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.
Highlights
Tissue regeneration entails the reconstitution of normal architecture and function after tissue injury
Consistent with Jensen et al was an increase in acinar cell proliferation as determined by nuclear MKI67, which served as a biomarker for tissue regeneration and peaked on Day 3 after the caerulein injections (Fig 1E and 1F) [5, 26, 27]
Anterior Gradient 2 (AGR2) is not expressed in the normal pancreas, but is induced early in the course of pancreatitis, which results in EGFR delivery to the cell surface where signaling doi:10.1371/journal.pone.0164968.g006
Summary
Tissue regeneration entails the reconstitution of normal architecture and function after tissue injury. AGR2-Dependent Tissue Regeneration in Pancreatitis inflammation, and cell apoptosis; followed by cell proliferation and organ restoration in one week [1,2,3,4]. During this process, exocrine acinar cells undergo a metaplastic transformation characterized by dedifferentiation and the expression of developmental genes [5]. Caeruleininduced pancreatitis results in a pronounced increase in acinar cell proliferation that peaks on day 3 after the caerulein injections, and serves as a functional biomarker for tissue regeneration [5]
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