Diversity of the protein disulfide isomerase family: Identification of breast tumor induced Hag2 and Hag3 as novel members of the protein family

Persson, Staffan; Rosenquist, Magnus; Knoblach, Barbara; Khosravi‐Far, Roya; Sommarin, Marianne; Michalak, Marek

doi:10.1016/j.ympev.2005.04.002

Cited by 102 publications

(104 citation statements)

References 21 publications

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“…AGR2 was initially assumed to be a secreted protein, based on the presence of a predicted signal peptide at the amino terminus (8). However, more recent analysis identified an ER localization signal and thioredoxin-like domain sequences, suggesting that AGR2 is a PDI (3,12). We found that AGR2 is localized to the ER in intestinal epithelial cells and did not detect AGR2 in secretory granules or in the intestinal lumen.…”

Section: Discussionmentioning

confidence: 50%

“…AGR2 is one of 19 known PDI family members expressed in humans and other mammals. Differences in the number and type of thioredoxin-like domains and in cell type-specific expression patterns of PDIs (1)(2)(3) suggest that there is likely to be considerable diversity in PDI function, but the in vivo functions of mammalian PDIs are largely unknown. In a previous study involving gene targeting of a PDI family member, loss of the PDI ERp57, which works together with calnexin and calreticulin during processing of many glycoproteins in the ER (27), resulted in embryonic lethality (28).…”

Section: (C and D) Periodic Acid-schiff Staining Of Glycoproteins In mentioning

confidence: 99%

“…PDI family members are defined by the presence of 1 or more thioredoxin-like domains and by localization to the ER. At least 19 human PDI family members have been identified (1)(2)(3), and each has a known mouse ortholog. Many PDI thioredoxin-like domains have a motif that contains 2 cysteine residues (CXXC).…”

mentioning

confidence: 99%

“…Anterior gradient homolog 2 (AGR2, also known as AG2, HAG-2, or GOB-4) was classified recently as a member of the PDI family based on a search for sequences with homology to known family members (3). Murine Agr2 was originally identified in a screen for mRNAs expressed selectively in intestinal goblet cells (8).…”

mentioning

confidence: 99%

“…However, AGR2 has a carboxyl-terminal KTEL sequence, and a recent analysis indicated that this sequence was recognized by ER retention receptors and served to localize AGR2 predominantly to the ER of transfected cells (12). In addition, AGR2 has a single thioredoxin-like domain with a CXXS motif (3). Because AGR2 has these structural characteristics of a PDI and is expressed selectively in mucus-producing cells, we hypothesized that AGR2 plays a special role in the production of mucus.…”

mentioning

confidence: 99%

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The protein disulfide isomerase AGR2 is essential for production of intestinal mucus

Park

Zhen²,

Verhaeghe³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

332

349

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Protein disulfide isomerases (PDIs) aid protein folding and assembly by catalyzing formation and shuffling of cysteine disulfide bonds in the endoplasmic reticulum (ER). Many members of the PDI family are expressed in mammals, but the roles of specific PDIs in vivo are poorly understood. A recent homology-based search for additional PDI family members identified anterior gradient homolog 2 (AGR2), a protein originally presumed to be secreted by intestinal epithelial cells. Here, we show that AGR2 is present within the ER of intestinal secretory epithelial cells and is essential for in vivo production of the intestinal mucin MUC2, a large, cysteine-rich glycoprotein that forms the protective mucus gel lining the intestine. A cysteine residue within the AGR2 thioredoxinlike domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. Mice lacking AGR2 were viable but were highly susceptible to colitis, indicating a critical role for AGR2 in protection from disease. We conclude that AGR2 is a unique member of the PDI family, with a specialized and nonredundant role in intestinal mucus production.colitis ͉ endoplasmic reticulum ͉ mucin ͉ goblet cell ͉ protein processing

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Section: Discussionmentioning

confidence: 50%

Section: (C and D) Periodic Acid-schiff Staining Of Glycoproteins In mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The protein disulfide isomerase AGR2 is essential for production of intestinal mucus

Park

Zhen²,

Verhaeghe³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

332

349

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Downregulation of AGR2, p21, and cyclin D and alterations in p53 function were associated with tumor progression and chemotherapy resistance in epithelial ovarian carcinoma

et al. 2018

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Anterior gradient 2 protein belongs to a family of chaperone‐like proteins, namely protein disulfide isomerase. Generally, AGR2 is highly expressed in mucus‐secreting cells and endocrine organs, and in this study, we aimed to evaluate AGR2 and cell cycle molecules in epithelial ovarian cancer and its implications on prognosis. One hundred seventy‐five patient's samples that were diagnosed with primary epithelial ovarian carcinoma were selected. All the patients were treated with platinum‐taxane standard chemotherapy after surgery and CA125 serum levels were routinely determined. Four‐micrometer‐thick sections were processed by immunohistochemistry using an automated immunostainer, Ventana BenchMark AutoStainer with AGR2, cyclin D1, p21WAF1, and p53. Forty‐nine of 167 cases (29.3%) showed strong to moderate cytoplasmic marking of AGR2, and 118 (70.7%) had weak to negative expression. The absence of the AGR2 protein was observed in high‐grade serous carcinoma (P < .001) and significantly associated with disease‐free survival (DFS; P = .034). The expression of G1‐S phase‐regulatory proteins showed loss of p21 in high‐grade serous carcinoma (P < .001) and was related with poor DFS (P = .003). Strong and diffuse immunoexpression of p53 plus complete absence of p53 staining was interpreted as likely indicating a TP53 gene mutation. This result showed worse DFS alone (P = .012) and combined with low levels of AGR2 (P = .005). The expression profile of AGR2 and cell cycle proteins here presented was showed as good prognosis marker in epithelial ovarian cancer. This finding suggests AGR2 and as putative biomarker of disease progression in chemotherapy‐treated high‐grade serous carcinoma patients.

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An update of the regulatory factors of sperm migration from the uterus into the oviduct by genetically manipulated mice

Xiong

Wang

Shen

2019

Molecular Reproduction Devel

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Mammalian reproductive processes involve spermatogenesis, which occurs in the testis, and fertilization, which takes place in the female genital tract. Fertilization is a successive, multistep, and extremely complicated event that usually includes sperm survival in the uterus, sperm migration through the uterotubal junction (UTJ) and the oviduct, sperm penetration through the cumulus cell layer and the zona pellucida, and sperm–egg fusion. There may be a complex molecular mechanism to ensure that the above processes run smoothly. Previous studies have discovered essential factors for these fertilization steps through in vitro fertilization experiments. However, recent gene disruption approaches in mice have revealed that many of the factors previously described as important for fertilization are largely dispensable in gene‐knockout animals, and some previously unknown factors are emerging. As a result, the molecular mechanisms of fertilization, especially sperm migration from the uterus into the oviduct, have recently been revised by the emergence of genetically modified animals. In this review, we only focus on and update the essential genes for sperm migration through the UTJ and describe recent advances in our knowledge of the basis of mammalian sperm migration.

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Diversity of the protein disulfide isomerase family: Identification of breast tumor induced Hag2 and Hag3 as novel members of the protein family

Cited by 102 publications

References 21 publications

The protein disulfide isomerase AGR2 is essential for production of intestinal mucus

The protein disulfide isomerase AGR2 is essential for production of intestinal mucus

Downregulation of AGR2, p21, and cyclin D and alterations in p53 function were associated with tumor progression and chemotherapy resistance in epithelial ovarian carcinoma

An update of the regulatory factors of sperm migration from the uterus into the oviduct by genetically manipulated mice

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