Differential expression of proliferative, cytoskeletal, and adhesive proteins during postnatal development of the hamster submandibular gland

Fernandes, Rui; Cotanche, Douglas A.; Lennon-Hopkins, Kelley; Erkan, F; Menko, A. Sue; Kukuruzinska, Maria A.

doi:10.1007/s004180050345

Cited by 17 publications

(18 citation statements)

References 31 publications

(30 reference statements)

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“…DPAGT1 and protein N-glycosylation have been shown to be regulated with development and differentiation, and in response to cell density information, but the underlying mechanisms have remained obscure (Clark et al, 1983;Fernandes et al, 1999;Hayes and Lucas, 1983;Meissner et al, 1999;Mota et al, 1994;Welply et al, 1985). Here, using MDCK cells, we report that under normal physiological conditions, DPAGT1 senses cell density via canonical Wnt signaling and AJ maturity.…”

Section: Introductionmentioning

confidence: 64%

“…Since DPAGT1 has also been shown to be downregulated in growth arrested cells (Fernandes et al, 1999), we examined whether this was a direct consequence of reduced canonical Wnt activity. Analyses of DPAGT1 transcript levels by quantitative PCR revealed a 50% reduction in dense cells compared to sparse cultures (Fig.…”

Section: Dpagt1 Senses Cell Density Information Through Canonical Wntmentioning

confidence: 99%

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Coordinate regulation of N-glycosylation gene DPAGT1, canonical Wnt signaling and E-cadherin adhesion

Sengupta

Bouchie

Niță-Lazăr

et al. 2013

Journal of Cell Science

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SummaryThe metabolic pathway of protein N-glycosylation influences intercellular adhesion by affecting the composition and cytoskeletal association of E-cadherin protein complexes, or adherens junctions (AJs). In sparse cells, E-cadherin is modified extensively with complex N-glycans and forms nascent AJs, while in dense cultures, hypoglycosylated E-cadherin drives the assembly of mature AJs with increased levels of c-and a-catenins. N-glycosylation of E-cadherin is controlled by the DPAGT1 gene, a key regulator of the Nglycosylation pathway. DPAGT1 is a target of the canonical Wnt signaling pathway, with both b-and c-catenins binding to Tcf at its promoter. We now report that DPAGT1 senses cell density through canonical Wnt signaling. In dense cells, depletion of b-catenin from the DPAGT1 promoter correlated with downregulation of its cellular abundance, while loss of nuclear c-catenin reflected its greater recruitment to AJs. DPAGT1 itself affected canonical Wnt signaling, with forced changes in its expression resulting in corresponding changes in transcriptionally active b-catenin and canonical Wnt activity. Remarkably, a 2.4-fold increase in the DPAGT1 mRNA level resulted in increased N-glycosylation and reduced membrane localization of E-cadherin, coincident with dramatic changes in cell morphology. Lastly, we present evidence that N-glycosylation status of E-cadherin controls its antagonism of canonical Wnt signaling. Transfection of hypoglycosylated E-cadherin mutant, V13, but not fully N-glycosylated E-cadherin, into sparse cells inhibited canonical Wnt activity by depleting nuclear b-and c-catenins. Collectively, our studies show that cells coordinate DPAGT1 expression and protein N-glycosylation with canonical Wnt signaling and E-cadherin adhesion via positive and negative feedback mechanisms.

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Section: Introductionmentioning

confidence: 64%

Section: Dpagt1 Senses Cell Density Information Through Canonical Wntmentioning

confidence: 99%

Coordinate regulation of N-glycosylation gene DPAGT1, canonical Wnt signaling and E-cadherin adhesion

Sengupta

Bouchie

Niță-Lazăr

et al. 2013

Journal of Cell Science

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“…Previous studies have indicated that salivary gland development entails temporal and spatial coordination among cell proliferation, cytoarchitectural organization, and the establishment of stable cell-substratum interactions (Fernandes et al 1999). However, the molecular mechanisms underlying these events are not known.…”

Section: Discussionmentioning

confidence: 99%

Homeobox Protein, Hmx3, in Postnatally Developing Rat Submandibular Glands

Shaw

Zhang

Russo

et al. 2003

J Histochem Cytochem.

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S U M M A R Y Homeobox-containing (Hox) genes play important roles in development, particularly in the development of neurons and sensory organs, and in specification of body plan. The Hmx gene family is a new class of homeobox-containing genes defined by a conserved homeobox region and a characteristic pattern of expression in the central nervous system that is more rostral than that of the Hox genes. To date, three closely related members of the Hmx family, Hmx1, Hmx2, and Hmx3, have been described. All three Hmx genes are expressed in the craniofacial region of developing embryos. Here we show, for the first time, the expression of the transcription factor Hmx3 in postnatally developing salivary glands. Hmx3 protein is expressed in a cell type-specific manner in rat salivary glands. Hmx3 is present in both the nuclei and cytoplasm of specific groups of duct cells of the submandibular, parotid, and sublingual glands. Hmx3 expression increases during postnatal development of the submandibular gland. The duct cells show increasing concentrations of Hmx3 protein with progressive development of the submandibular gland. In contrast, the acinar cells of the three salivary glands do not exhibit detectable levels of Hmx3 protein.

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“…Protein N-glycosylation has been shown to be regulated with cell proliferation and differentiation (8,14,37). Thus, we reasoned that as a key regulator of N-glycosylation, the DPAGT1 gene is likely a downstream target of signaling pathways with roles in development.…”

Section: Dpagt1 Promoter Contains Tcf/lef-binding Sequences-mentioning

confidence: 99%

“…N-Glycosylation has been shown to be indispensable for development, and its dysregulation has been linked to various diseases, including cancer (3,4,10,11). Expression of DPAGT1, the gene that initiates the synthesis of the lipid-linked oligosaccharide precursor for protein N-glycosylation in the endoplasmic reticulum and is a key determinant of the extent of protein N-glycosylation (12,13), is down-regulated with cellular differentiation, suggesting that attenuation of N-glycosylation is required for the establishment of a differentiated phenotype (14). Indeed, recent studies have documented that DPAGT1 is an upstream regulator of N-glycosylation status of E-cadherin and that its diminished expression is required for the formation of mature intercellular adhesion complexes (15).…”

mentioning

confidence: 99%

N-Glycosylation Gene DPAGT1 Is a Target of the Wnt/β-Catenin Signaling Pathway

Sengupta

Bouchie

Kukuruzinska

2010

Journal of Biological Chemistry

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Protein N-glycosylation and the Wnt/␤-catenin signaling pathways play critical roles in development and cancer. Although N-glycosylation has been shown to influence Wnt signaling through its effects on Wnt ligands, it is unclear whether the Wnt/␤-catenin pathway impacts protein N-glycosylation. In this study, we show that promoters of the first N-glycosylation gene, DPAGT1, from Chinese hamster ovary (CHO), MadinDarby canine kidney (MDCK), and human epidermoid carcinoma (A253) cells contain the T-cell factor/lymphoid enhancerbinding factor (TCF/LEF) consensus sequence. Treatment of cells with a Wnt activator, lithium chloride, up-regulated DPAGT1 transcript levels that correlated with an increase in the ␤-catenin abundance. Furthermore, exposure of cells to a Wnt receptor ligand, Wnt3a, resulted in an increase in the DPAGT1 transcript levels that was abrogated by the Wnt inhibitor, Dickkopf-1. DNA mobility shift assays revealed specific protein complexes at the DPAGT1 TCF/LEF binding region that were competed off with antibodies to either Tcf3/4 or ␤-catenin. Chromatin immunoprecipitation analysis confirmed the presence of ␤-catenin at the DPAGT1 promoter in vivo. In addition, the DPAGT1 TCF/LEF sequence drove the expression of the luciferase reporter gene. Furthermore, up-regulation of DPAGT1 transcripts by Wnt3a led to altered N-glycosylation of E-cadherin. Interestingly, the DPAGT1 TCF/LEF sequence also interacted with ␥-catenin, a close homologue of ␤-catenin, although not in a lithium chloride-dependent manner. Our results provide the first evidence that the Wnt/␤-catenin signaling pathway regulates the metabolic pathway of protein N-glycosylation by targeting DPAGT1 expression. Moreover, they suggest the existence of another regulatory mechanism involving the interaction of Tcf with ␥-catenin at the DPAGT1 promoter.

show abstract

Differential expression of proliferative, cytoskeletal, and adhesive proteins during postnatal development of the hamster submandibular gland

Cited by 17 publications

References 31 publications

Coordinate regulation of N-glycosylation gene DPAGT1, canonical Wnt signaling and E-cadherin adhesion

Coordinate regulation of N-glycosylation gene DPAGT1, canonical Wnt signaling and E-cadherin adhesion

Homeobox Protein, Hmx3, in Postnatally Developing Rat Submandibular Glands

N-Glycosylation Gene DPAGT1 Is a Target of the Wnt/β-Catenin Signaling Pathway

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