Abstract
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 neoplasiawith 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 cancercell proliferation. Our results reveal an unsuspected mechanism of mitogenic signaling activationvia LAMTOR3 and suggest that PAF-induced MAPK hyperactivation contributes to pancreatic tumorigenesis
Original language | English (US) |
---|---|
Pages (from-to) | 314-322 |
Number of pages | 9 |
Journal | Cell Reports |
Volume | 5 |
Issue number | 2 |
DOIs | |
State | Published - 2013 |
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
MD Anderson CCSG core facilities
- Advanced Technology Genomics Core
- Flow Cytometry and Cellular Imaging Facility
- Genetically Engineered Mouse Facility
- Research Animal Support Facility