title: AGR2 gene function requires a unique endoplasmic reticulum localization motif.
abstract: Soluble proteins are enriched in the endoplasmic reticulum (ER) by retrograde transport from the Golgi that is mediated by the KDEL receptors. In addition to the classic carboxyl-terminal KDEL motif, a variety of sequence variants are also capable of receptor binding that result in ER localization. Although different ER localization signals that exhibit varying affinities for the KDEL receptors exist, whether there are functional implications was unknown. The present study determines whether AGR2 requires a specific ER localization signal to be functionally active. AGR2 is expressed in most human adenocarcinomas and serves a role in promoting growth and the transformed phenotype. Using two different cell lines in which AGR2 induces expression of either the EGFR ligand amphiregulin or the transcription factor CDX2, only the highly conserved wild-type carboxyl-terminal KTEL motif results in the appropriate outcome. Deletion of the KTEL motif results in AGR2 secretion and loss of AGR2 function. AGR2 function is also lost when ER residence is achieved with a carboxyl-terminal KDEL or KSEL instead of a KTEL motif. Thus variations in ER localization sequences may serve a specific functional role, and in the case of AGR2, this role is served specifically by KTEL.
authors.affiliation: Department of Medicine and the Stanford Digestive Disease Center, Stanford University, Stanford, California 94305, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Gupta
authors.forename: Aiwen
authors.initials: A
authors.lastname: Dong
authors.forename: Anson W
authors.initials: AW
authors.lastname: Lowe
mesh_terms: D020816:Amino Acid Motifs; D066258:Amphiregulin; D000818:Animals; D045744:Cell Line, Tumor; D066255:EGF Family of Proteins; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D009088:Mucoproteins; D015513:Oncogene Proteins; D021382:Protein Sorting Signals / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: C502296:AGR2 protein, human; C587848:AREG protein, human; D066258:Amphiregulin; C587850:Areg protein, rat; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C064459:KDEL receptor; D009088:Mucoproteins; D015513:Oncogene Proteins; D021382:Protein Sorting Signals; D011506:Proteins; D018000:Receptors, Peptide