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Epithelial cell-cell adhesion is mediated by E-cadherin, an intercellular N-glycoprotein adhesion receptor that functions in the assembly of multiprotein complexes anchored to the actin cytoskeleton named adherens junctions (AJs). E-cadherin ectodomains 4 and 5 contain three potential N-glycan addition sites, although their significance in AJ stability is unclear. Here we show that sparse cells lacking stable AJs produced E-cadherin that was extensively modified with complex N-glycans. In contrast, dense cultures with more stable AJs had scarcely N-glycosylated E-cadherin modified with high mannose/hybrid and limited complex N-glycans. This suggested that variations in AJ stability were accompanied by quantitative and qualitative changes in E-cadherin N-glycosylation. To further examine the role of N-glycans in AJ function, we generated E-cadherin N-glycosylation variants lacking selected N-glycan addition sites. Characterization of these variants in CHO cells, lacking endogenous E-cadherin, revealed that site 1 on ectodomain 4 was modified with a prominent complex N-glycan, site 2 on ectodomain 5 did not have a substantial oligosaccharide, and site 3 on ectodomain 5 was decorated with a high mannose/hybrid N-glycan. Removal of complex N-glycan from ectodomain 4 led to a dramatically increased interaction of E-cadherin-catenin complexes with vinculin and the actin cytoskeleton. The latter effect was further enhanced by the deletion of the high mannose/hybrid N-glycan from site 3. In MDCK cells, which produce E-cadherin, a variant lacking both complex and high mannose/hybrid N-glycans functioned like a dominant positive displaying increased interaction with gamma-catenin and vinculin compared with the endogenous E-cadherin. Collectively, our studies show that N-glycans, and complex oligosaccharides in particular, destabilize AJs by affecting their molecular organization. 相似文献
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Differential expression of proliferative, cytoskeletal, and adhesive proteins during postnatal development of the hamster submandibular gland 总被引:1,自引:1,他引:0
Fernandes RP Cotanche DA Lennon-Hopkins K Erkan F Menko AS Kukuruzinska MA 《Histochemistry and cell biology》1999,111(2):153-162
Although the submandibular gland (SMG) plays important exocrine and endocrine roles, little is known about the molecular
details underlying its development. Previously, we reported that in the postnatally developing hamster SMG, GPT, the protein
product of the first N-glycosylation gene, ALG7, was an in vivo marker for salivary cell proliferation. Here we investigated the proliferative,
cytoskeletal, and adhesive changes during SMG postnatal development. The cellular localization and abundance of GPT, filamentous
actin, and β1 integrin receptor were examined using confocal microscopy and immunoblotting. In neonatal glands, high GPT levels
marked extensive cell proliferation throughout the tissue. The apical regions of immature salivary cells displayed intense
actin staining, while most of the β1 integrin was diffusely distributed throughout the tissue. As development proceeded, discrete
regions of the gland expressed attenuated levels of GPT, an increased organization of actin to the cell cortex, and β1 integrin
to the basal lamina. In the adult SMG, differentiated salivary cells displayed low levels of GPT and actin. While the abundance
of β1 integrin remained unchanged throughout development, in the adult, it was found exclusively in regions where cells contact
the basal lamina. These data indicate that SMG development entails regionalized cell proliferation and polarization, and that
these processes are temporally and spatially coordinated with the establishment of stable cell-substratum interactions.
Accepted: 26 October 1998 相似文献
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Tsao PN Chen F Izvolsky KI Walker J Kukuruzinska MA Lu J Cardoso WV 《The Journal of biological chemistry》2008,283(43):29532-29544
Little is known about the mechanisms by which the lung epithelial progenitors are initially patterned and how proximal-distal boundaries are established and maintained when the lung primordium forms and starts to branch. Here we identified a number of Notch pathway components in respiratory progenitors of the early lung, and we investigated the role of Notch in lung pattern formation. By preventing gamma-secretase cleavage of Notch receptors, we have disrupted global Notch signaling in the foregut and in the lung during the initial stages of murine lung morphogenesis. We demonstrate that Notch signaling is not necessary for lung bud initiation; however, Notch is required to maintain a balance of proximal-distal cell fates at these early stages. Disruption of Notch signaling dramatically expands the population of distal progenitors, altering morphogenetic boundaries and preventing formation of proximal structures. Our data suggest a novel mechanism in which Notch and fibroblast growth factor signaling interact to control the proximal-distal pattern of forming airways in the mammalian lung. 相似文献
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Mendelsohn RD Helmerhorst EJ Cipollo JF Kukuruzinska MA 《Biochimica et biophysica acta》2005,1723(1-3):33-44
The modification of proteins at asparagine residues with oligosaccharides (N-glycans) plays critical roles in diverse cell functions. N-glycans originate from a common lipid-linked oligosaccharide (LLO) precursor whose synthesis is initiated by the Dol-P-dependent GlcNAc-1-P transferase (GPT) encoded by an essential ALG7 gene. To identify cellular processes affected by ALG7 and N-glycosylation, we replaced the genomic copy of ALG7 with its hypomorphic allele in two genetically distinct haploid yeast cells. We show that ALG7 knockdown gave rise to an unexpected phenotype of mitochondrial dysfunction. The alg7 mutants did not grow on glycerol and DNA arrays revealed the absence of mitochondrial genes' expression. Accordingly, the alg7 mutants displayed no detectable mtDNA and respiratory activity. Both mutants exhibited diminished abundance of LLO and under-glycosylation of carboxypeptidase Y (CPY). Moreover, another N-glycosylation mutant with a LLO defect, alg6, was respiratory deficient. Collectively, our studies provide evidence that the dysregulation of N-glycosylation in haploid yeast cells leads to mitochondrial dysfunction. 相似文献
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