Loss of ER retention motif of AGR2 can impact mTORC signaling and promote cancer metastasis

Oncogene. 2019 Apr;38(16):3003-3018. doi: 10.1038/s41388-018-0638-9. Epub 2018 Dec 21.


Anterior gradient 2 (AGR2) is a member of the protein disulfide isomerase (PDI) family, which plays a role in the regulation of protein homeostasis and the unfolded protein response pathway (UPR). AGR2 has also been characterized as a proto-oncogene and a potential cancer biomarker. Cellular localization of AGR2 is emerging as a key component for understanding the role of AGR2 as a proto-oncogene. Here, we provide evidence that extracellular AGR2 (eAGR2) promotes tumor metastasis in various in vivo models. To further characterize the role of the intracellular-resident versus extracellular protein, we performed a comprehensive protein-protein interaction screen. Based on these results, we identify AGR2 as an interacting partner of the mTORC2 pathway. Importantly, our data indicates that eAGR2 promotes increased phosphorylation of RICTOR (T1135), while intracellular AGR2 (iAGR2) antagonizes its levels and phosphorylation. Localization of AGR2 also has opposing effects on the Hippo pathway, spheroid formation, and response to chemotherapy in vitro. Collectively, our results identify disparate phenotypes predicated on AGR2 localization. Our findings also provide credence for screening of eAGR2 to guide therapeutic decisions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Endoplasmic Reticulum / genetics*
  • HEK293 Cells
  • Humans
  • MCF-7 Cells
  • Male
  • Mechanistic Target of Rapamycin Complex 2 / genetics*
  • Mice
  • Mice, Nude
  • Mucoproteins
  • Neoplasm Metastasis / genetics*
  • Neoplasm Metastasis / pathology*
  • Neoplasms / genetics*
  • Neoplasms / pathology*
  • Oncogene Proteins
  • PC-3 Cells
  • Protein Disulfide-Isomerases / genetics
  • Proteins / genetics*
  • Proto-Oncogene Mas
  • Signal Transduction / genetics
  • Unfolded Protein Response / genetics


  • AGR2 protein, human
  • MAS1 protein, human
  • Mucoproteins
  • Oncogene Proteins
  • Proteins
  • Proto-Oncogene Mas
  • Mechanistic Target of Rapamycin Complex 2
  • Protein Disulfide-Isomerases