Role of the pro-oncogenic Protein Disulfide Isomerase (PDI)-family member Anterior Gradient 2 (AGR2) in the control of Endoplasmic Reticulum homeostasis

Title	Role of the pro-oncogenic Protein Disulfide Isomerase (PDI)-family member Anterior Gradient 2 (AGR2) in the control of Endoplasmic Reticulum homeostasis
Publication Type	Journal Article
Year of Publication	2011
Authors	Higa, A, Mulot A, Delom F, Bouchecareilh M, Nguyen DT, Boismenu D, Wise MJ, Chevet E
Journal	Journal of Biological Chemistry
ISSN	1083-351X
Abstract	The Protein disulfide isomerase (PDI) family member Anterior Gradient 2 (AGR2) has been reported to be overexpressed in numerous cancers and to play a role in cancer development. However, to date the molecular functions of AGR2 molecular remain to be characterized. Herein we identified AGR2 as bound to newly synthesized cargo proteins using a proteomics analysis of endoplasmic reticulum (ER) membrane-bound ribosomes. Nascent protein chains that translocate into the ER associate with specific ER luminal proteins, which in turn ensure proper folding and post-translational modifications. Using both imaging and biochemical approaches we confirm that AGR2 localizes to the lumen of the ER and indirectly associates with ER membrane-bound ribosomes through nascent protein chains. We show that AGR2 expression is controlled by the Unfolded Protein Response (UPR) and is in turn is involved in maintenance of ER homeostasis. Remarkably, we demonstrate that siRNA-mediated knockdown of AGR2 significantly alters the expression of components of the ER-associated degradation (ERAD) machinery and reduces the cells ability to cope with acute ER stress, properties that might be relevant to AGR2s role in cancer development.
DOI	10.1074/jbc.M111.275529
Short Title	Journal of Biological Chemistry