Multicellularity in the cellular slime mold Dictyostelium discoideum is achieved by the expression of two types of cell–cell adhesion sites. The EDTA‐sensitive adhesion sites are expressed very early in the developmental cycle and a surface glycoprotein of 24000 Da is known to be responsible for these sites. The EDTA‐resistant contact sites begin to accumulate on the cell surface at the aggregation stage of development. Several glycoproteins have been implicated in the EDTA‐resistant type of cell– (...) class='Hi'>cell binding and the best characterized one has an Mr of 80000 (gp80). gp80 mediates cell–cell binding via homophilic interaction and its cell binding site has been mapped to an octapeptide sequence. The mechanism by which gp80 mediates cell–cell adhesion will be discussed. (shrink)

There are many morphologically distinct membrane structures with different functions at the surface of epithelial cells. Among these, adherens junctions (AJ) and tight junctions (TJ) are responsible for the mechanical linkage of epithelial cells and epithelial barrier function, respectively. In the process of new cell–cell adhesion formation between two epithelial cells, such as after wounding, AJ form first and then TJ form on the apical side of AJ. This process is very complicated because AJ formation triggers drastic (...) changes in the organization of actin cytoskeleton, the activity of Rho family of small GTPases, and the lipid composition of the plasma membrane, all of which are required for subsequent TJ formation. In this review, the authors focus on the relationship between AJ and TJ as a representative example of specialization of plasma membrane regions and introduce recent findings on how AJ formation promotes the subsequent formation of TJ. (shrink)

Tumor progression involves the transition from normal to malignant cells, through a series of cumulative alterations. During this process, invasive and migratory properties are acquired, enabling cells to metastasize (reach and grow in tissues far from their origin). Numerous cellular changes take place during epithelial malignancy, and disruption of E‐cadherin based cell‐cell adhesion is a major event. The small Rho GTPases (Rho, Rac and Cdc42) have been implicated in multiple steps during cellular transformation, including alterations on the (...) adhesion status of the tumor cells. This review focuses on recent in vivo evidence that implicates RhoGTPases in epithelial tumor progression. In addition, we discuss different hypotheses to explain disruption of cadherin‐mediated cell–cell adhesion, directly or indirectly, through activation of Rho GTPases. Understanding the molecular mechanism of how cadherin adhesion and RhoGTPases interplay in normal cells and how this balance is altered during cellular transformation will provide clues as to how to interfere with tumor progression. © 2003 Wiley Periodicals, Inc. BioEssays 25:452–463, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Neural cell adhesion molecules of the immunoglobulin superfamily are important components of the network of guidance cues and receptors that govern axon growth and guidance during development. For neural cell adhesion molecule L1, the combined application of human genetics, knockout mouse technology, and cell biology is providing fundamental insight into the role of L1 in mediating neuronal differentiation. Disease-causing mutations as well as mouse models of L1 disruption can now be used to examine the relevance (...) of L1 binding specificities and signal transduction pathways that have been observed in vitro. BioEssays 20:668–675, 1998.© 1998 John Wiley & Sons Inc. (shrink)

Focal adhesions disassemble during mitosis, but surprisingly little is known about how these structures respond to other phases of the cell cycle. Three recent papers reveal unexpected results as they examine adhesions through the cell cycle. A biphasic response is detected where focal adhesions grow during S phase before disassembly begins early in G2. In M phase, activated integrins at the tips of retraction fibers anchor mitotic cells, but these adhesions lack the defining components of focal adhesions, such (...) as talin, paxillin, and zyxin. Re‐examining cell‐matrix adhesion reveals reticular adhesions, a new class of adhesion. These αVβ5 integrin‐mediated adhesions also lack conventional focal adhesion components and anchor mitotic cells to the extracellular matrix. As reviewed here, these studies present insight into how adhesion complexes vary through the cell cycle, and how unconventional adhesions maintain attachment during mitosis while providing spatial memory to guide daughter cell re‐spreading after cell division. (shrink)

Neural cell adhesion molecules of the immunoglobulin superfamily are important components of the network of guidance cues and receptors that govern axon growth and guidance during development. For neural cell adhesion molecule L1, the combined application of human genetics, knockout mouse technology, and cell biology is providing fundamental insight into the role of L1 in mediating neuronal differentiation. Disease-causing mutations as well as mouse models of L1 disruption can now be used to examine the relevance (...) of L1 binding specificities and signal transduction pathways that have been observed in vitro. BioEssays 20:668–675, 1998.© 1998 John Wiley & Sons Inc. (shrink)

Physical forces regulate numerous biological processes during development, physiology, and pathology. Forces between the external environment and intracellular actin cytoskeleton are primarily transmitted through integrin‐containing focal adhesions and cadherin‐containing adherens junctions. Crosstalk between these complexes is well established and modulates the mechanical landscape of the cell. However, integrins and cadherins constitute large families of adhesion receptors and form multiple complexes by interacting with different ligands, adaptor proteins, and cytoskeletal filaments. Recent findings indicate that integrin‐containing hemidesmosomes oppose force transduction (...) and traction force generation by focal adhesions. The cytolinker plectin mediates this crosstalk by coupling intermediate filaments to the actin cytoskeleton. Similarly, cadherins in desmosomes might modulate force generation by adherens junctions. Moreover, mechanotransduction can be influenced by podosomes, clathrin lattices, and tetraspanin‐enriched microdomains. This review discusses mechanotransduction by multiple integrin‐ and cadherin‐based cell adhesion complexes, which together with the associated cytoskeleton form an integrated network that allows cells to sense, process, and respond to their physical environment. (shrink)

Cell recognition and adhesion, being of prime importance for the formation and integrity of tissues, are mediated by cell adhesion molecules, which can be divided into several distinct protein superfamilies. The cell adhesion molecule C‐CAM (cell‐CAM 105) belongs to the immunoglobulin superfamily, and more specifically is a member of the carcinoembryonic antigen (CEA) gene family. C‐CAM can mediate adhesion between hepatocytes in vitro in a homophilic, calcium‐independent binding reaction. The molecule, which occurs (...) in various isoforms, is expressed in liver, several epithelia, vessel endothelia, platelets and granulocytes and its expression is dynamically regulated under various physiological and pathological conditions. It is proposed that C‐CAM in different cells and tissues plays different functional roles, where the common denominator is membrane‐membrane binding. (shrink)

During vertebrate limb development, various genes of the Hox family, the products of which influence skeletal element identity, are expressed in specific spatiotemporal patterns in the limb bud mesenchyme. At the same time, the cells also exhibit ‘self‐organizing’ behavior – interacting with each other via extracellular matrix and cell‐cell adhesive molecules to form the arrays of mesenchymal condensations that lead to the cartilaginous skeletal primordia. A recent study by Yokouchi et al.(1) establishes a connection between these phenomena. They (...) misexpressed the product of the Hoxa‐13 gene in chick limb buds and demonstrated both skeletal pattern perturbations and changes in cell‐cell adhesivity in mesenchyme aberrantly expressing this protein. (shrink)

Members of the CAR group of Ig‐like type I transmembrane proteins mediate homotypic cell adhesion, share a common overall extracellular domain structure and are closely related at the amino acid sequence level. CAR proteins are often found at tight junctions and interact with intracellular scaffolding proteins, suggesting that they might modulate tight junction assembly or function. However, impairment of tight junction integrity has not been reported in mouse knockout models or zebrafish mutants of CAR members. In contrast, in (...) the same knockout models deficits in gap junction communication were detected in several organ systems, including the atrioventricular node of the heart, smooth muscle cells of the intestine and the ureter and in Sertoli cells of the testes. Possible interactions between BT‐IgSF and connexin41.8 on the disturbed pattern of pigment stripes found in zebrafish mutants and between ESAM and connexin43 during hematopoiesis in the mouse are also discussed. On the basis of the combined data and phenotypic similarities between CAR member mutants and connexin mutants I hypothesize that they primarily play a role in the organization of gap junction communication. Also see the video abstract here: https://youtu.be/i0yq2KhuDAE. (shrink)

Bidirectional trans‐synaptic signaling is essential for the formation, maturation, and plasticity of synaptic connections. Synaptic cell adhesion molecules (CAMs) are prime drivers in shaping the identities of trans‐synaptic signaling pathways. A series of recent studies provide evidence that diverse presynaptic cell adhesion proteins dictate the regulation of specific synaptic properties in postsynaptic neurons. Focusing on mammalian synaptic CAMs, this article outlines several exemplary cases supporting this notion and highlights how these trans‐synaptic signaling pathways collectively contribute to (...) the specificity and diversity of neural circuit architecture. (shrink)

The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins, named catenins, which are structurally related in different cell types of various species. This complex formation connects uvnomorulin and cytoskeletal structures and might, moreover, be involved in other adhesion‐dependent mechanisms.

One of the most important cell–cell interactions is that of the sperm with the egg. This interaction, which begins with cell adhesion and culminates with membrane fusion, is mediated by multiple molecules on the gametes. One of the best-characterized of these molecules is fertilin β, a ligand on mammalian sperm and one of the first ADAMs (A Disintegrin and A Metalloprotease domain) to be identified. Fertilin β (also known as ADAM2) participates in sperm–egg membrane binding, and (...) it has long been hypothesized that this function is achieved through the interaction of the disintegrin domain of fertilin β with an integrin on the egg surface. There are now approximately 30 members of the ADAM family and, to date, five different ADAMs (fertilin β, ADAM9, ADAM12, ADAM15, ADAM23) have been described to interact with integrins (specifically α6β1, αvβ3, α9β1, αvβ5, and/or α5β1). This field will be discussed with respect to what is known about specific ADAMs and the integrins with which they interact, and what the implications are for sperm–egg interactions and for integrin function. These data will also be discussed in the context of recent knockout studies, which show that eggs lacking the α6 integrin subunit can be fertilized, and eggs lacking the integrin-associated tetraspanin protein CD9 fail to fertilize. Key issues in cell adhesion that pertain to gametes and fertilization will also be highlighted. BioEssays 23:628–639, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Cadherins are a large family of single‐pass transmembrane proteins principally involved in Ca2+‐dependent homotypic cell adhesion. The cadherin molecules comprise three domains, the intracellular domain, the transmembrane domain and the extracellular domain, and form large complexes with a vast array of binding partners (including cadherin molecules of the same type in homophilic interactions and cellular protein catenins), orchestrating biologically essential extracellular and intracellular signalling processes. While current, contrasting models for classic cadherin homophilic interaction involve varying numbers of specific (...) repeats found in the extracellular domain, the structure of the domain itself clearly remains the main determinant of cell stability and binding specificity. Through intracellular interactions, cadherin enhances its adhesive properties binding the cytoskeleton via cytoplasmic associated factors α‐ catenin, β‐catenin and p120ctn. Recent structural studies on classic cadherins and these catenin molecules have provided new insight into the essential mechanisms underlying cadherin‐mediated cell interaction and catenin‐mediated cellular signalling. Remarkable structural diversity has been observed in β‐catenin recognition of other cellular factors including APC, Tcf and ICAT, proteins that contribute to or compete with cadherin/catenin functioning. BioEssays 26:497–511, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Integrins are ubiquitous trans‐membrane adhesion molecules that mediate the interaction of cells with the extracellular matrix (ECM). Integrins link cells to the ECM by interacting with the cell cytoskeleton. In cases such as leukocyte binding, integrins mediate cell‐cell interactions and cell‐ECM interactions. Recent research indicates that integrins also function as signal transduction receptors, triggering a number of intracellular signaling pathways that regulate cell behavior and development. A number of integrins are known to stimulate changes (...) in intracellular calcium levels, resulting in integrin activation. Although changes in intracellular calcium regulate a vast number of cellular functions, this review will discuss the stimulation of calcium signaling by integrins and the role of intracellular calcium in the regulation of integrin‐mediated adhesion. (shrink)

Muscular dystrophies are associated with mutations in genes encoding several classes of proteins. These range from extracellular matrix and integral membrane proteins to cytoskeletal proteins, but also include a heterogeneous group of proteins including proteases, nuclear proteins, and signalling molecules. Muscular dystrophy phenotypes have also become evident in studies on various knockout mice defective in proteins not previously considered or known to be mutated in muscular dystrophies. Some unifying themes are beginning to emerge from all of these data. This review (...) will consider recent advances in our understanding of the molecules involved and bring together data that suggest a role for the cytoskeleton and cell adhesion in muscular dystrophies. BioEssays 24:542–552, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The collagen family of extracellular matrix proteins has played a fundamental role in the evolution of multicellular animals. At the present, 28 triple helical proteins have been named as collagens and they can be divided into several subgroups based on their structural and functional properties. In tissues, the cells are anchored to collagenous structures. Often the interaction is indirect and mediated by matrix glycoproteins, but cells also express receptors, which have the ability to directly bind to the triple helical domains (...) in collagens. Some receptors bind to sites that are abundant in all collagens. However, increasing evidence indicates that the coevolution of collagens and cell adhesion mechanisms has given rise to receptors that bind to specific motifs in collagens. These receptors may also recognize the different members of the large collagen family in a selective manner. This review summarizes the present knowledge about the properties of collagen subtypes as cell adhesion proteins. BioEssays 29:1001–1010, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Zyxin is a low abundance phosphoprotein that is localized at sites of cell‐substratum adhesion in fibroblasts. Zyxin displays the architectural features of an intracellular signal transducer. The protein exhibits an extensive proline‐rich domain, a nuclear export signal and three copies of the LIM motif, a double zinc‐finger domain found in many proteins that play central roles in regulation of cell differentiation. Zyxin interacts with α‐actinin, members of the cysteine‐rich protein (CRP) family, proteins that display Src homology 3 (...) (SH3) domains and Ena/VASP family members. Zyxin and its partners have been implicated in the spatial control of actin filament assembly as well as in pathways important for cell differentiation. Based on its repertoire of binding partners and its behavior, zyxin may serve as a scaffold for the assembly of multimeric protein machines that function in the nucleus and at sites of cell adhesion. (shrink)

Protein‐carbohydrate interactions have been found to be important in many steps in lymphocyte recirculation and inflammatory responses. A family of carbohydrate‐binding proteins or lectins, termed selectins, has been discovered and shown to be involved directly in these processes. The three known selectins, termed L‐, E‐ and P‐selectins, have domains homologous to other Ca2+‐dependent (C‐type) lectins. L‐selectin is expressed constitutively on lymphocytes, E‐selectin is expressed by activated endothelial cells, and P‐selectin is expressed by activated platelets and endothelial cells. Here, we review (...) the nature of the carbohydrate determinants in tissues recognized by these selectins. The expression of specific sialylated, fucosylated and sulfated carbohydrates in activated endothelium and high endothelial venules promotes interactions with L‐selectin on leukocyte surfaces. In contrast, E‐ and P‐selectins recognize specific carbohydrate determinants related to sialyl Lex antigen on neutrophil and monocyte surfaces. The discovery of the selectins has generated excitemient among glycoconjugate researchers that other carbohydrate‐binding proteins and their cognate ligands will be found to function in regulating many types of cellular interactions. (shrink)

Focal adhesion kinase (FAK) is a nonreceptor protein‐tyrosine kinase implicated in controlling cellular responses to the engagement of cell‐surface integrins, including cell spreading and migration, survival and proliferation. Aberrant FAK signaling may contribute to the process of cell transformation by certain oncoproteins, including v‐Src. Progress toward elucidating the events leading to FAK activation following integrin‐mediated cell adhesion, as well as events downstream of FAK, has come through the identification of FAK phosphorylation sites and interacting (...) proteins. A signaling partnership is formed between FAK and Src‐family kinases, leading to tyrosine phosphorylation of FAK and associated ‘docking’ proteins Cas and paxillin. Subsequent recruitment of proteins containing Src homology 2 domains, including Grb2 and c‐Crk, to the complex is likely to trigger adhesion‐induced cellular responses, including changes to the actin cytoskeleton and activation of the Ras‐MAP kinase pathway. (shrink)

While the control of cell migration by biochemical and biophysical factors is largely documented, a precise quantification of cell migration parameters in different experimental contexts is still questionable. Indeed, these phenomenological parameters can be evaluated from data obtained either at the cell population level or at the individual cell level. However, the range within which both characterizations of cell migration are equivalent remains unclear. We analyse here to which extent both sources of data could be (...) integrated within a unified description of cell migration by considering the motility of the endothelial cell line EAhy926. Using time-lapse video-microscopy and associated analysis of digital image time series, we quantified EAhy926 random motility coefficient, migration speed and trajectory persistence time in two different migration assays: the in vitro wound healing assay, and the cell-populated agarose drop assay. In order to analyse the agreement between independent quantifications of cell motility based either on individual cell analysis or cell population dynamic analysis, a theoretical multi-agents cellular model was developed and discussed as a possible theoretical framework able to unify these multi-scale data. Model simulations especially reveal the potential bias induced by cell proliferation and cell-cell adhesion when cell migration parameters are estimated from the extensively used in vitro wound healing assay. (shrink)

Cell communication plays a key role in multicellular organisms. In developing embryos as in adult organisms, cells communicate by coordinating their differentiation through the establishment and/or renewal of a variety of cell communication channels. Under both these conditions, cells interact by either receptor signalling, surface recognition of specific cell adhesion molecules or transfer of cytoplasmic components through junctional coupling. In recent years, it has become apparent that cells may also communicate through the extracellular release of microvesicles. (...) They may originate as either exosomes from the endosomal compartment upon fusion of multivesicular bodies with the plasma membrane or be shed directly from the plasma membrane via extensions of the cell surface. Microvesicles may disperse over long distances through body fluids and deliver their molecular cargo onto a variety of target cells. As a general rule, the metabolic fate of these cells is determined by the molecular nature of the vesicular cargo, while targeting itself depends on the affinity of the molecules expressed on the enclosing membrane. In this paper, we will be arguing that intercellular vesicular transfer is substantially different from other types of cell communication, allowing cells and molecules to interact on varying levels. Cells interacting via ligand signalling owe their specificity to the steric coupling with cognate receptor molecules. As such, it is a pure molecular process that affects target cells only upon integration into their responding repertoire. In this relationship, coupled cells are reciprocally adapted to each other through the selection of their respective signalling capacities, following exploration of their receptor specificity. Interaction by intercellular vesicles realizes a substantially different type of cell communication. Vesicular traffic allows donor cells to carry out a horizontal type of gene transfer and target this information over long distances via independently controlled mechanisms. Because of this independence, cells interacting via vesicular traffic are not expected to adapt their signalling correspondences, but to control instead the efficiency of their cargo delivery irrespective of the receptor repertoire expressed by the target tissue. In this paper, the multifaceted functions of the intercellular vesicular traffic will be discussed in a multilevel biosemiotic perspective with the aim of unravelling the cellular mechanisms devised by nature to accomplish communication. (shrink)

Cell adhesion complexes are critical for the physical coordination of cell–cell interactions and the morphogenesis of tissues and organs. Many adhesion receptors are anchored to the plasma membrane by a glycosylphosphatidylinositol (GPI) moiety and are thereby partitioned into membrane rafts. In this review, we focus on reciprocal interactions between rafts and adhesion molecules, leading to receptor clustering and raft expansion and stability. A model for a three‐stage adhesion complex assembly process is also proposed. (...) First, GPI‐anchored adhesion molecules are recruited into rafts, which in turn promote receptor cis‐oligomerization and thereby produce precursory complexes primed for avid trans‐interactions. Second, trans‐interactions of the receptors cross‐link and stabilize large amalgams of rafts at sites of adhesion complex assembly. Finally, the enlarged and stabilized rafts acquire enhanced abilities to recruit the cytoskeleton and induce signaling. This process exemplifies how the domain structure of the plasma membrane can impact the function of its receptors. BioEssays 24:996–1003, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

The recognition of extracellular molecules by cell surface receptors is the principal mechanism used by cells to sense their environment. Consequently, signals transduced as a result of these interactions make a major contribution to the regulation of cellular phenotype. Historically, particular emphasis has been placed on elucidating the intracellular consequences of growth factor and cytokine binding to cells. In addition to these interactions, however, cells are usually in intimate contact with a further source of complex structural and functional information, (...) namely immobilised extracellular matrix and/or cell surface adhesion proteins. A key question in recent years has been whether cells use the myriad of adhesion protein‐receptor interactions purely for structural and migratory function, or whether these interactions also make a more varied contribution to cell phenotype. Here we review dynamic aspects of the function of one major class of adhesion receptor, the integrins. In particular, we focus on the evidence for shape changes in integrin molecules, the mechanisms responsible for regulating ligand binding, and the signals transduced following integrin occupancy. (shrink)

The myelin basic proteins are a set of peripheral membrane polypeptides which play an essential role in myelination. Their most well‐documented property is the unique ability to ‘seal’ the cytoplasmic aspects of the myelin membrane, but this is probably not the only function for these highly charged molecules. Despite extensive homology, the individual myelin basic proteins (MBPs) exhibit different expression patterns and biochemical properties, and so it is now believed that the various isoforms are not functionally equivalent in myelinating cells. (...) We now think that while the major MBPs are intracellular adhesion molecules, some of the quantitatively less abundant isoforms that are expressed very early in development may have regulatory effects on the myelination program. (shrink)

The expression of epithelial cell adhesion and cytoskeletal genes is orchestrated by an apparently unique set of rules. No tissue‐specific transactivator proteins have been found to drive them; only ubiquitous factors are utilized. In non‐epithelial cells, they are actively repressed. Moreover, it was recently found that a single protein (adenovirus E1a) coordinately represses non‐epithelial genes while inducing epithelial genes. A simple model is offered to explain how epithelial gene expression is coordinated. Under this model, the epithelial cell (...) gene expression program is a transcriptional ‘default’; that is, it occurs in the absence of tissue‐specific transactivation. Conversion to this default requires only that mesenchymal transactivators are not expressed, or that central ‘integrator’ proteins are inactive. In their absence, mesenchymal gene expression cannot occur. Moreover, because the repressors cease to be expressed, the epithelial genes are induced. Oncogenes generally cause the breakdown of the epithelial phenotype ‐ generating carcinomas ‐ so genes such as E1a that cause epithelial conversion may prove useful for both understanding and controlling cancer. (shrink)

Integrin‐mediated cell adhesion and subsequent cell spreading are essential for the growth and survival of many cell types. While integrin engagement is known to activate various signalling pathways, the role that cell spreading plays in the control of growth and survival is not clear. Using a novel technique, however, Chen et al.(1) demonstrate that the effect of cell spreading on growth and survival is not a consequence of increased area of contact with the extracellular (...) matrix, supporting the hypothesis that regulation through changes in cell tension and architecture play a key role. (shrink)

Plant cells are caged within a distended polymeric network (the cell wall), which enlarges by a process of stress relaxation and slippage (creep) of the polysaccharides that make up the load‐bearing network of the wall. Protein mediators of wall creep have recently been isolated and characterized. These proteins, called expansins, appear to disrupt the noncovalent adhesion of matrix polysaccharides to cellulose microfibrils, thereby permitting turgor‐driven wall enlargement. Expansin activity is specifically expressed in the growing tissues of dicotyledons and (...) monocotyledons. Sequence analysis of cDNAs indicates that expansins are novel proteins, without previously known functional motifs. Comparison of expansin cDNAs from cucumber, pea, Arabidopsis and rice shows that the proteins are highly conserved in size and amino acid sequence. Phylogenetic analysis of expansin sequences suggests that this multigene family diverged before the evolution of angiosperms. Speculation is presented about the role of this gene family in plant development and evolution. (shrink)

In the seminiferous tubule of the mammalian testis, one type A1 spermatogonium (diploid, 2n) divides and differentiates into 256 spermatozoa (haploid, n) during spermatogenesis. To complete spermatogenesis and produce ∼150 × 106 spermatozoa each day in a healthy man, germ cells must migrate progressively across the seminiferous epithelium yet remain attach to the nourishing Sertoli cells. This active cell migration process involves precisely controlled restructuring events at the tight (TJ) and anchoring junctions at the cell–cell interface. While (...) the hormonal events that regulate spermatogenesis by follicle‐stimulating hormone and testosterone from the pituitary gland and Leydig cells, respectively, are known, less is known about the mechanism(s) that regulates junction restructuring during germ cell movement in the seminiferous epithelium. The relative position of tight (TJs) and anchoring junctions in the testis is of interest. Sertoli cell TJs that constitute the blood–testis barrier (BTB) are present side by side with anchoring junctions and are adjacent to the basement membrane. This intimate physical association with the TJs, the anchoring junctions and the basement membrane (a modified form of extracellular matrix, ECM) suggests a role for the ECM in the junction dynamics of the testis. Indeed, evidence is accumulating that ECM proteins are crucial to Sertoli cell TJ dynamics. In this review, we discuss the pivotal role of tumor necrosis factor α (TNFα) on BTB dynamics via its effects on the homeostasis of ECM proteins. In addition, discussion will also be focused on the novel findings regarding the role of non‐basement‐membrane‐associated ECM proteins and components of focal adhesion (a cell–matrix anchoring junction type) in the regulation of junction dynamics in the testis. BioEssays 26:978–992, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

New molecular markers for epidermal stem cells have enabled their isolation both in vitro and from the epidermis lying between hair follicles. Micro‐dissection experiments have localised a second population of stem cells within hair follicles. Epidermal stem cells have a patterned distribution in vivo. The patterning can be reconstituted in vitro, showing that it is generated by interactions between keratinocytes and that the differentiation of epidermal stem cells is regulated by signals from other keratinocytes. Recent evidence from transgenic mice suggests (...) that stem cell behaviour in the gut may be regulated by similar cell‐cell interactions in vivo. Candidate genes for mediating these interactions are the homologues of Drosophila cell fate patterning genes such as Notch and Wingless and the Cadherin family of cell‐cell adhesion molecules. The roles of stem cells and of mutations of the Patched gene in epithelial carcinogenesis are discussed. (shrink)

How environmental mechanical forces affect cellular functions is a central problem in cell biology. Theoretical models of cellular biomechanics provide relevant tools for understanding how the contributions of deformable intracellular components and specific adhesion conditions at the cell interface are integrated for determining the overall balance of mechanical forces within the cell. We investigate here the spatial distributions of intracellular stresses when adherent cells are probed by magnetic twisting cytometry. The influence of the cell nucleus (...) stiffness on the simulated nonlinear torque-bead rotation response is analyzed by considering a finite element multi-component cell model in which the cell and its nucleus are considered as different hyperelastic materials. We additionally take into account the mechanical properties of the basal cell cortex, which can be affected by the interaction of the basal cell membrane with the extracellular substrate. In agreement with data obtained on epithelial cells, the simulated behaviour of the cell model relates the hyperelastic response observed at the entire cell scale to the distribution of stresses and strains within the nucleus and the cytoskeleton, up to cell adhesion areas. These results, which indicate how mechanical forces are transmitted at distant points through the cytoskeleton, are compared to recent data imaging the highly localized distribution of intracellular stresses. (shrink)

Embryogenesis requires the precise movement and reorganization of many cell and tissue types. Presumably, cell surface receptors allow cells to interact selectively with adjacent cells and with the extracellular environment, as well as initiate differentiative events by transducing appropriate signals across the plasma membrane. One cell surface component that serves as a receptor during a variety of cellular interactions is β1,4‐galactosyltransferase. Cell surface galactosyltransferase participates in diverse cellular interactions by binding its specific glycoconjugate substrate on adjacent (...) cell surfaces or in the extracellular matrix. Biochemical, immunological, and molecular probes are being used to better define cell surface galactosyl‐transferase functional in cellular interactions during fertilization, intercellular adhesion, cell migration, and growth control. (shrink)

For over a century, Haeckel's Gastraea theory remained a dominant theory to explain the origin of multicellular animals. According to this theory, the animal ancestor was a blastula‐like colony of uniform cells that gradually evolved cell differentiation. Today, however, genes that typically control metazoan development, cell differentiation, cell‐to‐cell adhesion, and cell‐to‐matrix adhesion are found in various unicellular relatives of the Metazoa, which suggests the origin of the genetic programs of cell differentiation and (...) adhesion in the root of the Opisthokonta. Multicellular stages occurring in the complex life cycles of opisthokont protists (mesomycetozoeans and choanoflagellates) never resemble a blastula. Here, we discuss a more realistic scenario of transition to multicellularity through integration of pre‐existing transient cell types into the body of an early metazoon, which possessed a complex life cycle with a differentiated sedentary filter‐feeding trophic stage and a non‐feeding blastula‐like larva, the synzoospore. Choanoflagellates are considered as forms with secondarily simplified life cycles. (shrink)

Metastatic spread of tumor cells is one of the most common causes of death in cancer patients. Therefore, elucidation of the molecular mechanisms that underlie the formation of metastatic colonies has been one of the major objectives of cancer research during the last two decades. In this review we will mainly discuss the mechanisms that cause a malignant cell to grow at a given site rather than at other possible sites, taking into account experimental and clinical evidence published on (...) the subject. As a whole this evidence tends to confirm the hypothesis that organ‐specific colonization by malignant cells often follows very specific and close interactions between the cancer cell and the target organ, either in terms of specific cellular adhesion or growth promotion. In this paper we would like to underscore the fact that cellular adhesion, either specific or unspecific, is a necessary but, by itself, insufficient condition for the development of metastases. It is the ability of the tumor cells to grow at the site where they arrested that ultimately determines whether a metastatic colony develops or fails to develop at that site. (shrink)

Cadherin‐mediated cell‐cell adhesion is perturbed in protein tyrosine kinase (PTK)‐transformed cells. While cadherins themselves appear to be poor PTK substrates, their cytoplasmic binding partners, the Arm catenins, are excellent PTK substrates and therefore good candidates for mediating PTK‐induced changes in cadherin behavior. These proteins, p120ctn, β‐catenin and plakoglobin, bind to the cytoplasmic region of classical cadherins and function to modulate adhesion and/or bridge cadherins to the actin cytoskeleton. In addition, as demonstrated recently for β‐catenin, these proteins (...) also have crucial signaling roles that may or may not be related to their effects on cell‐cell adhesion. Tyrosine phosphorylation of cadherin complexes is well documented and widely believed to modulate cell adhesiveness. The data to date, however, is largely correlative and the mechanism of action remains unresolved. In this review, we discuss the current literature and suggest models whereby tyrosine phosphorylation of Arm catenins contribute to regulation or perturbation of cadherin function. (shrink)

The study of adhesion plaques in normal and transformed cells provides a series of phenotypic markers by which the process of transformation can be followed. Several proteins which are concentrated in adhesion plaques have now been identified; a few of these can act as targets for tyrosine kinase. In an attempt to characterize the relationship between tyrosine phosphorylation and cell transformation, the reactions of three such proteins – vinculin, talin and integrin – with a range of tyrosine (...) kinase oncogene products have been studied in detail. (shrink)

Constraining collective cell migration in vitro using different types of engineered substrates such as microstructured surfaces or adhesive patterns of different shapes and sizes often leads to the emergence of specific patterns of motion. Recently, analogies between the behavior of cellular assemblies and that of active fluids have enabled significant advances in our understanding of collective cell migration; however, the physiological relevance and potential functional consequences of the resulting migration patterns remain elusive. Here we describe the different patterns (...) of collective cell migration that have been reported in vitro in response to geometrical constraints, explore the in vivo pertinence of the in vitro systems used to impose the geometrical constraints, and discuss the potential physiological ramifications of the collective migration patterns that emerge as a result of physical constraints. We conclude by highlighting key upcoming challenges in the exciting field of constrained collective cell migration. (shrink)

T lymphocyte recognition of foreign antigens and migration throughout the body require the regulated adhesion of lymphocytes to diverse types of cells and to the extracellular matrix. The lymphocyte adhesion ‘receptor’ LFA‐1, a member of the integrin family, interacts with ICAM‐1 and other counter‐receptors to mediate adhesion. The LFA‐1/ICAM‐1 interaction is regulated by signals transmitted from the cytoplasm to the extracellular space. Conversely, LFA‐1 transmits signals from the extracellular space to the cytoplasm to regulate T lymphocyte activation. (...) The observed properties of LFA‐1 and related adhesion ‘receptors’ are incorporated into a general model for adhesion during immune surveillance and recognition of foreign antigens. (shrink)

Shape and locomotion of tissue cells depend on the interaction of elements of the cytoskeleton, adhesion to the substrate and an intracellular hydrostatic pressure. The existence of this pressure becomes obvious from increase in cell volume on cessation of contractile forces and from observations with ultrasound acoustic microscopy. Wherever such an internal pressure is established, it is involved in generation of shape and driving force of cell locomotion. Therefore each hypothesis on cell shape and locomotion must (...) consider this property of a living cell. Apparently different types of locomotion depend on differences in substrate adhesion and/or cytoskeleton organisation. (shrink)

Receptor tyrosine kinases and integrins are activated by growth factors and extracellular matrix, respectively. Their activation leads to signal transduction cascades that control many aspects of cell phenotype, including progression through the G1 phase of the cell cycle. However, the signalling cassettes driven by growth factors and matrix do not work independently of each other. Integrin triggering is essential to facilitate kinase‐ and GTPase‐mediated signals and thereby drive efficient transfer of information through the growth factor–cyclin axis. A recent (...) study indicates that an additional type of player has a key role in adhesion‐regulated control of cell cycle, namely ubiquitin ligase.(1) BioEssays 24:17–21, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

The ability of two or more cells to unite to form a new syncytial cell has been utilized in metazoans throughout evolution to form many complex organs, such as muscles, bones and placentae. This requires migration, recognition and adhesion between cells together with fusion of their plasma membranes and rearrangement of their cytoplasmic contents. Until recently, understanding of the mechanisms of cell fusion was restricted to fusion between enveloped viruses and their target cells. The identification of new (...) factors that take part in developmental cell fusion in C. elegans opens the way to understanding how cells fuse and what the functions of this process are. In this review, we describe current knowledge on the mechanisms and putative roles of developmental cell fusion in C. elegans and how cell fusion is regulated, together with other intercellular processes to promote organogenesis. BioEssays 25:672–682, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The sophisticated function of the central nervous system (CNS) is largely supported by proper interactions between neural cells and blood vessels. Accumulating evidence has demonstrated that neurons and glial cells support the formation of blood vessels, which in turn, act as migratory scaffolds for these cell types. Neural progenitors are also involved in the regulation of blood vessel formation. This mutual interaction between neural cells and blood vessels is elegantly controlled by several chemokines, growth factors, extracellular matrix, and (...) class='Hi'>adhesion molecules such as integrins. Recent research has revealed that newly migrating cell types along blood vessels repel other preexisting migrating cell types, causing them to detach from the blood vessels. In this review, we discuss vascular formation and cell migration, particularly during development. Moreover, we discuss how the crosstalk between blood vessels and neurons and glial cells could be related to neurodevelopmental disorders. (shrink)

Nitric oxide (NO) is a pleiotropic signalling molecule that subserves a wide variety of basic cellular functions and also manifests itself pathophysiologically. As regards cancer and its progression, however, the reported role of NO appears surprisingly inconsistent. In this review, we focus on metastasis, the process of cancer cell spread and secondary tumour formation. In a ‘reductionist’ approach, we consider the metastatic cascade to be made up of a series of basic cellular behaviours (such as proliferation, apoptosis, adhesion, (...) secretion migration, invasion and angiogenesis). We evaluate how NO controls such behaviours, in comparison with normal cells. The available information suggests strongly that NO signalling would be expected to regulate these behaviours both positively and negatively and this probably leads to the observed apparent variability in the NO status of cancer cells and tissues. Thus, the role of NO in cancer is more complex than previously thought. A number of suggestions are made, including consideration of novel mechanisms, such as ion channels, in order to achieve a more consistent and integrated understanding of NO signalling in cancer and to realise its clinical potential. BioEssays 27:1228–1238, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Recently it has become clear that trafficking of integrins to late endosomes is key to the regulation of integrin expression and function during cell migration. Here we discuss the molecular machinery that dictates whether integrins are sorted to recycling endosomes or are targeted to late endosomes and lysosomes. Integrins and other receptors that are sorted to late endosomes are not necessarily degraded and, under certain circumstances, can be spared destruction and returned to the cell surface to drive (...) class='Hi'>cell migration and invasion. We will discuss how the exchange of adhesion receptors and other key regulators of cell migration between late endosomes/lysosomes and the plasma membrane can promote dynamic turnover of adhesions during cell migration. (shrink)

There are many blank areas in understanding the brain dynamics and especially how it gives rise to consciousness. Quantum mechanics is believed to be capable of explaining the enigma of conscious experience, however till now there is not good enough model considering both the data from clinical neurology and having some explanatory power! In this paper is presented a novel model in defence of macroscopic quantum events within and between neural cells. The beta-neurexin-neuroligin-1 link is claimed to be not just (...) the core of the central neural synapse, instead it is a device mediating entanglement between the cytoskeletons of the cortical neurons. Thus a macroscopic quantum state can extend throughout large brain cortical areas and the subsequent collapse of the wavefunction could affect simultaneously the subneuronal events in millions of neurons. The beta-neurexin-neuroligin-1 complex also controls the process of exocytosis and provides an interesting and simple mechanism for retrograde signalling during learning-dependent changes in synaptic connectivity. (shrink)