PAF-Mediated MAPK Signaling Hyperactivation via LAMTOR3 Induces Pancreatic Tumorigenesis

Abstract

SUMMARY 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 identified a distinct function of PAF (PCNA-associated factor) 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, independent of Ras or Raf mutations. Intriguingly, PAF transcriptionally activated the expression of late endosomal/lysosomal adaptor, MAPK and mTOR activator 3 (LAMTOR3) that hyperphosphorylates MEK and ERK, which was 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.

Comparison of the effect of recombinant bovine wild and mutant lipopolysaccharide-binding protein in lipopolysaccharide-challenged bovine mammary epithelial cells

“…MP1, which with LAMTOR2 (p14) forms a heterodimer as part of the larger regulator complex that includes LAMTOR3 (MP1), LAMTOR2 (p14), LAMTOR1 (p18), LAMTOR4 (c7 or f59) and LAMTOR5 (HBXIP), is required for MAPK and mTOR1 signalling from late endosomes/lysosomes (de Araujo et al 2013). Some results have revealed an unsuspected mechanism of mitogenic signalling activation via LAMTOR3, a scaffolding protein for ERK and MEK (Jun et al 2013). Aside from those genes relevant to inflammation, both mutant and wild LBP caused downregulation of genes encoding structural molecules (e.g.…”

Microarray expression profile analysis of long non-coding RNAs in pancreatic ductal adenocarcinoma

“…Among these pathways, the gene category 'B cell receptor signaling pathway (human)' is involved in the initiation and growth of human pancreatic ductal adenocarcinoma (69). The gene category Wnt signaling pathway, has been reported to be involved in metastasis of pancreatic carcinogenesis (25), and the gene category MAPK signaling pathway has been shown to participate in the progression of pancreatic cancer though multiple mechanisms (26)(27)(28)70). The gene categories FoxO signaling pathway have been reported to suppress or activate pancreatic cancer progression by different drugs or compound (29,30).…”

Identification of KIAA1199 as a Biomarker for Pancreatic Intraepithelial Neoplasia

“…Our parameters included P < 0.0001, fold change >2, and the top 1% of ranked genes, as previously described4041.…”

“…As previously described40, Pdx1-Cre : K-Ras LSLG12D compound strains were generated by breeding each strain. All experimental protocols were approved by the Institutional Animal Care and Use Committee of The University of Texas MD Anderson Cancer Center, and experiments were carried out in accordance with approved guidelines.…”