binding globulin–like) domain. The structure revealed a delicate neuroligin-neurexin assembly mediated by a hydrophilic, Ca 2+ -mediated and solvent-supplemented interface, rendering it capable of being modulated by alternative splicing and other regulatory factors. Thermodynamic data supported a mechanism wherein splicing site B of NL1 acts by modulating a salt bridge at the edge of the NL1-NX1β interface. Mapping neuroligin mutations implicated in autism indicated that most such mutations are structurally destabilizing, supporting deficient neuroligin biosynthesis and processing as a common cause for this brain disorder.

Key Points Cell adhesion molecules (CAMs) of the cadherin and immunoglobulin superfamilies mediate cell–cell adhesion by engaging in homophilic and heterophilic interactions and, therefore, promote the formation and stabilization of adhesive structures. Cell–cell adhesion triggers CAM-mediated signalling, which regulates cytoskeletal dynamics, permeability, cell polarity, contact inhibition of growth and other processes. Besides adhesion-dependent signalling, cadherins and immunoglobulin-like CAMs (Ig-CAMs) are also able to induce signal transduction in the absence of cell–cell adhesion. Such adhesion-independent CAM signalling occurs with different modalities and influences various cellular responses, including migration, proliferation, survival and differentiation. Growth factor receptors represent prominent effectors in adhesion-independent CAM signalling. CAMs can either modulate the receptor response to their cognate ligand or they can act themselves as non-canonical ligands that activate receptor-mediated signalling cascades. The shedding of CAM ectodomains generates biologically active fragments that can stimulate signalling by interacting with cell surface molecules. CAMs also have an important function in gene expression, for example, by regulating the nuclear trafficking of proteins involved in transcription (for example, catenins) or through the nuclear translocation of CAM-derived cytoplasmic fragments that have transcription-modulating properties. The signalling activity of cell adhesion molecules (CAMs) such as cadherins, immunoglobulin-like CAMs or integrins has been considered a direct consequence of their adhesive properties. However, in some cases CAMs can activate signalling in the absence of cell adhesion, which significantly extends their range of biological activities. 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.

Epithelial cell adhesion molecule (EpCAM) is a cell surface protein that was discovered as a tumour marker of epithelial origins nearly four decades ago. EpCAM is expressed at basal levels in the basolateral membrane of normal epithelial cells. However, EpCAM expression is upregulated in solid epithelial cancers and stem cells. EpCAM can also be found in disseminated tumour cells and circulating tumour cells. Various OMICs studies have demonstrated that EpCAM plays roles in several key biological processes such as cell adhesion, migration, proliferation and differentiation. Additionally, EpCAM can be detected in the bodily fluid of cancer patients suggesting that EpCAM is a pathophysiologically relevant anti-tumour target as well as being utilized as a diagnostic/prognostic agent for a variety of cancers. This review will focus on the structure-features of EpCAM protein and discuss recent evidence on the pathological and physiological roles of EpCAM in modulating cell adhesion and signalling pathways in cancers as well as deliberating the clinical implication of EpCAM as a therapeutic target.

In epithelial-derived cancers, altered regulation of cell–cell adhesion facilitates the disruption of tissue cohesion that is central to the progression to malignant disease. Although numerous intercellular adhesion molecules participate in epithelial adhesion, the immunoglobulin superfamily (IgSF) member activated leukocyte cell adhesion molecule (ALCAM), has emerged from multiple independent studies as a central contributor to tumor progression. ALCAM is an archetypal member of the IgSF with conventional organization of five Ig-like domains involved in homo- and heterotypic adhesions. Like many IgSF members, ALCAM is broadly expressed and involved in cellular adhesion across many cellular processes. While the redundancy of intercellular adhesion molecules (CAMs) could diminish the impact of any single CAM, consistent correlation between ALCAM expression and patient outcome for multiple cancers underscores its role in tumor progression. Unlike most oncogenes and tumor suppressors, ALCAM is neither mutated nor amplified or deleted. Experimental disruption of ALCAM-mediated adhesions implies that this IgSF member contributes to tumor progression through dynamic turnover of the protein at the cell surface. Since ALCAM is not frequently altered at the gene level, it appears to promote malignant behavior through regulation of its availability rather than its specific activity. These observations help explain its heterogeneous expression within malignant disease and the drastic changes in protein levels across tumor progression. To reveal how ALCAM contributes to tumor progression, we review regulation of its gene expression, alternative splicing, targeted proteolysis, binding partners, and surface shedding within the context of cancer. Studying ALCAM regulation has led to a novel understanding of the fine-tuning of cell adhesive state through the utilization of otherwise normal regulatory processes, which thereby enable tumor cell invasion and metastasis.

Reelin is an essential glycoprotein for the establishment of the highly organized six-layered structure of neurons of the mammalian neocortex. Although the role of Reelin in the control of neuronal migration has been extensively studied at the molecular level, the mechanisms underlying Reelin-dependent neuronal layer organization are not yet fully understood. In this study, we directly showed that Reelin promotes adhesion among dissociated neocortical neurons in culture. The Reelin-mediated neuronal aggregation occurs in an N-cadherin–dependent manner, both in vivo and in vitro. Unexpectedly, however, in a rotation culture of dissociated neocortical cells that gradually reaggregated over time, we found that it was the neural progenitor cells [radial glial cells (RGCs)], rather than the neurons, that tended to form clusters in the presence of Reelin. Mathematical modeling suggested that this clustering of RGCs could be recapitulated if the Reelin-dependent promotion of neuronal adhesion were to occur only transiently. Thus, we directly measured the adhesive force between neurons and N-cadherin by atomic force microscopy, and found that Reelin indeed enhanced the adhesiveness of neurons to N-cadherin; this enhanced adhesiveness began to be observed at 30 min after Reelin stimulation, but declined by 3 h. These results suggest that Reelin transiently (and not persistently) promotes N-cadherin–mediated neuronal aggregation. When N-cadherin and stabilized β-catenin were overexpressed in the migrating neurons, the transfected neurons were abnormally distributed in the superficial region of the neocortex, suggesting that appropriate regulation of N-cadherin–mediated adhesion is important for correct positioning of the neurons during neocortical development.

This comprehensive work discusses novel biomolecular surfaces that have been engineered to either control or measure cell function at the atomic, molecular, and cellular levels. Each chapter presents real results, concepts, and expert perspectives of how cells interact with biomolecular surfaces, with particular emphasis on interactions within complex mechanical environments such as in the cardiovascular system. In addition, the book provides detailed coverage of inflammation and cellular immune response as a useful model for how engineering concepts and tools may be effectively applied to complex systems in biomedicine. -Accessible to biologists looking for new ways to model their results and engineers interested in biomedical applications -Useful to researchers in biomaterials, inflammation, and vascular biology -Excellent resource for graduate students as a textbook in cell & tissue engineering or cell mechanics courses

Background Angiotensin-converting enzyme 2 (ACE2) is a counter-regulator against ACE by converting angiotensin II (Ang-II) to Ang-(1–7), but the effect of ACE2 and Ang-(1–7) on endothelial cell function and atherosclerotic evolution is unknown. We hypothesized that ACE2 overexpression and Ang-(1–7) may protect endothelial cell function by counterregulation of angiotensin II signaling and inhibition of inflammatory response. Methods We used a recombinant adenovirus vector to locally overexpress ACE2 gene (Ad-ACE2) in human endothelial cells in vitro and in apoE-deficient mice in vivo. The Ang II-induced MCP-1, VCAM-1 and E-selectin expression, endothelial cell migration and adhesion of human monocytic cells (U-937) to HUVECs by ACE2 gene transfer were evaluated in vitro. Accelerated atherosclerosis was studied in vivo, and atherosclerosis was induced in apoE-deficient mice which were divided randomly into four groups that received respectively a ACE2 gene transfer, Ad-ACE2, Ad-EGFP, Ad-ACE2 + A779, an Ang-(1–7) receptor antagonist, control group. After a gene transfer for 4 weeks, atherosclerotic pathology was evaluated. Results ACE2 gene transfer not only promoted HUVECs migration, inhibited adhesion of monocyte to HUVECs and decreased Ang II-induced MCP-1, VCAM-1 and E-selectin protein production in vitro, but also decreased the level of MCP-1, VCAM-1 and interleukin 6 and inhibit atherosclerotic plaque evolution in vivo. Further, administration of A779 increased the level of MCP-1, VCAM-1 and interleukin 6 in vivo and led to further advancements in atherosclerotic extent. Conclusions ACE2 and Ang-(1–7) significantly inhibit early atherosclerotic lesion formation via protection of endothelial function and inhibition of inflammatory response.

Key Points Cell-adhesion molecules of the cadherin and immunoglobulin-like cell-adhesion molecule (Ig-CAM) superfamilies not only exert their functions by mediating cell–cell and cell–matrix adhesion, but also by directly eliciting signals that are involved in tissue morphogenesis and tumour progression. In addition, signalling molecules are also able to modulate the adhesion status of the cell by acting on cell-adhesion molecules themselves, or on other components of signalling complexes. The function of epithelial (E)-cadherin is altered in most epithelial tumours during the progression to tumour malignancy. E-cadherin function can be disrupted by various genetic and epigenetic mechanisms, including modulation by signalling molecules. Loss of E-cadherin function elicits active signals that support tumour-cell migration, invasion and metastatic dissemination. In several cancer types, loss of E-cadherin function is accompanied by the gain of expression of mesenchymal cadherins, for example, neuronal (N)-cadherin and cadherin-11, in a process that is known as the cadherin switch. N-cadherin interacts with members of the fibroblast growth factor receptor (FGFR) family, thereby inducing pro-migratory and invasive signalling cascades. Neural CAM (NCAM) also associates with FGFRs. Loss of NCAM function during tumour progression affects cell–matrix adhesion through the loss of FGFR-induced, integrin-mediated cell–matrix adhesion. Several other members of the cadherin and Ig-CAM families interact with signalling molecules, thereby modulating physiological and pathological processes. In addition to their adhesive functions, cell-adhesion molecules modulate signal-transduction pathways by interacting with molecules such as receptor tyrosine kinases, components of the WNT signalling pathway and RHO-family GTPases. So, changes in the expression of cell-adhesion molecules affect not only the adhesive repertoire of a cell, but also its signal-transduction status. Conversely, signalling pathways can modulate the function of cell-adhesion molecules, altering the interactions between cells and their environment. Recent experimental evidence indicates that such processes have a crucial role in tumour progression, in particular during invasion and metastasis.

As obligate intracellular parasites, viruses must traverse the host-cell plasma membrane to initiate infection. This presents a formidable barrier, which they have evolved diverse strategies to overcome. Common to all entry pathways, however, is a mechanism of specific attachment to cell-surface macromolecules or ‘receptors’. Receptor usage frequently defines viral tropism, and consequently, the evolutionary changes in receptor specificity can lead to emergence of new strains exhibiting altered pathogenicity or host range. Several classes of molecules are exploited as receptors by diverse groups of viruses, including, for example, sialic acid moieties and integrins. In particular, many cell-adhesion molecules that belong to the immunoglobulin-like superfamily of proteins (IgSF CAMs) have been identified as viral receptors. Structural analysis of the interactions between viruses and IgSF CAM receptors has not shown binding to specific features, implying that the Ig-like fold may not be key. Both proteinaceous and enveloped viruses exploit these proteins, however, suggesting convergent evolution of this trait. Their use is surprising given the usually occluded position of CAMs on the cell surface, such as at tight junctions. Nonetheless, the reason for their widespread involvement in virus entry most probably originates in their functional rather than structural characteristics.