title: Anterior Gradient 2 (AGR2) Induced Epidermal Growth Factor Receptor (EGFR) Signaling Is Essential for Murine Pancreatitis-Associated Tissue Regeneration.
abstract: A recently published study identified Anterior Gradient 2 (AGR2) as a regulator of EGFR signaling by promoting receptor presentation from the endoplasmic reticulum to the cell surface. AGR2 also promotes tissue regeneration in amphibians and fish. Whether AGR2-induced EGFR signaling is essential for tissue regeneration in higher vertebrates was evaluated using a well-characterized murine model for pancreatitis. The impact of AGR2 expression and EGFR signaling on tissue regeneration was evaluated using the caerulein-induced pancreatitis mouse model. EGFR signaling and cell proliferation were examined in the context of the AGR2-/- null mouse or with the EGFR-specific tyrosine kinase inhibitor, AG1478. In addition, the Hippo signaling coactivator YAP1 was evaluated in the context of AGR2 expression during pancreatitis. Pancreatitis-induced AGR2 expression enabled EGFR translocation to the plasma membrane, the initiation of cell signaling, and cell proliferation. EGFR signaling and tissue regeneration were partially inhibited by the tyrosine kinase inhibitor AG1478, but absent in the AGR2-/- null mouse. AG1478-treated and AGR2-/- null mice with pancreatitis died whereas all wild-type controls recovered. YAP1 activation was also dependent on pancreatitis-induced AGR2 expression. AGR2-induced EGFR signaling was essential for tissue regeneration and recovery from pancreatitis. The results establish tissue regeneration as a major function of AGR2-induced EGFR signaling in adult higher vertebrates. Enhanced AGR2 expression and EGFR signaling are also universally present in human pancreatic cancer, which support a linkage between tissue injury, regeneration, and cancer pathogenesis.
authors.affiliation: Department of Medicine, Stanford University, Stanford, California, United States of America.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Wodziak
authors.affiliation: Department of Medicine, Stanford University, Stanford, California, United States of America.
authors.forename: Aiwen
authors.initials: A
authors.lastname: Dong
authors.affiliation: Department of Medicine, Stanford University, Stanford, California, United States of America.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Basin
authors.affiliation: Department of Medicine, Stanford University, Stanford, California, United States of America.
authors.forename: Anson W
authors.initials: AW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002108:Ceruletide / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D018628:Gene Dosage / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D000090683:Hippo Signaling Pathway; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009088:Mucoproteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins; D010195:Pancreatitis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C526445:Agr2 protein, mouse; D009088:Mucoproteins; D015513:Oncogene Proteins; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D002108:Ceruletide; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases