title: PAF-mediated MAPK signaling hyperactivation via LAMTOR3 induces pancreatic tumorigenesis.
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 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.
authors.forename: Sohee
authors.initials: S
authors.lastname: Jun
authors.forename: Sunhye
authors.initials: S
authors.lastname: Lee
authors.forename: Han-Cheon
authors.initials: HC
authors.lastname: Kim
authors.forename: Christopher
authors.initials: C
authors.lastname: Ng
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Schneider
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Ying
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Park
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D063646:Carcinogenesis; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C114559:Lamtor3 protein, mouse; C561966:PAF protein, mouse; D034741:RNA, Small Interfering; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins