The metastasis-inducing protein AGR2 is O-glycosylated upon secretion from mammary epithelial cells

Clarke, Christopher J.; Rudland, Philip S.; Barraclough, Roger

doi:10.1007/s11010-015-2502-3

Cited by 16 publications

(16 citation statements)

References 62 publications

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“…Recently, AGR2 was demonstrated to be O-glycosylated upon secretion ( Clarke et al, 2015 ). Protein O-GlcNAcylation was examined in non-tumor organoids overexpressing AGR2 (HBEC-AGR2) or not (HBEC-EV) following eAGR2 immunoprecipitation ( Figure 5—figure supplement 1C ).…”

Section: Resultsmentioning

confidence: 99%

Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties

Fessart

Domblides

Avril

et al. 2016

eLife

113

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The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER-retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis.DOI: http://dx.doi.org/10.7554/eLife.13887.001

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Section: Resultsmentioning

confidence: 99%

Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties

Fessart

Domblides

Avril

et al. 2016

eLife

113

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“…Tumor secreted AGR2 has cell‐autocrine/paracrine effect which plays a pivotal role in tumor microenvironment . Cancer‐secreted AGR2 has been reported to promote the invasion and migration of Fibro., program cell death of stromal cells, and disrupt the polarity of epithelial cells . Remarkably, several functional domains of AGR2 like PDI activity domain, dimerization site, and adhesion domain may be involved in the process of cell migration .…”

Section: Discussionmentioning

confidence: 99%

“…by regulating the formation of focal adhesions. These AGR2 functions in wound healing involve FAK and JNK signaling pathways and require AGR2 adhesion domain (amino acids [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. Our finding indicates that external AGR2 may represent an alternative strategy for the development of therapeutics for wounds with large exposure area or difficult-to-heal chronic wounds.…”

Section: Introductionmentioning

confidence: 97%

Anterior gradient 2 is induced in cutaneous wound and promotes wound healing through its adhesion domain

et al. 2017

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Anterior gradient 2 (AGR2), a member of protein disulfide isomerase (PDI) family, is both located in cytoplasm and secreted into extracellular matrix. The orthologs of AGR2 have been linked to limb regeneration in newt and wound healing in zebrafish. In mammals, AGR2 influences multiple cell signaling pathways in tumor formation and in normal cell functions related to new tissue formation like angiogenesis. However, the function of AGR2 in mammalian wound healing remains unknown. This study aimed to investigate AGR2 expression and its function during skin wound healing and the possible application of external AGR2 in cutaneous wound to accelerate the healing process. Our results showed that AGR2 expression was induced in the migrating epidermal tongue and hyperplastic epidermis after skin excision. Topical application of recombinant AGR2 significantly accelerated wound-healing process by increasing the migration of keratinocytes (Kera.) and the recruitment of fibroblasts (Fibro.) near the wounded area. External AGR2 also promoted the migration of Kera. and Fibro. in vitro in a dose-dependent manner. The adhesion domain of AGR2 was required for the formation of focal adhesions in migrating Fibro., leading to the directional migration along AGR2 gradient. These results indicate that recombinant AGR2 accelerates skin wound healing through regulation of Kera. and Fibro. migration, thus demonstrating its potential utility as an alternative strategy of the therapeutics to accelerate the healing of acute or chronic skin wounds.

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“…On the other hand, the functions of amphibian and fish AGs, in salamander [ 4 ], Xenopus [ 3 ] and zebrafish [ 20 ], involve secretion and extracellular action, and nAG is secreted after transfection of cultured cells [ 4 ]. Furthermore AGR2 is found in high concentrations in gastrointestinal mucus [ 21 ], and is secreted by human and rat mammary epithelial cells as an O-glycosylated molecule [ 22 ]. We address several of these issues, including the activity of secreted nAG, the dependence on the single Cys residue in the thioredoxin active site, and the variation of ER retention versus secretion in different AG proteins.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Action of Secreted Newt Anterior Gradient Protein

et al. 2016

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Anterior gradient (AG) proteins have a thioredoxin fold and are targeted to the secretory pathway where they may act in the ER, as well as after secretion into the extracellular space. A newt member of the family (nAG) was previously identified as interacting with the GPI-anchored salamander-specific three-finger protein called Prod1. Expression of nAG has been implicated in the nerve dependence of limb regeneration in salamanders, and nAG acted as a growth factor for cultured newt limb blastemal (progenitor) cells, but the mechanism of action was not understood. Here we show that addition of a peptide antibody to Prod1 specifically inhibit the proliferation of blastema cells, suggesting that Prod1 acts as a cell surface receptor for secreted nAG, leading to S phase entry. Mutation of the single cysteine residue in the canonical active site of nAG to alanine or serine leads to protein degradation, but addition of residues at the C terminus stabilises the secreted protein. The mutation of the cysteine residue led to no detectable activity on S phase entry in cultured newt limb blastemal cells. In addition, our phylogenetic analyses have identified a new Caudata AG protein called AG4. A comparison of the AG proteins in a cell culture assay indicates that nAG secretion is significantly higher than AGR2 or AG4, suggesting that this property may vary in different members of the family.

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The metastasis-inducing protein AGR2 is O-glycosylated upon secretion from mammary epithelial cells

Cited by 16 publications

References 62 publications

Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties

Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties

Anterior gradient 2 is induced in cutaneous wound and promotes wound healing through its adhesion domain

Mechanism of Action of Secreted Newt Anterior Gradient Protein

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