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

Oncogene volume 38, pages 3003–3018 (2019)Cite this article

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Abstract

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.

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Data availability

Raw proteomics files have been deposited (https://goo.gl/N5NNuZ). Annotated supplemental tables include the final data and will be made available through BIOGRID.

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Acknowledgments

Drs. Philip Roux and Dos Sarbossov provided valuable insight and reagents (Roux) on the mTOR pathway. We are grateful for the guidance of Dr. David Agus and the generous financial support of the Lawrence J. Ellison Medical Foundation. We appreciate the support of Autumn Beemer, Lisa Flashner, Laura Ng, and Jeffrey Wang.

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Affiliations

  1. University of Southern California, Keck School of Medicine, Lawrence J. Ellison Institute for Transformative Medicine, Los Angeles, CA, USA

    Katrin Tiemann, Carolina Garri, Sang Bok Lee, Paymaneh D. Malihi, Mincheol Park, Ruth M. Alvarez, Jonathan E. Katz, Mitchell E. Gross & Kian Kani

  2. Department of Radiology, Keck School of Medicine, Los Angeles, CA, USA

    Li Peng Yap

  3. Stanford University, Department of Radiology, Los Angeles, CA, USA

    Parag Mallick

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  1. Katrin Tiemann
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  2. Carolina Garri
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Correspondence to Kian Kani.

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Tiemann, K., Garri, C., Lee, S.B. et al. Loss of ER retention motif of AGR2 can impact mTORC signaling and promote cancer metastasis. Oncogene 38, 3003–3018 (2019). https://doi.org/10.1038/s41388-018-0638-9

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