Unique intracellular trafficking processes associated with neural cell adhesion molecule and its intracellular signaling

Homophilic binding of the neural cell adhesion molecule (NCAM) results in intracellular signaling, which also involves heterophilic engagement of coreceptors such as the fibroblast growth factor receptor (FGFR) and receptor protein tyrosine phosphatase-α (RPTPα). NCAM's own cellular dynamic itinerary includes endocytosis and recycling to the plasma membrane. Recent works suggest that NCAM could influence the trafficking of other receptor molecules that it associates with, particularly the FGFR. Furthermore, it was demonstrated that NCAM could undergo proteolytic processing upon activation. A processed fragment of NCAM, together with an N-terminal fragment of focal adhesion kinase (FAK), is translocated into the nucleus. Here, the authors discuss these rather unique (though not without precedence and analogues) receptor trafficking activities that are associated with NCAM and NCAM signaling.     

Geometry-induced inhomogeneity of distribution of cell adhesion molecules along branching processes

There is evidence that inhomogeneity of lateral distribution of cell adhesion molecules (CAM) in the plasma membrane is crucial for cell motility and growth. It is known that the cells move when the cell-substratum adhesiveness is within a certain critical range. We have carried out simulation studies of the factors governing inhomogeneous CAM distribution along uniform and branching cylinder-shaped cell processes on a flat substrate evenly covered with a ligand. Our model included the following mechanisms: intracellular transportation of CAM to an active (growing) part of the cell, installation in the plasma membrane, lateral diffusive redistribution of mobile CAM, formation and dissociation of CAM/ligand complexes, and CAM internalization by endocytosis. Since the rate of growth is two and one order of magnitude slower than the rate of trafficking and lateral diffusion, respectively, we analyzed steady distributions of CAM. We showed that interplay of the mechanisms included in the model may lead to the occurrence of CAM distributions with inhomogeneity, whose range is critical for translocation of an active part of the cell. It was shown that a difference in the diameters of asymmetric sister branches can cause different inhomogeneous distributions of CAM along these branches and thus can define conditions of their growth. Depending on the branching geometry, one or both sister branches may appear within this critical range, and a difference in the diameters may define a difference in the rate of growth and, correspondingly, in the length. This may constitute the basis for self-control of neurite outgrowth.     

Extracellular matrix molecules and cell adhesion molecules induce neurites through different mechanisms

It has recently become clear that both extracellular matrix (ECM) glycoproteins and various cell adhesion molecules (CAMs) can promote neurite outgrowth from primary neurons, though little is known of the intracellular mechanisms through which these signals are transduced. We have previously obtained evidence that protein kinase C function is an important part of the neuronal response to laminin (Bixby, J.L. 1989. Neuron. 3:287-297). Because such CAMs as L1 (Lagenauer, C., and V. Lemmon. 1987. Proc. Natl. Acad. Sci. USA. 84:7753-7757) and N-cadherin (Bixby, J.L. and R. Zhang. 1990. J. Cell Biol. 110:1253-1260) can be purified and used as substrates to promote neurite growth, we have now tested whether the response to CAMs is similarly dependent on protein kinase C. We find that inhibition of protein kinase C inhibits growth on fibronectin or collagen as well as on laminin. In contrast, C kinase inhibition actually potentiates the initial growth response to L1 or N- cadherin. The later "phase" of outgrowth on both of these CAMs is inhibited, however. Additionally, phorbol esters, which have no effect on neurite growth when optimal laminin concentrations are used, potentiate growth even on optimal concentrations of L1 or N-cadherin. The results indicate that different intracellular mechanisms operate during initial process outgrowth on ECM substrates as compared to CAM substrates, and suggest that protein kinase C function is required for continued neurite growth on each of these glycoproteins.     

Isolation and characterization of Chinese hamster ovary cell mutants defective in intracellular low density lipoprotein-cholesterol trafficking

This paper reports the isolation and characterization of Chinese hamster ovary cell mutants defective in low density lipoprotein (LDL)-cholesterol trafficking. The parental cell line was 25-RA, which possesses LDL receptors and various cholesterogenic enzyme activities that are partially resistant to down regulation by exogenous sterols (Chang, T. Y., and J. S. Limanek. 1980. J. Biol. Chem. 255:7787-7795). Because these cells accumulate a large amount of intracellular cholesteryl ester when grown in medium containing 10% fetal calf serum, mutagenized populations of 25-RA cells were grown in the presence of a specific inhibitor of acyl-coenzyme A: cholesterol acyltransferase (ACAT), which depleted their cholesteryl ester stores. Without this cholesterol ester storage, 99% of 25-RA cells die after 5-d growth in cholesterol starvation medium, while the mutant cells, which accumulate free cholesterol intracellularly, survived. In two mutant clones chosen for characterization, activation of cholesteryl ester synthesis by LDL was markedly reduced in the mutant cells compared with 25-RA cells. This lack of activation of cholesterol ester synthesis in the mutant cells could not be explained by defective uptake and/or processing of LDL or by a decreased amount of ACAT, as determined by in vitro enzyme activity. Mutant cells grown in the presence of LDL contain numerous cytosolic particles that stain intensely with the fluorescent compound acridine orange, suggesting that they are acidic. The particles are also stained with filipin, a cholesterol-specific fluorescent dye. Indirect immunofluorescence with a monoclonal antibody specific for a lysosomal/endosomal fraction revealed a staining pattern that colocalized with the filipin signal. The mutant phenotype was recessive. The available evidence indicates that the mutant cells can take up and process LDL normally, but the hydrolyzed cholesterol accumulates in an acidic compartment, probably the lysosomes, where it can not be transported to its normal intracellular destinations.     

Inconstancy of Taylor'sb: Simulated sampling with different quadrat sizes and spatial distributions

Taylor 's power law, s²=am^b, provides a precise summary of the relationship between sample variance (s²) and sample mean (m) for many organisms. The coefficient b has been interpreted as an index of aggregation, with a characteristic value for a given species in a particular environment, and has been thought to be independent of the sample unit. Simulation studies were conducted that demonstrate that the value of b may vary with the size of the sample unit in quadrat sampling, and this relationship, in turn, depends on the underlying spatial distribution of the population. For example, simulated populations with hierarchical aggregation on a large scale produced values of b that increased with the size of the sample unit. In contrast, for a simulated population with randomly distributed clusters of individuals, the value of b eventually decreased with increasing quadrat size, as sample counts became more uniform. A single value ofTaylor 's b, determined with a particular sample unit, provides neither a fixed index of aggregation nor a complete picture of a species' spatial distribution. Rather, it describes a consistent relationship between sample variance and sample mean over a range of densities, on a spatial scale related to the size of the sample unit. This relationship may reflect, but not uniquely define, density-dependent population and behavioral processes governing the spatial distribution of the organism. Interpretation ofTaylor 'sb for a particular organism should be qualified by reference to the sample unit, and comparisons should not be made between cases in which different sample units were used. Whenever possible, a range of sample units should be used to provide information about the pattern of distribution of a population on various spatial scales.     

Regulation of nucleocytoplasmic trafficking by cell adhesion receptors and the cytoskeleton

It has become widely accepted that adhesion receptors can either directly activate, or significantly modulate, many of the signaling cascades initiated by circulating growth factors. An interesting recent development is the realization that adhesion receptors and their cytoskeletal partners can regulate the trafficking of signaling proteins between the cytoplasm and nucleus. Cell adhesion molecule control of nucleocytoplasmic trafficking allows adhesion to influence many cell decisions, and highlights the diversity of nuclear import and export mechanisms.     

Epithelial cell cytoskeleton and intracellular trafficking V. Confluence of membrane trafficking and motility in epithelial cell models

Migration of epithelial cells occurs in a variety of important biological processes including tissue morphogenesis, wound healing, and the metastasis of epithelial tumors. In some instances, the cells remain attached to each other and migrate together as a sheet, maintaining epithelial integrity. In others (e.g., metastasis), junctional complexes are disrupted and cells migrate individually. In both cases, motility involves the extension of membranous protrusions (filopodia and lamellipodia) in the direction of movement and the transient assembly and disassembly of integrin-mediated adhesions with the extracellular matrix. The driving force for these events is provided by regulated changes in the organization of the actin cytoskeleton, which are thought to be coordinated with alterations in intracellular membrane traffic. In this themes article, I review current hypotheses about how these processes are integrated and attempt to identify fruitful areas for future research.     

Plasticity in epithelial cell phenotype: modulation by expression of different cadherin cell adhesion molecules

A primary function of cadherins is to regulate cell adhesion. Here, we demonstrate a broader function of cadherins in the differentiation of specialized epithelial cell phenotypes. In situ, the rat retinal pigment epithelium (RPE) forms cell-cell contacts within its monolayer, and at the apical membrane with the neural retina; Na+, K(+)-ATPase and the membrane cytoskeleton are restricted to the apical membrane. In vitro, RPE cells (RPE-J cell line) express an endogenous cadherin, form adherens junctions and a tight monolayer, but Na+,K(+)-ATPase is localized to both apical and basal-lateral membranes. Expression of E- cadherin in RPE-J cells results in restriction and accumulation of both Na+,K(+)-ATPase and the membrane cytoskeleton at the lateral membrane; these changes correlate with the synthesis of a different ankyrin isoform. In contrast to both RPE in situ and RPE-J cells that do not form desmosomes, E-cadherin expression in RPE-J cells induces accumulation of desmoglein mRNA, and assembly of desmosome-keratin complexes at cell-cell contacts. These results demonstrate that cadherins directly affect epithelial cell phenotype by remodeling the distributions of constitutively expressed proteins and by induced accumulation of specific proteins, which together lead to the generation of structurally and functionally distinct epithelial cell types.     

Regulation of intracellular trafficking of human CD1d by association with MHC class II molecules

CD1 family members are antigen-presenting molecules capable of presenting bacterial or synthetic glycolipids to T cells. Here we show that a subset of human CD1d molecules are associated with major histocompatibility complex (MHC) class II molecules, both on the cell surface and in the late endosomal/lysosomal compartments where class II molecules transiently accumulate during transport. The interaction is initiated in the endoplasmic reticulum with class II-invariant chain complexes and appears to be maintained throughout the class II trafficking pathway. A truncated form of CD1d which lacks its cytoplasmic YXXZ internalization motif is transported to late endosomal/lysosomal compartments in the presence of class II molecules. Furthermore, the same CD1d deletion mutant is targeted to lysosomal compartments in HeLa cells expressing class II molecules and invariant chain by transfection. The deletion mutant was also found in lysosomal compartments in HeLa cells expressing only the p33 form of the invariant chain. These data suggest that the intracellular trafficking pathway of CD1d may be altered by class II molecules and invariant chain induced during inflammation.     

Regulation of intracellular membrane trafficking and cell dynamics by syntaxin-6

Intracellular membrane trafficking along endocytic and secretory transport pathways plays a critical role in diverse cellular functions including both developmental and pathological processes. Briefly, proteins and lipids destined for transport to distinct locations are collectively assembled into vesicles and delivered to their target site by vesicular fusion. SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptor) proteins are required for these events, during which v-SNAREs (vesicle SNAREs) interact with t-SNAREs (target SNAREs) to allow transfer of cargo from donor vesicle to target membrane. Recently, the t-SNARE family member, syntaxin-6, has been shown to play an important role in the transport of proteins that are key to diverse cellular dynamic processes. In this paper, we briefly discuss the specific role of SNAREs in various mammalian cell types and comprehensively review the various roles of the Golgi- and endosome-localized t-SNARE, syntaxin-6, in membrane trafficking during physiological as well as pathological conditions.     

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

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

Trypanosoma cruzi: adhesion to the host cell and intracellular survival

Both invasion of the host cell by T. cruzi and its establishment into the mammalian host are critical steps. In this review, the adhesion step and the intracellular survival in non-professional phagocytes are particularly focused on, with special emphasis on the role of Gp85/trans-sialidase (Gp85/TS) superfamily. Excellent reviews have been published lately, some covering other aspects of T. cruzi-host interaction and will be cited instead of the original articles due to limited number of listed references.     

The roles of cell adhesion molecules in tumor suppression and cell migration

In addition to mediating cell adhesion, many cell adhesion molecules act as tumor suppressors. These proteins are capable of restricting cell growth mainly through contact inhibition. Alterations of these cell adhesion molecules are a common event in cancer. The resulting loss of cell-cell and/or cell-extracellular matrix adhesion promotes cell growth as well as tumor dissemination. Therefore, it is conventionally accepted that cell adhesion molecules that function as tumor suppressors are also involved in limiting tumor cell migration. Paradoxically, in 2005, we identified an immunoglobulin superfamily cell adhesion molecule hepaCAM that is able to suppress cancer cell growth and yet induce migration. Almost concurrently, CEACAM1 was verified to co-function as a tumor suppressor and invasion promoter. To date, the reason and mechanism responsible for this exceptional phenomenon remain unclear. Nevertheless, the emergence of these intriguing cell adhesion molecules with conflicting roles may open a new chapter to the biological significance of cell adhesion molecules.     

Lectin cell adhesion molecules (LEC-CAMs): a new family of cell adhesion proteins involved with inflammation.

The means by which leukocytes, including lymphocytes, monocytes, and neutrophils, migrate from the circulation to sites of acute and chronic inflammation is an area of intense research interest. Although a number of soluble mediators of these important cellular interactions have been identified, a major site of great importance to the inflammatory response is the physical interface between the white cell and the endothelium. This critical association is mediated by an array of cell surface adhesion molecules. Previous data have demonstrated that the integrin subfamily of heterotypic adhesion molecules was a major component of these adhesive interactions, although it was clear that other, non-integrin-like molecules of unknown identity also seemed to be involved during the inflammatory process. A number of these other cell-surface glycoproteins which may be involved with inflammation have recently been characterized by molecular cloning. These glycoproteins, including the peripheral lymph node homing receptor (pln HR), the endothelial cell adhesion molecule (ELAM), and PADGEM/gmp140, are all members of a family of proteins which are unified by the inclusion of three characteristic protein motifs: a lectin or carbohydrate recognition domain, an epidermal growth factor (egf) domain, and a variable number of short consensus repeats (scr) which are also found in members of the complement regulatory proteins. The appearance of lectin domains in all of these adhesion molecules is consistent with the possibility that these glycoproteins function by binding to carbohydrates which are expressed in a cell and/or region specific manner, and the members of this adhesion family have been given the generic name LEC-CAM (lectin cell adhesion molecules).(ABSTRACT TRUNCATED AT 250 WORDS)     

神经细胞粘附分子结构特征和生理功能

神经细胞粘附分子是一类调节细胞与细胞、细胞与细胞外基质间粘附作用的膜表面糖蛋白,主要有NCAM-180、NCAM-140、NCAM-120三种形式,多与PSA结合在一起。在神经系统中,NCAM的表达具有时间和空间特异性,最主要的作用为调节神经系统的可塑性,这种作用可能是通过PSA-NCAM对AMPA的调节作用,主要是通过调节蛋白激酶的表达和细胞内Ca^2 浓度来实现的。     

Evaluation of cross-sectional geometry and mass density distributions of humans and laboratory animals using computerized tomography

The purpose of this study was to determine the cross-sectional geometry and mass density distribution of a young porcine subject using the X-ray computerized tomographic (CT) method and to perform a comparative study of anatomical features of this subject and a 3 yr old female child specimen. The cross-sectional CT scans of the porcine subject were obtained at 1 cm intervals. The outlines of each cross section and of selected anatomical components within each section were obtained by standard picture processing techniques. The mass and inertia tensor for each cross section and for each anatomical structure in a section were computed based on the CT numbers. The porcine subject was then sacrificed, frozen, sectioned and photographed. These sectional photographs were then compared with those obtained from the CT method. Tabulated cross-sectional mass and inertia tensor obtained from CT scans of the porcine subject were also used to compare with similar results derived from previously completed CT scans of the 3 yr old female child specimen. In particular, the comparisons were made on the location of the center of gravity and the inertia tensor in the head, neck, head and neck and cervical spine regions. Some immediate applications of this data are inputs to finite element models, lumped parameter biodynamic models, computer simulation of vehicle crash victims, and dummy design.