Dimerization of pro-oncogenic protein Anterior Gradient 2 is required for the interaction with BiP/GRP78

Ryu, Joohyun; Park, Sung Goo; Lee, Phil Young; Cho, Sayeon; Lee, Do Hee; Kim, Gwang Hoon; Kim, Jeong Hoon; Park, Byoung Chul

doi:10.1016/j.bbrc.2012.11.105

Cited by 28 publications

(38 citation statements)

References 40 publications

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“…Wild type AGR2, after treatment with disuccinimidyl suberate (DSS), is dimeric (Additional file 1: Figure S1). The C81S mutation targets the thioredoxin domain of AGR2 and impairs its catalytic activity and dimer formation, while the E60A mutation impairs AGR2 dimer formation [29-31]. Nthy-ori 3–1 AGR2, AGR2 (C → S), AGR2 (E → A) and pcDNA cells showed comparable growth rates (Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, it was recently demonstrated that dimerization of AGR2 attenuates ER stress-induced cell death through the association with BiP/GRP78 [29-31]. …”

Section: Discussionmentioning

confidence: 99%

“…AGR2 expression is induced by ER stress, and siRNA-mediated knockdown of AGR2 increased ER stress response [27,28]. It has been shown that AGR2 exists in monomer/dimer equilibrium and that intermolecular salt bridges involving glutamic acid 60 or cysteine 81 (in the thioredoxin domain of AGR2) stabilize the dimer [29-31]. Importantly, it was demonstrated that dimerization of AGR2 is crucial in mediating the ER stress signaling pathway [29].…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown that AGR2 exists in monomer/dimer equilibrium and that intermolecular salt bridges involving glutamic acid 60 or cysteine 81 (in the thioredoxin domain of AGR2) stabilize the dimer [29-31]. Importantly, it was demonstrated that dimerization of AGR2 is crucial in mediating the ER stress signaling pathway [29]. AGR2 localizes in the ER of normal intestinal epithelial cells and is essential for in vivo production of mucus [32,33].…”

Section: Introductionmentioning

confidence: 99%

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Anterior gradient protein 2 promotes survival, migration and invasion of papillary thyroid carcinoma cells

et al. 2014

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BackgroundThrough a transcriptome microarray analysis, we have isolated Anterior gradient protein 2 (AGR2) as a gene up-regulated in papillary thyroid carcinoma (PTC). AGR2 is a disulfide isomerase over-expressed in several human carcinomas and recently linked to endoplasmic reticulum (ER) stress. Here, we analyzed the expression of AGR2 in PTC and its functional role.MethodsExpression of AGR2 was studied by immunohistochemistry and real time PCR in normal thyroids and in PTC samples. The function of AGR2 was studied by knockdown in PTC cells and by ectopic expression in non-transformed thyroid cells. The role of AGR2 in the ER stress was analyzed upon treatment of cells, expressing or not AGR2, with Bortezomib and analyzing by Western blot the expression levels of GADD153.ResultsPTC over-expressed AGR2 at mRNA and protein levels. Knockdown of AGR2 in PTC cells induced apoptosis and decreased migration and invasion. Ectopic expression of AGR2 in non-transformed human thyroid cells increased migration and invasion and protected cells from ER stress induced by Bortezomib.ConclusionsAGR2 is a novel marker of PTC and plays a role in thyroid cancer cell survival, migration, invasion and protection from ER stress.

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Section: Resultsmentioning

confidence: 99%

“…Interestingly, it was recently demonstrated that dimerization of AGR2 attenuates ER stress-induced cell death through the association with BiP/GRP78 [29-31]. …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anterior gradient protein 2 promotes survival, migration and invasion of papillary thyroid carcinoma cells

et al. 2014

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“…The monomer to dimer equilibrium in AGR2 might therefore be important in disulphide exchange to assemble correctly folded di-sulphide bridges in client cargo proteins; perhaps especially since AGR2 only has one cysteine and the geometry of the dimer might be critical in association and dissociation assays. In addition to this dimeric structure mediated through amino acids 60-64, AGR2 can form an alternatively shaped dimeric structure in which oxidation-dependent homo-dimerisation occurs through Cysteine-81 mediated disulphide bond formation that would re-orientate the dimer into a different conformation [34]. This oxidised homodimer in equilibrium with its canonical dimer interface through amino acids 60-64 might be an important determinant in the chaperonin re-association cycle to control redox state of its client proteins in the endoplasmic reticulum (Figs.…”

Section: Three Paradigms From Studies On the Biological Functions Of mentioning

confidence: 99%

Mechanisms of anterior gradient-2 regulation and function in cancer

Brychtová

Mohtar

Vojtěšek

et al. 2015

Seminars in Cancer Biology

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

2015

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AGR2 is overexpressed in multiple cancers, particularly those arising from breast and prostate tissues, and higher levels of AGR2 are associated with earlier patient death. Although AGR2 is normally resident within the endoplasmic reticulum, the protein has been found in the extracellular space in several model systems. However, it has never been expressly demonstrated that this extracellular form of the protein is secreted and does not just accumulate in the extracellular space as a result of cell lysis. We show in this paper that AGR2 protein is secreted by both human and rat mammary epithelial cells in culture. Furthermore, this secreted form of AGR2 becomes O-glycosylated, with no detectable presence of N-glycosylation. Importantly, this post-translationally modified AGR2 is only detected in the conditioned medium from non-leaky cells, suggesting that membrane integrity must be maintained to allow AGR2 glycosylation. The results suggest a possible role for O-glycosylation in modulating the extracellular functions of AGR2.

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Dimerization of pro-oncogenic protein Anterior Gradient 2 is required for the interaction with BiP/GRP78

Cited by 28 publications

References 40 publications

Anterior gradient protein 2 promotes survival, migration and invasion of papillary thyroid carcinoma cells

Anterior gradient protein 2 promotes survival, migration and invasion of papillary thyroid carcinoma cells

Mechanisms of anterior gradient-2 regulation and function in cancer

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

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