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Cell adhesion molecules are ubiquitous in multicellular organisms, specifying precise cell-cell interactions in processes as diverse as tissue development, immune cell trafficking and the wiring of the nervous system1-4. Here we show that a wide array of synthetic cell adhesion molecules can be generated by combining orthogonal extracellular interactions with intracellular domains from native adhesion molecules, such as cadherins and integrins. The resulting molecules yield customized cell-cell interactions with adhesion properties that are similar to native interactions. The identity of the intracellular domain of the synthetic cell adhesion molecules specifies interface morphology and mechanics, whereas diverse homotypic or heterotypic extracellular interaction domains independently specify the connectivity between cells. This toolkit of orthogonal adhesion molecules enables the rationally programmed assembly of multicellular architectures, as well as systematic remodelling of native tissues. The modularity of synthetic cell adhesion molecules provides fundamental insights into how distinct classes of cell-cell interfaces may have evolved. Overall, these tools offer powerful abilities for cell and tissue engineering and for systematically studying multicellular organization.
Cell adhesion molecules (CAMs) of the cadherin, integrin, immunoglobulin, and selectin protein families are indispensable for the formation and maintenance of multicellular tissues, especially epithelia. In the epidermis, they are involved in cell-cell contacts and in cellular interactions with the extracellular matrix (ECM), thereby contributing to the structural integrity and barrier formation of the skin. Bulk and single cell RNA sequencing data show that >170 CAMs are expressed in the healthy human skin, with high expression levels in melanocytes, keratinocytes, endothelial, and smooth muscle cells. Alterations in expression levels of CAMs are involved in melanoma propagation, interaction with the microenvironment, and metastasis. Recent mechanistic analyses together with protein and gene expression data provide a better picture of the role of CAMs in the context of skin physiology and melanoma. Here, we review progress in the field and discuss molecular mechanisms in light of gene expression profiles, including recent single cell RNA expression information. We highlight key adhesion molecules in melanoma, which can guide the identification of pathways and strategies for novel anti-melanoma therapies.
Granular cell tumors (GCTs) are characterized by abundant eosinophilic cytoplasmic granules. Based on the hypothesis that canine intracranial GCT is a subtype of meningioma and its cytoplasmic granules are formed through autophagy processes, histopathological and immunohistochemical examination were performed on biopsy samples from 7 cases of canine intracranial GCTs and 15 cases of conventional meningiomas. Histopathologically, 7/7 cases of GCTs involved the meninges; foci of meningothelial-like cells were observed in 3/7 cases; brain invasion was observed in 2/7 cases. Immunohistochemically, neoplastic cells of GCTs were positive for E-cadherin and negative for S100, cytokeratin, CD204, and β-catenin in 7/7 cases. Neoplastic cells of 15/15 cases of meningiomas were positive for E-cadherin, and negative for S100 and CD204. Immunoreactivity of meningiomas for cytokeratin and β-catenin was observed in 6/15 cases and 8/15 cases, respectively. Cytoplasmic granules of GCTs were positive for ubiquitin (5/7), p62 (5/7), and LC3 (7/7). Compared to GCTs, the ratios of ubiquitin (6/15) and p62 (3/15) positive cases were lower in meningiomas, and 15/15 cases were negative for LC3. These findings indicate that the biological natures of GCTs including anatomical location, histopathological features and immunoreactivity for E-cadherin are almost in conformity with those of meningiomas. The immunoreactivity for autophagy associated molecules may suggest the possible involvement of autophagy in cytoplasmic granule formation of canine intracranial GCTs.
The expression of soluble adhesion molecules inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), besides activation of endothelial cells and transendothelial migration of leukocytes, play an important role in inflammation and progression of ischemic injury after acute stroke. The aim of this study was to determine serum levels of soluble ICAM-1 and VCAM-1 in patients with acute ischemic stroke and controls and correlate them according to etiological subtypes (thromboembolic or lacunar stroke), stroke severity and disability after acute stroke.
RNA modifications have attracted increasing interest in recent years because they have been frequently implicated in various human diseases, including cancer, highlighting the importance of dynamic post‑transcriptional modifications. Methyltransferase‑like 6 (METTL6) is a member of the RNA methyltransferase family that has been identified in many cancers; however, little is known about its specific role or mechanism of action. In the present study, we aimed to study the expression levels and functional role of METTL6 in hepatocellular carcinoma (HCC), and further investigate the relevant pathways. To this end, we systematically conducted bioinformatics analysis of METTL6 in HCC using gene expression data and clinical information from a publicly available dataset. The mRNA expression levels of METTL6 were significantly upregulated in HCC tumor tissues compared to that in adjacent non‑tumor tissues and strongly associated with poorer survival outcomes in patients with HCC. CRISPR/Cas9‑mediated knockout of METTL6 in HCC cell lines remarkably inhibited colony formation, cell proliferation, cell migration, cell invasion and cell attachment ability. RNA sequencing analysis demonstrated that knockout of METTL6 significantly suppressed the expression of cell adhesion‑related genes. However, chromatin immunoprecipitation sequencing results revealed no significant differences in enhancer activities between cells, which suggests that METTL6 may regulate genes of interest post‑transcriptionally. In addition, it was demonstrated for the first time that METTL6 was localized in the cytosol as detected by immunofluorescence analysis, which indicates the plausible location of RNA modification mediated by METTL6. Our findings provide further insight into the function of RNA modifications in cancer and suggest a possible role of METTL6 as a therapeutic target in HCC.
Tumor necrosis factor-alpha, interleukin-1, and endotoxin stimulate the expression of vascular endothelial cell (EC) adhesion molecules. Here we describe a novel pathway of adhesion molecule induction that is independent of exogenous factors, but which is dependent on integrin signaling and cell-cell interactions. Cells plated onto gelatin, fibronectin, collagen or fibrinogen, or anti-integrin antibodies, expressed increased amounts of E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1. In contrast, ECs failed to express E-selectin when plated on poly-L-lysine or when plated on fibrinogen in the presence of attachment-inhibiting, cyclic Arg-Gly-Asp peptides. The duration and magnitude of adhesion molecule expression was dependent on EC density. Induction of E-selectin on ECs plated at confluent density was transient and returned to basal levels by 15 h after plating when only 7 +/- 2% (n = 5) of cells were positive. In contrast, cells plated at low density displayed a 17-fold greater expression of E-selectin than did high density ECs with 57 +/- 4% (n = 5) positive for E-selectin expression 15 h after plating, and significant expression still evident 72 h after plating. The confluency-dependent inhibition of expression of E-selectin was at least partly mediated through the cell junctional protein, platelet/endothelial cell adhesion molecule-1 (PECAM-1). Antibodies against PECAM-1, but not against VE-cadherin, increased E-selectin expression on confluent ECs. Co- culture of subconfluent ECs with PECAM-1- coated beads or with L cells transfected with full-length PECAM-1 or with a cytoplasmic truncation PECAM-1 mutant, inhibited E-selectin expression. In contrast, untransfected L cells or L cells transfected with an adhesion-defective domain 2 deletion PECAM-1 mutant failed to regulate E-selectin expression. In an in vitro model of wounding the wound front displayed an increase in the number of E-selectin-expressing cells, and also an increase in the intensity of expression of E-selectin positive cells compared to the nonwounded monolayer. Thus we propose that the EC junction, and in particular, the junctional molecule PECAM-1, is a powerful regulator of endothelial adhesiveness.
Adoptive cell therapy (ACT) using ex vivo engineered/expanded immune cells demonstrated poor efficacy against solid tumors, despite its great success in treating various hematopoietic malignancies. To improve ACT for solid tumors, it is crucial to comprehend how the numerous components of the tumor microenvironment (TME) surrounding solid tumor cells influence killing ability of immune cells. In this study, we sought to determine the effects of extracellular adhesion provided by extracellular matrix (ECM) of TME on immune cell cytotoxicity by devising microwell arrays coated with proteins either preventing or promoting cell adhesion. Solid tumor cells in bovine serum albumin (BSA)-coated microwells did not attach to the surfaces and exhibited a round morphology, but solid tumor cells in fibronectin (FN)-coated microwells adhered firmed to the substrates with a flat shape. The seeding densities of solid tumor cells and immune cells were tuned to maximize one-to-one pairing within a single microwell, and live cell imaging was performed to examine dynamic cell-cell interactions and immune cell cytotoxicity at a single cell level. Both natural killer (NK) cells and T cells showed higher cytotoxicity against round tumor cells in BSA-coated microwells compared to flat tumor cells in FN-coated microwells, suggesting that extracellular adhesion-mediated firm adhesion of tumor cells made them more resistant to immune cell-mediated killing. Additionally, NK cells and T cells in FN-coated microwells exhibited divergent dynamic behaviors, indicating that two distinct subsets of cytotoxic lymphocytes respond differentially to extracellular adhesion cues during target cell recognition.
Textbook models of synaptogenesis position cell adhesion molecules such as neurexin as initiators of synapse assembly. Here we discover a mechanism for presynaptic assembly that occurs prior to neurexin recruitment, while supporting a role for neurexin in synapse maintenance. We find that the cytosolic active zone scaffold SYD-1 interacts with membrane phospholipids to promote active zone protein clustering at the plasma membrane, and subsequently recruits neurexin to stabilize those clusters. Employing molecular dynamics simulations to model intrinsic interactions between SYD-1 and lipid bilayers followed by in vivo tests of these predictions, we find that PIP2-interacting residues in SYD-1's C2 and PDZ domains are redundantly necessary for proper active zone assembly. Finally, we propose that the uncharacterized yet evolutionarily conserved short γ isoform of neurexin represents a minimal neurexin sequence that can stabilize previously assembled presynaptic clusters, potentially a core function of this critical protein.
Endometrial receptivity is a decisive factor in human reproduction. Human chorionic gonadotropin (hCG) is one of the first embryonic signals that precedes the implantation by trophoblast invasion into the endometrium. Meta-analysis of randomized controlled trials reports a moderate-quality evidence for improved live birth rate for an intrauterine hCG dose ≥ 500 IU. Nevertheless, all hCG endometrial effects are not completely understood. We, therefore, utilized endometrial tissue from 12 patients after estradiol and progesterone treatment with or without intrauterine hCG flushing at the window of implantation (WOI) to analyze cellular composition by measuring marker proteins for stromal, endothelial, epithelial and immune cells. Flow cytometry analysis revealed that significantly more cells expressed the endothelial adhesion molecules VE-cadherin (CD144) and S-Endo-1 (CD146) after intrauterine hCG administration. In contrast, the endothelial marker CD31 and markers involved in vessel formation (VEGFR1 and VEGFR2) remained unchanged in their expression. Similarly, stroma markers (CD73, CD90 and CD105), epithelial markers (Desmocollin-2 and E-Cadherin) and immune cell markers (CD11b, CD45, CD79a and HLA-DR) displayed no alterations in their expression. This finding directs the focus on endothelial adhesion molecules as a potential mechanistically explanation of hCG conveyed increase of embryo implantation and pregnancy rates in women undergoing ART.
Paraneoplastic neurological syndromes (PNS) are rare neurological disorders in which ectopic expression of neural antigens by a tumor results in an autoimmune attack against the nervous system. Onconeural antibodies not only guide PNS diagnosis but may also help detecting underlying malignancies. Our project aims to uncover new potential antibodies in paraneoplastic neuropathies (PN).
Nectin and nectin-like cell adhesion molecules (collectively referred as nectin family henceforth) are known to mediate cell-cell adhesion and related functions. While current literature suggests that nectins are prevalent in vertebrates, there are no in-depth analyses regarding the evolution of nectin family as a whole. In this work, we examine the evolutionary origin of the nectin family, using selected multicellular metazoans representing diverse clades whose whole genome sequencing data is available. Our results show that this family may have appeared earlier during metazoan evolution than previously believed. Systematic analyses indicate the order in which various members of nectin family seem to have evolved, with some nectin-like molecules appearing first, followed by the evolution of other members. Furthermore, we also found a few possible ancient homologues of nectins. While our study confirms the previous grouping of the nectin family into nectins and nectin-like molecules, it also shows poliovirus receptor (PVR/nectin-like-5) to possess characteristics that are intermediate between these two groups. Interestingly, except for PVR, the other nectins show surprising sequence conservations across species, suggesting evolutionary constraints due to critical roles played by these proteins.
IgLON family is a subgroup of the immunoglobulin superfamily cell adhesion molecules and composed of limbic system-associated protein (LAMP), opioid binding cell adhesion molecule (OBCAM), neurotrimin (Ntm) and Kilon. In the present study, we investigated the overexpression of LAMP, OBCAM, Ntm and Kilon on the proliferation and cell size of type-1 astrocytes in vitro. Quantitative analysis using bromodeoxyuridine immunocytochemistry revealed that the expression of OBCAM had greater inhibitory effect on astrocytic proliferation as compared with LAMP, Ntm and Kilon ones. OBCAM overexpression increased the cell size of astrocytes as compared with the control. The treatment of FGF-2 had greater proliferative effect on OBCAM-transfected astrocytes as compared with the control. These results suggest that OBCAM is more potent regulator for controlling the proliferation and cell size of astrocytes as compared with other IgLON proteins possibly through FGF-2 receptor-mediated pathway.
Cyclodextrins (CDs) are used as drug delivery agents. In this study, we examined whether CDs have an inflammatory effect on endothelial cells. First, we found that β-CD promoted cell proliferation in bovine aortic endothelial cells and elevated nitric oxide (NO) production through dephosphorylation of threonine-495 (T-495) in endothelial nitric oxide synthetase (eNOS). Dephosphorylation of T-495 is known to activate eNOS. Phosphorylation of T-495 was found to be catalyzed by protein kinase Cε (PKCε). We then found that β-CD inhibits binding of PKCε to diacylglycerol (DAG) via formation of a β-CD-DAG complex, indicating that β-CD inactivates PKCε. Furthermore, β-CD controls activation of PKCε by reducing the recruitment of PKCε into the plasma membrane. Finally, β-CD inhibits expression of intercellular and vascular cell adhesion molecule-1 by increasing NO via control of PKCε/eNOS and suppression of THP-1 cell adhesion to endothelial cells. These findings imply that β-CD plays an important role in anti-inflammatory processes.
Resveratrol, a safe and multi-targeted agent, has been associated with suppression of survival, proliferation and metastasis of cancer, however, the underlying mechanisms for its anti-cancer activity, particularly on cellular signaling during cancer cell migration still remain poorly understood. We investigated the invasion response of two human colorectal cancer (CRC) cells (HCT116 and SW480) to resveratrol and studied the effect of specific pharmacological inhibitors, cytochalasin D (CytD) and focal adhesion kinase-inhibitor (FAK-I) on FAK, cell viability and migration in CRC. We found that resveratrol altered cell phenotype of both CRC cells, reduced cell viability and the results were comparable to FAK-I and CytD. These effects of resveratrol were associated with marked Sirt1 up-regulation, FAK down-regulation, inhibition of focal adhesion and potentiation of effects by combinatorial treatment of resveratrol and inhibitors. Interestingly, inhibition of FAK with FAK-I or treatment with CytD suppressed resveratrol-induced Sirt1 up-regulation and markedly down-regulated FAK expression. Resveratrol or combination treatment with inhibitors significantly activated caspase-3 and potentiated apoptosis. Moreover, resveratrol suppressed invasion and colony forming capacity, cell proliferation, β1-Integrin expression and activation of FAK of cells in alginate tumor microenvironment, similar to FAK-I or CytD. Finally, we demonstrated that resveratrol, FAK-I or CytD inhibited activation of NF-κB, suppressed NF-κB-dependent gene end-products involved in invasion, metastasis, and apoptosis; and these effects of resveratrol were potentiated by combination treatment with FAK-I or CytD. Our data illustrated that the anti-invasion effect of resveratrol by inhibition of FAK activity has a potential beneficial role in disease prevention and therapeutic management of CRC.
Drosophila reproductive behaviors are directed by fruitless neurons. A reanalysis of genomic studies shows that genes encoding dpr and DIP immunoglobulin superfamily (IgSF) members are expressed in fru P1 neurons. We find that each fru P1 and dpr/DIP (fru P1 ∩ dpr/DIP) overlapping expression pattern is similar in both sexes, but there are dimorphisms in neuronal morphology and cell number. Behavioral studies of fru P1 ∩ dpr/DIP perturbation genotypes indicate that the mushroom body functions together with the lateral protocerebral complex to direct courtship behavior. A single-cell RNA-seq analysis of fru P1 neurons shows that many DIPs have high expression in a small set of neurons, whereas the dprs are often expressed in a larger set of neurons at intermediate levels, with a myriad of dpr/DIP expression combinations. Functionally, we find that perturbations of sex hierarchy genes and of DIP-ε change the sex-specific morphologies of fru P1 ∩ DIP-α neurons.
In the post-genomic era, computational identification of cell adhesion molecules (CAMs) becomes important in defining new targets for diagnosis and treatment of various diseases including cancer. Lack of a comprehensive CAM-specific database restricts our ability to identify and characterize novel CAMs. Therefore, we developed a comprehensive mammalian cell adhesion molecule (MCAM) database. The current version is an interactive Web-based database, which provides the resources needed to search mouse, human and rat-specific CAMs and their sequence information and characteristics such as gene functions and virtual gene expression patterns in normal and tumor tissues as well as cell lines. Moreover, the MCAM database can be used for various bioinformatics and biological analyses including identifying CAMs involved in cell-cell interactions and homing of lymphocytes, hematopoietic stem cells and malignant cells to specific organs using data from high-throughput experiments. Furthermore, the database can also be used for training and testing existing transmembrane (TM) topology prediction methods specifically for CAM sequences. The database is freely available online at http://app1.unmc.edu/mcam.
The 293 cell line, used extensively in various types of studies due to the ease with which these cells can be transfected, was thought to be derived by the transformation of primary cultures of human embryonic kidney cells with sheared adenovirus type 5 DNA. Although the 293 cells were assumed to originate from epithelial cells, the exact origin of these cells remains unknown. Previous attempts to characterize these cells combined immunostaining, immunoblot analysis and microarray analysis to demonstrate that 293 cells express neurofilament subunits, α-internexin, and several other proteins typically found in neurons. These findings raised the possibility that the 293 cell line may have originated from human neuronal lineage cells. Contrary to this suggestion, in this study, we found that the 293 cells expressed N-cadherin and vimentin, which are marker proteins expressed in mesenchymal cells. Furthermore, the 293 cells also expressed E-cadherin, cytokeratins 5/8 and desmoglein 2, which are epithelial cell markers. When the cells, primarily cultured from the kidneys of Clawn miniature swine and passaged 10-15 generations [termed porcine kidney epithelial (PKE) cells] were examined, they were found to be positive for the expression of both mesenchymal and epithelial markers. Thus, transformation by adenovirus was not necessary for the cells to express N-cadherin. Occludin and zonula occludens (ZO)-1, two components of tight junctions in epithelial and endothelial cells, were detected in the 293 and the PKE cells. Thus, the findings of the present study demonstrate that 293 cells retain several characteristics of epithelial cells.
Cell adhesion molecules (CAMs) in the nervous system have long been a research focus, but many mice lacking CAMs show very subtle phenotypes, giving an impression that CAMs may not be major players in constructing the nervous system. However, recent human genetic studies suggest CAM involvement in many neuropsychiatric disorders, implicating that they must have significant functions in nervous system development, namely in circuitry formation. As CAMs can provide specificity through their molecular interactions, this review summarizes possible mechanisms on how alterations of CAMs can result in neuropsychiatric disorders through circuitry modification.
Human PRICKLE1 gene has been associated with epilepsy. However, the underlying pathogenetic mechanisms remain elusive. Here we report a Drosophila prickle mutant pk IG1-1 exhibiting strong epileptic seizures and, intriguingly, abnormal glial wrapping. We found that pk is required in both neurons and glia, particularly neuropil ensheathing glia (EGN), the fly analog of oligodendrocyte, for protecting the animal from seizures. We further revealed that Pk directly binds to the membrane skeleton binding protein Ankyrin 2 (Ank2), thereby regulating the cell adhesion molecule Neuroglian (Nrg). Such protein interactions also apply to their human homologues. Moreover, nrg and ank2 mutant flies also display seizure phenotypes, and expression of either Nrg or Ank2 rescues the seizures of pk IG1-1 flies. Therefore, our findings indicate that Prickle ensures neuron-glial interaction within neuropils through regulating cell adhesion between neurons and ensheathing glia. Dysregulation of this process may represent a conserved pathogenic mechanism underlying PRICKLE1-associated epilepsy.
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