PAF-Mediated MAPK Signaling Hyperactivation via LAMTOR3 Induces Pancreatic Tumorigenesis
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, via la protéine LAMTOR3, une hyperactivation de la signalisation MAPK favorise le développement d'une tumeur du pancréas
Deregulation of mitogen-activated protein kinase (MAPK) signaling leads to development of pancreatic cancer. Although Ras-mutation-driven pancreatic tumorigenesis is well understood, the underlying mechanism of Ras-independent MAPK hyperactivation remains elusive. Here, we have identified a distinct function of PCNA-associated factor (PAF) in modulating MAPK signaling. PAF is overexpressed in pancreatic cancer and required for pancreatic cancer cell proliferation. In mouse models, PAF expression induced pancreatic intraepithelial neoplasia with expression of pancreatic cancer stem cell markers. PAF-induced ductal epithelial cell hyperproliferation was accompanied by extracellular signal-regulated kinase (ERK) phosphorylation independently of Ras or Raf mutations. Intriguingly, PAF transcriptionally activated the expression of late endosomal/lysosomal adaptor, MAPK and mTOR activator 3 (LAMTOR3), which hyperphosphorylates MEK and ERK and is necessary for pancreatic cancer cell proliferation. Our results reveal an unsuspected mechanism of mitogenic signaling activation via LAMTOR3 and suggest that PAF-induced MAPK hyperactivation contributes to pancreatic tumorigenesis. "Overexpressed PAF is required for pancreatic cancer cell proliferation "PAF ectopic expression develops pancreatic ductal neoplasia in mouse models"PAF hyperactivates MAPK signaling in vitro and in vivo "PAF-induced MAPK activation is mediated by LAMTOR3 transactivation Deregulation of mitogen-activated protein kinase (MAPK) signaling leads to the development of pancreatic cancer. Although Ras-mutation-driven pancreatic tumorigenesis is well understood, the underlying mechanism of Ras-independent MAPK hyperactivation remains elusive. Park and colleagues have identified a distinct mechanism of PCNA-associated factor (PAF) in modulating MAPK signaling. PAF is overexpressed in pancreatic cancer and induces pancreatic intraepithelial neoplasia. This is due to PAF-induced transcriptional activation of late endosomal/lysosomal adaptor, MAPK and mTOR activator 3 (LAMTOR3), which hyperphosphorylates MEK and ERK and contributes to pancreatic tumorigenesis.
http://linkinghub.elsevier.com/retrieve/pii/S2211124713005494 2013