Classical cadherin adhesion molecules: coordinating cell adhesion, signaling and the cytoskeleton

Classical cadherin adhesion molecules are fundamental determinants of tissue organization in both health and disease. Recent advances in understanding the molecular and cellular basis of cadherin function have revealed that these adhesion molecules serve as molecular couplers, linking cell surface adhesion and recognition to both the actin cytoskeleton and cell signalling pathways. We will review some of these developments, to provide an overview of progress in this rapidly-developing area of cell and developmental biology.     

T cell adhesion mechanisms revealed by receptor lateral mobility

Cell surface receptors mediate the exchange of information between cells and their environment. In the case of adhesion receptors, the spatial distribution and molecular associations of the receptors are critical to their function. Therefore, understanding the mechanisms regulating the distribution and binding associations of these molecules is necessary to understand their functional regulation. Experiments characterizing the lateral mobility of adhesion receptors have revealed a set of common mechanisms that control receptor function and thus cellular behavior. The T cell provides one of the most dynamic examples of cellular adhesion. An individual T cell makes innumerable intercellular contacts with antigen presenting cells, the vascular endothelium, and many other cell types. We review here the mechanisms that regulate T cell adhesion receptor lateral mobility as a window into the molecular regulation of these systems, and we present a general framework for understanding the principles and mechanisms that are likely to be common among these and other cellular adhesion systems. We suggest that receptor lateral mobility is regulated via four major mechanisms-reorganization, recruitment, dispersion, and anchoring-and we review specific examples of T cell adhesion receptor systems that utilize one or more of these mechanisms.     

Modeling and simulation of chemomechanics at the cell-matrix interface

Chemomechanical characteristics of the extracellular materials with which cells interact can have a profound impact on cell adhesion and migration. To understand and modulate such complex multiscale processes, a detailed understanding of the feedback between a cell and the adjacent microenvironment is crucial. Here, we use computational modeling and simulation to examine the cell-matrix interaction at both the molecular and continuum lengthscales. Using steered molecular dynamics, we consider how extracellular matrix (ECM) stiffness and extracellular pH influence the interaction between cell surface adhesion receptors and extracellular matrix ligands, and we predict potential consequences for focal adhesion formation and dissolution. Using continuum level finite element simulations and analytical methods to model cell-induced ECM deformation as a function of ECM stiffness and thickness, we consider the implications toward design of synthetic substrata for cell biology experiments that intend to decouple chemical and mechanical cues.Key words: cell adhesion, focal adhesion, steered molecular dynamics, finite element, chemomechanics, multiscale modeling, elasticity theory     

CELL BEHAVIOUR AND MOLECULAR MECHANISMS OF CELL-CELL ADHESION

1. At the behavioural level, cell adhesion is generally non-specific. The search for molecular mechanisms of adhesion should be conducted on this basis.
2. Cells in general, be they from slime moulds or vertebrate epithelia, possess multiple molecular adhesive mechanisms. In epithelial cells this is shown by the number of their different ultrastructurally recognizable intercellular junctions. Elucidation of the structure and composition of such intercellular junctions will make a valuable contribution to the understanding of cell adhesion.
3. The measurement of cell adhesion is fraught with difficulties. Commonly used assays by aggregation cannot give a true representation of the normal adhesive interactions of cells in tissues, and the results they yield must be interpreted with caution. This is because it takes dissociated tissue cells up to 24 h to develop their full adhesiveness after making initial contact.
4. Cell-cell adhesion probably depends largely upon the interaction of complementary molecules on adjacent cell surfaces. Glycoproteins seem the most likely candidates but, as yet, there is no compelling evidence in any individual case and mechanisms of cell adhesion still remain obscure.     

Cell adhesion: old and new questions

Metazoans clearly need cell adhesion to hold themselves together, but adhesion does much more than that. Adhesion receptors make transmembrane connections, linking extracellular matrix and adjacent cells to the intracellular cytoskeleton, and they also serve as signal transducers. In this article, I briefly summarize our present understanding of the molecular basis and biological consequences of cell adhesion and discuss how our current knowledge sheds light on questions of specificity of cell adhesion. I offer some thoughts and speculations about the evolution of cell-adhesion molecules and processes, consider their inter-relationships with other forms of cell–cell communication and discuss unresolved questions ripe for investigation as we enter the postgenomic era.     

Cell adhesion: old and new questions

Metazoans clearly need cell adhesion to hold themselves together, but adhesion does much more than that. Adhesion receptors make transmembrane connections, linking extracellular matrix and adjacent cells to the intracellular cytoskeleton, and they also serve as signal transducers. In this article, I briefly summarize our present understanding of the molecular basis and biological consequences of cell adhesion and discuss how our current knowledge sheds light on questions of specificity of cell adhesion. I offer some thoughts and speculations about the evolution of cell-adhesion molecules and processes, consider their inter-relationships with other forms of cell–cell communication and discuss unresolved questions ripe for investigation as we enter the postgenomic era.     

Cell adhesion: old and new questions

Metazoans clearly need cell adhesion to hold themselves together, but adhesion does much more than that. Adhesion receptors make transmembrane connections, linking extracellular matrix and adjacent cells to the intracellular cytoskeleton, and they also serve as signal transducers. In this article, I briefly summarize our present understanding of the molecular basis and biological consequences of cell adhesion and discuss how our current knowledge sheds light on questions of specificity of cell adhesion. I offer some thoughts and speculations about the evolution of cell-adhesion molecules and processes, consider their inter-relationships with other forms of cell–cell communication and discuss unresolved questions ripe for investigation as we enter the postgenomic era.     

Intercellular adhesive selectivity. II. Properties of embryonic chick liver cell-cell adhesion

Studies directed at understanding the molecular basis of liver cell homotypic adhesion are presented. An assay which measures the rate of adhesion of isotopically labeled (32PO4) embryonic chick liver cells to liver cell aggregates, described in a companion paper, has been used to investigate the problem of intercellular adhesive selectivity. Cation requirements, the effects of various inhibitors of metabolism and protein synthesis, of chelators (EDTA and EGTA), and the effects of temperature on liver cell adhesion are reported. Two mechanisms of inhibition of liver intercellular adhesion are suggested. One involves destruction of cell-surface adhesion receptors (sensitivity to proteases); the other is an energy-dependent step which may involve alterations in plasma membrane conformation and/or membrane fluidity. Finally, a model is suggested for liver cell-cell adhesion that incorporates the early tissue selectivity of intercellular adhesion previously reported, followed by a multistep process which leads to histogenic aggregation.     

Towards understanding the mode of action of the multifaceted cell adhesion receptor CD146

CD146, also known as melanoma cell adhesion molecule or MCAM, is a key cell adhesion protein in vascular endothelial cell activity and angiogenesis. CD146 promotes tumor progression of many cancers including melanoma and prostate. Strikingly, its expression is frequently lost in breast carcinoma cells, and it may act as a suppressor of breast cancer progression. While upstream mechanisms regulating CD146 are well documented, our understanding of the downstream molecular events underlying its mode of action remains to be elucidated. This review aims to focus on the progress in understanding the signaling mechanisms and the functional relevance of CD146, a multifaceted molecule, in cancer with particular emphasis on its role in inhibiting breast cancer progression.     

Modeling and simulation of chemomechanics at the cell-matrix interface

Chemomechanical characteristics of the extracellular materials with which cells interact can have a profound impact on cell adhesion and migration. To understand and modulate such complex multiscale processes, a detailed understanding of the feedback between a cell and the adjacent microenvironment is crucial. Here, we use computational modeling and simulation to examine the cell-matrix interaction at both the molecular and continuum lengthscales. Using steered molecular dynamics, we consider how extracellular matrix (ECM) stiffness and extracellular pH influence the interaction between cell surface adhesion receptors and extracellular matrix ligands, and we predict potential consequences for focal adhesion formation and dissolution. Using continuum-level finite element simulations and analytical methods to model cell-induced ECM deformation as a function of ECM stiffness and thickness, we consider the implications toward design of synthetic substrata for cell biology experiments that intend to decouple chemical and mechanical cues.     

Focal Adhesion: A Focal Point in Current Cell Biology and Molecular Medicine

Cell-extracellular matrix (ECM) is an important property of virtually all cells in multi-cellular organisms. Cell-ECM adhesion research, therefore, has broad impact on biology and medicine. Studies over the past three decades have resulted in tremendous advance in our understanding of the molecular basis and functions of cell-ECM adhesion. Here, I focus on some of the general lessons that we have learned from recent studies on cell-ECM adhesion. In addition, I highlight several topics in this rapidly advancing research area. These topics, which include assembly, disassembly and regulation of cell-ECM adhesion structures, the molecular mechanisms of bi-directional signaling through cell-ECM adhesions, and the tissue and organ pathobiology of cell-ECM adhesion, are pertinent to our understanding of cell-ECM adhesion and signaling.Key Words: Focal adhesion, integrins, extracellular matrix, cytoskeleton, cell migrationCell-ECM adhesion is a fundamental process through which cells interact and communicate with the environment. Cell-ECM adhesion is essential for organogenesis during embryonic development. In adult, it is vital for maintenance of tissue integrity and organ functions. Alterations of cell-ECM adhesion hence are frequently associated with human diseases. Because of the broad significance of cell-ECM adhesion in biology and pathology, understanding how cell-ECM adhesion is mediated and regulated and determining how cell-ECM adhesion influences cell behavior have been the subjects of numerous studies. In particular, studies over the past three decades have led to major breakthroughs in our understanding of cell-ECM adhesion. Many of the key discoveries, including identification of integrins as major transmembrane receptors for ECM proteins, demonstration of integrins as bi-directional (outside-in and inside-out) transmembrane signaling machines, identification of talin, focal adhesion kinase (FAK), integrin-linked kinase (ILK) and other cytoplasmic and membrane-associated proteins as key regulators and effectors of integrins, and delineation of multiple downstream signaling pathways that relay signals from cell surface integrins to diverse cytoplasmic and nuclear effectors, have been reviewed in refs. ^1–12. In this brief article, I will focus on some of the general features of cell-ECM adhesion and discuss from my personal perspective several key questions that remain to be answered in future studies.     

New insights into Nm23 control of cell adhesion and migration

The molecular mechanisms underlying the role of Nm23/NDP kinase in controlling cell migration and metastasis have been investigated. The recent progress in our understanding of cell migration at a molecular level gives us some clues to the putative Nm23 function as a suppressor of metastasis. Screening of the literature indicates that NDP kinases have pleiotropic effects. By modifying cytoskeleton organization and protein trafficking, some NDP kinase isoforms may indirectly promote adhesion to the extracellular matrix in some cell types. Conversely, Nm23 regulates cell surface expression of integrin receptors and matrix metallo-proteases, and thus directly controls the cell adhesion machinery. Finally, the recent discovery of the interaction between Nm23-H2 and the negative regulator of 1 integrin-mediated cell adhesion, ICAP-1, which targets the kinase to lamellipodia and cell protrusions, suggests that the Nm23-H2/ICAP-1 complex plays a role in integrin signaling, and exerts a fine-tuning between migration and spreading.     

Influence of Substrates on the Surface Characteristics and Membrane Proteome of Fibrobacter succinogenes S85

Although Fibrobacter succinogenes S85 is one of the most proficient cellulose degrading bacteria among all mesophilic organisms in the rumen of herbivores, the molecular mechanism behind cellulose degradation by this bacterium is not fully elucidated. Previous studies have indicated that cell surface proteins might play a role in adhesion to and subsequent degradation of cellulose in this bacterium. It has also been suggested that cellulose degradation machinery on the surface may be selectively expressed in response to the presence of cellulose. Based on the genome sequence, several models of cellulose degradation have been suggested. The aim of this study is to evaluate the role of the cell envelope proteins in adhesion to cellulose and to gain a better understanding of the subsequent cellulose degradation mechanism in this bacterium. Comparative analysis of the surface (exposed outer membrane) chemistry of the cells grown in glucose, acid-swollen cellulose and microcrystalline cellulose using physico-chemical characterisation techniques such as electrophoretic mobility analysis, microbial adhesion to hydrocarbons assay and Fourier transform infra-red spectroscopy, suggest that adhesion to cellulose is a consequence of an increase in protein display and a concomitant reduction in the cell surface polysaccharides in the presence of cellulose. In order to gain further understanding of the molecular mechanism of cellulose degradation in this bacterium, the cell envelope-associated proteins were enriched using affinity purification and identified by tandem mass spectrometry. In total, 185 cell envelope-associated proteins were confidently identified. Of these, 25 proteins are predicted to be involved in cellulose adhesion and degradation, and 43 proteins are involved in solute transport and energy generation. Our results supports the model that cellulose degradation in F. succinogenes occurs at the outer membrane with active transport of cellodextrins across for further metabolism of cellodextrins to glucose in the periplasmic space and inner cytoplasmic membrane.     

Non-Catalytic Functions of Pyk2 and Fyn Regulate Late Stage Adhesion in Human T Cells

T cell activation drives the protective immune response against pathogens, but is also critical for the development of pathological diseases in humans. Cytoskeletal changes are required for downstream functions in T cells, including proliferation, cytokine production, migration, spreading, and adhesion. Therefore, investigating the molecular mechanism of cytoskeletal changes is crucial for understanding the induction of T cell-driven immune responses and for developing therapies to treat immune disorders related to aberrant T cell activation. In this study, we used a plate-bound adhesion assay that incorporated near-infrared imaging technology to address how TCR signaling drives human T cell adhesion. Interestingly, we observed that T cells have weak adhesion early after TCR activation and that binding to the plate was significantly enhanced 30–60 minutes after receptor activation. This late stage of adhesion was mediated by actin polymerization but was surprisingly not dependent upon Src family kinase activity. By contrast, the non-catalytic functions of the kinases Fyn and Pyk2 were required for late stage human T cell adhesion. These data reveal a novel TCR-induced signaling pathway that controls cellular adhesion independent of the canonical TCR signaling cascade driven by tyrosine kinase activity.     

Human Endometrial Extracellular Vesicles Functionally Prepare Human Trophectoderm Model for Implantation: Understanding Bidirectional Maternal‐Embryo Communication

Embryo implantation into maternal endometrium is critical for initiation and establishment of pregnancy, requiring developmental synchrony between endometrium and blastocyst. However, factors regulating human endometrial–embryo cross talk and facilitate implantation remain largely unknown. Extracellular vesicles (EVs) are emerging as important mediators of this process. Here, a trophectoderm spheroid‐based in vitro model mimicking the pre‐implantation human embryo is used to recapitulate important functional aspects of blastocyst implantation. Functionally, human endometrial EVs, derived from hormonally treated cells synchronous with implantation, are readily internalized by trophectoderm cells, regulating adhesive and invasive capacity of human trophectoderm spheroids. To gain molecular insights into mechanisms underpinning endometrial EV‐mediated enhancement of implantation, quantitative proteomics reveal critical alterations in trophectoderm cellular adhesion networks (cell adhesion molecule binding, cell–cell adhesion mediator activity, and cell adherens junctions) and metabolic and gene expression networks, and the soluble secretome from human trophectodermal spheroids. Importantly, transfer of endometrial EV cargo proteins to trophectoderm to mediate changes in trophectoderm function is demonstrated. This is highlighted by correlation among endometrial EVs, the trophectodermal proteome following EV uptake, and EV‐mediated trophectodermal cellular proteome, important for implantation. This work provides an understanding into molecular mechanisms of endometrial EV‐mediated regulation of human trophectoderm functions—fundamental in understanding human endometrium–embryo signaling during implantation.     

Good Time for Cell Adhesion and Migration

Our understanding of the molecular and cellular mechanisms controlling cell adhesion and migration has never been so high. The era of “molecular interactions” requires an appropriate tool for exchanging views, presenting outstanding results and discussing new concepts in the field. This is why we decided to launch Cell Adhesion and Migration (CAM), a multi-disciplinary journal publishing original research articles and reviews covering the latest aspects of cellular and molecular mechanisms and their regulation both during physiological and pathological processes.     

细胞黏附和突触发生

突触是神经网络中神经细胞间相互连接的基本工作单位。突触的分子构建是一个引人入胜的问题,数十年来一直吸引着科学家们的注意。冯德培和许多其他科学家早期在神经肌肉接头领域做出了开创性的研究工作。至今,神经肌肉接头仍是一个杰出的突触标本,为我们研究中枢神经系统的突触形成铺平了道路。近期的研究又有新的亮点,发现一组细胞黏附分子具有很强的突触发生作用,使中枢突触形成的分子机制更加明朗。本文综述了这些表达在非神经细胞里能引起中枢突触形成的细胞黏附分子的功能与特性。     

Degradation of focal adhesion proteins during nocodazole-induced apoptosis in rat-1 cells

Nocodazole, a microtubule-disrupting agent, induced apoptosis in Rat-1 cells, as indicated by changes in cell morphology, DNA fragmentation, and eventual cell death. During nocodazole-induced apoptosis, normally flat cells became rounded in shape and detached from the extracellular matrix. These morphological changes appeared to be closely associated with degradation of focal adhesion proteins, including p130cas, p125(FAK) and paxillin. p130cas was also degraded in cells treated with staurosporine or etoposide, suggesting that degradation of focal adhesion proteins is a characteristic feature of apoptosis. Nocodazole-induced apoptosis was antagonized by Bcl-2: degradation of focal adhesion proteins was suppressed and cell viability was enhanced in bcl-2 over-expressing cells, even in the presence of nocodazole. Further study of the molecular mechanism of Bcl-2 activation should provide an understanding of the apoptosis induced by disruption of the microtubule network.     

Cell motility through plasma membrane blebbing

Plasma membrane blebs are dynamic cytoskeleton-regulated cell protrusions that have been implicated in apoptosis, cytokinesis, and cell movement. Influencing Rho-guanosine triphosphatase activities and subsequent actomyosin dynamics appears to constitute a core component for bleb formation. In this paper, we discuss recent evidence in support of a central role of nonapoptotic membrane blebbing for cell migration and cancer cell invasion as well as advances in our understanding of the underlying molecular mechanisms. Based on these studies, we propose that in a physiological context, bleb-associated cell motility reflects a cell's response to reduced substratum adhesion. The importance of blebbing as a functional protrusion is underscored by the existence of multiple molecular mechanisms that govern actin-mediated bleb retraction.