AGR2 Gene Function Requires a Unique Endoplasmic Reticulum Localization Motif

Abstract

Background: Whether AGR2 promotes adenocarcinoma growth as a secreted or ER-localized protein is not known. Results: A unique carboxyl-terminal motif, KTEL, is required for AGR2 ER localization and function. Conclusion: Not all ER localization motifs are interchangeable. Significance: Specific ER localization signals may be required for protein function. AGR2's tumor-promoting effects are mediated from the ER and not as a secreted protein.

Agr2 Mediates Paracrine Effects on Stromal Fibroblasts That Promote Invasion by Gastric Signet-Ring Carcinoma Cells

“…Agr2 contains a carboxyl terminal ER localization motif, KTEL, which is required for promotion of cancer cell growth, suggesting that Agr2 exerts its tumor-promoting effects from the ER (20). However, Agr2 is also present in the serum and urine of patients with cancer, suggesting that secreted Agr2 may also play roles in cancer progression.…”

“…This motif interacts with the receptor in ER membrane that binds proteins with the terminal KDEL ER retention sequence, leading to ER localization of Agr2 (20). In some types of cancer, however, Agr2 is also present in the extracellular space, serum, and urine (21,22).…”

Loss of Anterior Gradient 2 (Agr2) Expression Results in Hyperplasia and Defective Lineage Maturation in the Murine Stomach

“…Endoplasmic Reticulum Stress Response Genes Are Not Induced in Agr2 KO Mice-AGR2 protein resides and functions in the endoplasmic reticulum (ER) (43). A previous study of Agr2 null mice detected enhanced expression of genes associated with the ER stress response (42).…”

“…Previous work determined that AGR2 protein functions from within the endoplasmic reticulum (43), which may mediate the assembly or folding of yet to be defined regulatory proteins that reside or are in transit through the ER. Among the genes identified by the DNA microarrays were members of the Reg family of genes, which have been previously implicated in promoting gastric mucosal growth.…”

Mass spectrometry analysis of the oxidation states of the pro-oncogenic protein anterior gradient-2 reveals covalent dimerization via an intermolecular disulphide bond

“…The molecular mechanisms underlying these wide-ranging biological pathways trigged by AGR2 are still not completely defined and as the AGR2 gene is confined to vertebrates, the AGR2 gene pathway cannot be dissected using powerful genetic systems like yeast, flies, or worms [18]. However, emerging functions in the AGR2 pathway focus on (i) identifying its client proteins as it mediates protein folding in the endoplasmic reticulum [19] and as it stimulates receptor maturation [20] [21]; (ii) understanding its function in the endoplasmic reticulum in response to unfolded protein responses [22], (iii) defining the nature of its monomer-dimer equilibrium in tis chaperone cycle [23]; and (iv) understanding the significance of its highly specific peptide docking function which is relatively unique for a molecular chaperone [24] [25].…”