Abstract
PACS-2 is a multifunctional sorting protein that mediates cell homeostasis. We recently identified PACS-2 in a functional genome-wide siRNA screen for novel regulators of the metalloproteinase ADAM17, the main sheddase for ligands of the ErbB receptor family. Of note, we showed that Pacs2-/- mice have significantly reduced EGFR activity and proliferative index in the intestinal epithelium. As EGFR signaling is highly mitogenic for intestinal epithelial stem cells, and plays essential roles in intestinal epithelial regeneration and tumor development, we have now examined the role of PACS-2 in these processes. Specifically, we analyzed the role of Pacs2-deficiency in a DSS-induced colitis model as well as in the genetic ApcMin colon cancer model. We now report that loss of PACS-2 delays tissue regeneration after colonic injury with little effect on key inflammatory parameters. We did however not observe any apparent effects on tumor formation driven by excessive proliferative signaling downstream from APC-deficiency. Our findings reveal that the role of PACS-2 in regulating ADAM17-mediated shedding is not an obligate requirement for the epithelium to respond to the strong inflammatory or tumorigenic inducers in the models assessed here.
Highlights
Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional sorting protein involved in trafficking of various cargo molecules
We recently reported that PACS-2 regulates cellsurface availability of a disintegrin and metalloproteinase-17 (ADAM17), thereby fine-tuning ADAM17 activity and downstream ErbB signaling [3]
We observed a marked reduction in phosphorylated EGFR levels and proliferative index in the small intestinal epithelium and to a lesser extent in the colonic epithelium of Pacs2-/- mice
Summary
Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional sorting protein involved in trafficking of various cargo molecules. The dynamics of cell-surface localized ADAM17 are of importance because it cleaves a variety of cellsurface molecules, a process termed ectodomain shedding. ADAM17 sheds ErbB ligands, leading to activation of ErbB family receptors (epidermal growth factor receptor (EGFR), ErbB2, ErbB3, ErbB4) to trigger cell growth, survival, and migration [4]. By decreasing cell-surface levels of ADAM17, PACS2 knockdown led to a significant reduction in shedding of EGFR ligands. In vivo, this translated into reduced EGFR activition and proliferative index in the small intestinal epithelium and to a lesser extent in the colon of Pacs2-/- mice [3]. By controlling ADAM17 cell-surface availability, PACS-2 appears to fine-tune ADAM17 www.impactjournals.com/oncotarget and ErbB activity, with potential functional effects on intestinal homeostasis
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