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)

The integrins are receptors for proteins of the extracellular matrix, both providing a physical link to the cytoskeleton and transducing signals from the extracellular matrix. Activation of integrins leads to tyrosine and serine phosphorylation of a number of proteins, elevation of cytosolic calcium levels, cytoplasmic alkalinization, changes in phospholipid metabolism and, ultimately, changes in gene expression. The recently discovered focal adhesion kinase localizes to focal contacts, which are sites of integrin clustering, and focal (...) class='Hi'>adhesion kinase can physically associate with integrins in vitro. As integrins lack intrinsic catalytic activity, focal adhesion kinase is a candidate for a signaling molecule that is recruited by integrins in order to trigger the generation of intracellular second messengers. Thus, focal adhesion kinase may play a central role in signal transduction through integrins. (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)

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)

Rho, a member of the Ras superfamily of small GTPases, has multiple biological roles: it regulates signal trasduction pathways linking extracellular growth factors to the assembly of actin stress fibres and focal adhesion complexes; it is required for G1 progression and activates the SRF transcription factor when quiescent fibroblasts are stimulated to grow; and it plays a role later in the cell cycle during cytokinesis. Two groups have recently succeeded in identifying downstream effectors of Rho that may mediate (...) some of these biological effects. One protein identified by both groups is protein kinase N (PKN), a serine/threonine kinase whose catalytic domain is closely related to that of protein kinase C(1,2). (shrink)

The sites of tightest adhesion that form between cells and substrate surfaces in tissue culture are termed focal contacts. The external faces of focal contacts include specific receptors, belonging to the integrin family of proteins, for fibronectin and vitronectin, two common components of extracellular matrices. On the internal (cytoplasmic) side of focal contacts, several proteins, including talin and vinculin, mediate interactions with the actin filament bundles of the cytoskeleton. The changes that occur in (...) class='Hi'>focal contacts as a result of viral transformation are discussed. (shrink)

We propose a signaling pathway in which cell‐extracellular matrix (ECM) adhesion components PINCH‐1 and kindlin‐2 sense mechanical signals from ECM and link them to proline biosynthesis, a vital metabolic pathway for macromolecule synthesis, redox balance, and ECM remodeling. ECM stiffening promotes PINCH‐1 expression via integrin signaling, which suppresses dynamin‐related protein 1 (DRP1) expression and mitochondrial fission, resulting in increased kindlin‐2 translocation into mitochondria and interaction with Δ1‐pyrroline‐5‐carboxylate (P5C) reductase 1 (PYCR1). Kindlin‐2 interaction with PYCR1 protects the latter from proteolytic (...) degradation, leading to elevated PYCR1 level. Additionally, PINCH‐1 promotes P5C synthase (P5CS) expression and P5C synthesis, which, together with increased PYCR1 level, support augmented proline biosynthesis. This signaling pathway is frequently activated in fibrosis and cancer, resulting in increased proline biosynthesis and excessive collagen matrix production, which in turn further promotes ECM stiffening. Targeting this signaling pathway, therefore, may provide an effective strategy for alleviating fibrosis and cancer progression. (shrink)

Microfilament interactions with the plasma membranes of animal cells appear to vary with cell type and localization. In the erythrocyte, actin oligomers are associated with the membrane via spectrin and ankyrin. The ends of stress fibers in cultured cells, such as fibroblasts, are attached to the plasma membrane at focal adhesion sites and may involve the protein vinculin as a linking protein. In intestinal brush border microvilli a 110,000 dalton protein links the microfilament bundles to sites on the (...) microvillus. A transmembrane complex containing actin stably associated with a cell surface glycoprotein can be isolated from ascites tumor cell microvilli and can be obtained still associated with microfilaments by gentle extraction and gradient centrifugation of the microvilli. These varied interaction mechanisms are believed to be needed to satisfy the different structural and dynamic requirements of the particular systems. (shrink)

M. xanthus has a complex multicellular lifestyle including swarming, predation and development. These behaviors depend on the ability of the cells to achieve directed motility across solid surfaces. M. xanthus cells have evolved two motility systems including Type‐IV pili that act as grappling hooks and a controversial engine involving mucus secretion and fixed focal adhesion sites. The necessity for cells to coordinate the motility systems and to respond rapidly to environmental cues is reflected by a complex genetic network (...) involving at least three complete sets of chemosensory systems and eukaryotic‐like signaling proteins. In this review, we discuss recent advances suggesting that motor synchronization results from spatial oscillations of motility proteins. We further propose that these dynamics are modulated by the action of multiple upstream complementary signaling systems. M. xanthus is thus an exciting emerging model system to study the intricate processes of directed cell migration. BioEssays 30:733–743, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Cytoskeletal proteins provide the structural foundation that allows cells to exist in a highly organized manner. Recent evidence suggests that certain cytoskeletal proteins not only maintain structural integrity, but might also be associated with signal transduction and suppression of tumorigenesis. Since the time of the discovery of tensin, a fair amount of data has been gathered which supports the notion that tensin is one such protein possessing these characteristics. In this review, we discuss recent studies that: (1) elucidate (...) a role for tensin in maintenance of cellular structure and signal transduction; (2) implicate tensin as the anchor for actin filaments at the focal adhesion; (3) describe the phosphorylation of tensin; (4) describe potential targets for its Src homology region 2 domain; (5) describe the association between tensin and the nuclear protein p130; and (6) demonstrate that increased tensin expression in a cell line appears to reduce its transformation potential. (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)

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)

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)

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)

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)

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)

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)

Specific extracellular interaction between glycophosphatidylinositol (GPI)‐anchored proteins and adhesion G protein‐coupled receptors (aGPCRs) plays an important role in unique biological functions. GPI‐anchored proteins are derived from a novel post‐translational modification of single‐span membrane molecules, while aGPCRs are bona fide seven‐span transmembrane proteins with a long extracellular domain. Although various members of the two structurally‐distinct protein families are known to be involved in a wide range of biological processes, many remain as orphans. Interestingly, accumulating evidence has pointed (...) to a complex interaction and functional synergy between these two protein families. I discuss herein current understanding of specific functional partnerships between GPI‐anchored proteins and aGPCRs. (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)

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)

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)

PstS and DING proteins are members of a superfamily of secreted, high‐affinity phosphate‐binding proteins. Whereas microbial PstS have a well‐defined role in phosphate ABC transporters, the physiological function of DING proteins, named after their DINGGG N termini, still needs to be determined. PstS and DING proteins co‐exist in some Pseudomonas strains, to which they confer a highly adhesive and virulent phenotype. More than 30 DING proteins have now been purified, mostly from eukaryotes. They are often (...) associated with infections or with dysregulation of cell proliferation. Consequently, eukaryotic DING proteins could also be involved in cell–cell communication or adherence. The ubiquitous presence in eukaryotes of proteins structurally and functionally related to bacterial virulence factors is intriguing, as is the absence of eukaryotic genes encoding DING proteins in databases. DING proteins in eukaryotes could originate from unidentified commensal or symbiotic bacteria and could contribute to essential functions. Alternatively, DING proteins could be encoded by eukaryotic genes sharing special features that prevent their cloning. Both hypotheses are discussed. (shrink)

The protein Po has long been proposed to be responsible for the compact nature of peripheral myelin through interactions of both its extracellular and cytoplasmic domains. Recent studies support such a role for Po's extracellular region while more precise mapping of its adhesive domains are ongoing. As Po is a member of the immunoglobulin gene superfamily and perhaps bears the closest similarity to the ancestral molecule of this whole family, these studies may also have more general implications for adhesive interactions. (...) In addition, although long believed to be purely an inert, structural molecule, Po has been reported to promote neurite outgrowth, which suggests a more dynamic role for this interesting molecule. (shrink)

BACKGROUND: Alzheimer's disease is intimately tied to amyloid-beta peptide. Extraneuronal brain plaques consisting primarily of Abeta aggregates are a hallmark of AD. Intraneuronal Abeta subunits are strongly implicated in disease progression. Protein sequence mutations of the Abeta precursor protein account for a small proportion of AD cases, suggesting that regulation of the associated gene may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" , at -76/-47, from the (...) +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. RESULTS: EMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 , nm23 nucleoside diphosphate kinase/metastatic inhibitory protein , and specificity protein 1 . These sites crossed a known single nucleotide polymorphism . EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. CONCLUSIONS: We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging. (shrink)

Secreted Frizzled‐related proteins (SFRPs) are modulators of the intermeshing pathways in which signals are transduced by Wnt ligands through Frizzled (Fz) membrane receptors. The Wnt networks influence biological processes ranging from developmental cell fate, cell polarity and adhesion to tumorigenesis and apoptosis. In the five or six years since their discovery, the SFRPs have emerged as dynamically expressed proteins able to bind both Wnts and Fz, with distinctive structural properties in which cysteine‐rich domains from Fz‐ and from (...) netrin‐like proteins are juxtaposed. The abundant expression of SFRP genes in the early embryo, altered expression patterns in disease states, and potential significance in the evolution of the vertebrate body plan, make these intriguing molecules relevant to investigations in diverse fields of biology and biomedical sciences. BioEssays 24:811–820, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Cells express many proteins that bind to laminin, the major adhesive component of basement membranes. Some of these, specifically integrins, function as transmembrane receptors that ‘signal’ the presence of laminin on the cell surface to the cytoplasm. Lectins constitute a second class of laminin binding proteins that may augment integrin function by interacting with laminin carbohydrate. Caution must be used in ascribing functions to other laminin binding proteins, especially cytosolic proteins.

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)

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)

We have been using feather development as a model for understanding the molecular basis of pattern formation and to explore the roles of homeoproteins, retinoids and adhesion molecules in this process. Two kinds of homeobox (Hox) protein gradients in the skin have been identified: a ‘microgradient’ within a single feather bud and a ‘macrogradient’ across the feather tract. The asynchronous alignment of different Hox macrogradients establishes a unique repertoire of Hox expression patterns in skin appendages within the integument, designated (...) here as the ‘Hox codes of skin appendages’. It is hypothesized that these Hox codes contribute to the phenotypic determination of skin appendages. High doses of retinoic acid cause a morphological transformation between feather and scale, while low doses of retinoic acid cause an alteration of the axial orientation of skin appendages. We have tested the ability of molecules directly involved in the feather formation process to mediate the action of the Hox codes, and surmise that adhesion molecules are potential candidates. Using specific Fabs to suppress the activity of adhesion molecules, we have found that L‐CAM is involved in the formation of the hexagonal pattern, N‐CAM is involved in mediating dermal condensations, tenascin is involved in feather bud growth and elongation, and integrin β‐1 is essential for epithelial‐mesenchymal interactions. More work is in progress to fully understand the molecular pathways regulating the feather formation process. (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)

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)

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)

Adherens (AJ) and tight junctions (TJ) maintain cell‐cell adhesions and cellular polarity in normal tissues. Afadin, a multi‐domain scaffold protein, is commonly found in both adherens and tight junctions, where it plays both structural and signal‐modulating roles. Afadin is a complex modulator of cellular processes implicated in cancer progression, including signal transduction, migration, invasion, and apoptosis. In keeping with the complexities associated with the roles of adherens and tight junctions in cancer, afadin exhibits both tumor suppressive and pro‐metastatic functions. In (...) this review, we will explore the dichotomous roles that afadin plays during cancer progression. (shrink)

In order to distinguish between computers and humans, CAPTCHA is widely used in links such as website login and registration. The traditional CAPTCHA recognition method has poor recognition ability and robustness to different types of verification codes. For this reason, the paper proposes a CAPTCHA recognition method based on convolutional neural network with focal loss function. This method improves the traditional VGG network structure and introduces the focal loss function to generate a new CAPTCHA recognition model. First, we (...) perform preprocessing such as grayscale, binarization, denoising, segmentation, and annotation and then use the Keras library to build a simple neural network model. In addition, we build a terminal end-to-end neural network model for recognition for complex CAPTCHA with high adhesion and more interference pixel. By testing the CNKI CAPTCHA, Zhengfang CAPTCHA, and randomly generated CAPTCHA, the experimental results show that the proposed method has a better recognition effect and robustness for three different datasets, and it has certain advantages compared with traditional deep learning methods. The recognition rate is 99%, 98.5%, and 97.84%, respectively. (shrink)

Recent studies uncovered critical roles of the adhesion protein E‐cadherin in health and disease. Global inactivation of Cdh1, the gene encoding E‐cadherin in mice, results in early embryonic lethality due to an inability to form the trophectodermal epithelium. To unravel E‐cadherin's functions beyond development, numerous mouse lines with tissue‐specific disruption of Cdh1 have been generated. The consequences of E‐cadherin loss showed great variability depending on the tissue in question, ranging from nearly undetectable changes to a complete loss of tissue (...) structure and function. This review focuses on these studies and discusses how they provided important insights into E‐cadherin's role in cell adhesion, proliferation and differentiation, and its consequences for biological processes as epithelial‐to‐mesenchymal transition, vascularization, and carcinogenesis. Lastly, we present some perspectives and possible approaches for future research. (shrink)

The Drosophila position‐specific (PS) integrins are members of the integrin family of cell surface receptors and are thought to be receptors for extracellular matrix components. Each PS integrin consists of an α subunit, αPS1 or αPS2, and a βPS subunit. Mutations in the βPS subunit and the αPS2 subunit have been characterised and reveal that the PS integrins have an essential role in the adhesion of different cell layers to each other. The PS integrins are especially required for the (...) function of the cell‐matrix‐cell junctions, where the muscles attach to the epidermis and where one surface of the developing wing adheres to the other. These junctions are similar to vertebrate focal adhesions and hemidesmosomes, which also contain integrins. Integrin‐mediated cell to cell adhesion via the extracellular matrix provides a way for tissues to adhere to each other without intermingling of their cells. (shrink)

Interleukin‐15 (IL‐15) is a pleiotropic cytokine of the 4 α‐helix bundle family, which binds to a receptor complex that displays common elements with the IL‐2 receptor and a unique high‐affinity α chain. This review focuses on juxtacrine and reverse signaling levels in the IL‐15/IL‐15R system. Specifically, we discuss how agonistic stimulation of membrane‐bound IL‐15 induces phosphorylation of members of the MAP kinase family and of focal adhesion kinase (FAK), thereby upregulating processes including cytokine secretion, cell adhesion and (...) migration. In addition, we explore IL‐15 trans‐presentation and intracellular signaling, and define promising molecular targets for future pharmacological intervention in infectious diseases and immunological disorders. These frontiers in IL‐15/IL‐15Rα research serve as highly instructive examples for key concepts, unsolved problems and therapeutic opportunities in juxtacrine and reverse signaling in general. BioEssays 28: 362–377, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Engagement of integrins and other adhesion receptors can induce tyrosine phosphorylation of focal adhesion kinase (FAK), a tyrosine kinase present in focal adhesions. Furthermore, in addition to adhesion receptors, a surprising variety of stimuli, acting either on specific surface receptors or on intracellular molecules, such as PKC or Rho, can induce also tyrosine phosphorylation of FAK. I suggest that a potential mechanism by which such distinct factors may modulate the tyrosine phosphorylation of FAK is the (...) promotion of integrin or other adhesion receptor clustering at focal adhesions. BioEssays 21:1069–1075, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Proteinaceous stalks produced by Gram‐negative bacteria are often used to adhere to environmental surfaces. Among them, chaperone‐usher (CU) fimbriae adhesins, related to prototypical type 1 fimbriae, interact in highly specific ways with different ligands at different stages of bacterial infection or surface colonisation. Recent analyses revealed a large number of potential and often “cryptic” CU fimbriae homologues in the genome of commensal and pathogenic Escherichia coli and closely related bacteria. We propose that CU fimbriae form a yet unexplored arsenal of (...) lectins, carbohydrate‐binding proteins involved in various aspects of bacterial surface adhesion and tissue tropism. Combined efforts of molecular and structural biologists will be required to unravel the biological contribution of the bacterial lectome, however, current progress has already opened up new perspectives in the design of novel anti‐infective strategies. (shrink)

For focal neurodegenerative diseases or brain tumors, localized delivery of protein or genetic vectors may be sufficient to alleviate symptoms, halt disease progression, or even cure the disease. One may circumvent the limitation imposed by the blood-brain barrier by transplantation of genetically altered cell grafts or focal inoculation of virus or protein. However, permanent gene replacement therapy for diseases affecting the entire brain will require global delivery of genetic vectors. The neurotoxicity of currently available viral vectors and the (...) transient nature of transgene expression invivomust be overcome before their use in human gene therapy becomes clinically applicable. (shrink)

For focal neurodegenerative diseases or brain tumors, localized delivery of protein or genetic vectors may be sufficient to alleviate symptoms, halt disease progression, or even cure the disease. One may circumvent the limitation imposed by the blood-brain barrier by transplantation of genetically altered cell grafts or focal inoculation of virus or protein. However, permanent gene replacement therapy for diseases affecting the entire brain will require global delivery of genetic vectors. The neurotoxicity of currently available viral vectors and the (...) transient nature of transgene expression invivomust be overcome before their use in human gene therapy becomes clinically applicable. (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)

Ectopeptidases are transmembrane proteins present in a wide variety of tissues and cell types. Dysregulated expression of certain ectopeptidases in human malignancies suggests their value as clinical markers. Ectopeptidase interaction with agonistic antibodies or their inhibitors has revealed that these ectoenzymes are able to modulate bioactive peptide responses and to influence growth, apoptosis and differentiation, as well as adhesion and motility, all functions involved in normal and tumoral processes. There is evidence that ectopeptidase-mediated signal transduction frequently involves tyrosine (...) phosphorylation. Combined analyses of gene organization and regulation of ectopeptidases by various physiological factors have provided insights into their structure–function relationships. Understanding the roles of ectopeptidases in pathophysiology may have implications in considering them as therapeutic targets. BioEssays 23:251–260, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Affective disorders arise in stressful situations from aberrant sensory information integration that affects energetic nutrient (i.e., glucose) utilization to the cognitive centers of the brain. Because energy flow is mediated by molecular signals and receptors that evolved before the first complex brains, the phylogenetically oldest signaling systems are essential in the etiology of affective disorders. The corticotropin‐releasing factor (CRF) peptide subfamily is a phylogenetically old metazoan peptide family and is pivotal for regulating organismal energy response associated with stress. Highly conserved, (...) both the CRF peptide family and its receptors possess a structural relationship to the teneurins, and their receptors, latrophilins, respectively. The CRF homologous region of teneurin is defined as the “teneurin C‐terminal associated peptide” (TCAP) and antagonizes CRF action, regulates mitochondrial energy production, and is anxiolytic in vivo. Here, it is postulated that TCAP represents an ancient peptide that mediates intercellular information transfer of stressful and noxious events by regulating energy utilization among neurons. (shrink)

Aron Arthur Moscona was an Israeli-American developmental biologist whose name is associated with research on cell interactions during embryonic development. His appearance on the international scene dates back to a paper published in 1952, while he was working, together with his wife Haya Sobel Moscona, at the Strangeways Research Laboratory of Cambridge. Together they demonstrated that cells from previously dissociated chick tissues undergo histiotypical and organotypical aggregation in vitro. From 1952 to 1997, Moscona focused his research on cell recognition mechanisms, (...) ultimately demonstrating the role of transmembrane proteins in cellular adhesiveness, tissue segregation, and organ tridimensional assemblage during development. However, who was Aron Moscona before 1952 and what brought him to developmental biology? A Polish Jew who immigrated to Mandatory Palestine in 1933, Moscona belonged to the first generation of biologists formed in the newly established Zoology Department of the Hebrew University. With a particular focus on the Israeli context, the paper reconstructs the evolution of Moscona’s scientific thought by emphasizing the cultural and experimental context of his training and early research at the Hebrew University. The aim is to investigate how local scientific traditions influenced Moscona’s eventual research as well as enabled the relevant experimental innovation he contributed to the field of developmental biology and pathology. The paper can be read both as a scientific biography of Aron Moscona and as a preliminary contribution to the historiography of embryology in the Mandatory Palestine/Israeli context. (shrink)

Proteoglycan 4 (PRG4), first identified in synovial fluid, is an extracellular matrix structural protein in the joint implicated in reducing shear at the cartilage surface as well as controlling adhesion‐dependent synovial growth and regulating bulk protein deposition onto the cartilage. However, recent evidence suggests that it can bind to and effect downstream signaling of a number of cell surface receptors implicated in regulating the inflammatory response. Therefore, we pose the hypothesis: Does PRG4 regulate the inflammatory response and maintain tissue (...) homeostasis? Based on these novel findings implicating PRG4 as an inflammatory signaling molecule, we will present and discuss several hypotheses regarding potential mechanisms by which PRG4 may be able to regulate inflammation. If future studies can demonstrate that PRG4 is a potent inflammatory mediator, this will change current paradigms in the musculoskeletal and ophthalmological fields regarding the how the inflammatory microenvironment is regulated in these tissues and potentially others. (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)