title: The RON-receptor regulates pancreatic cancer cell migration through phosphorylation-dependent breakdown of the hemidesmosome.
abstract: The recepteur d'origine nantais (RON) receptor tyrosine kinase is overexpressed and stimulates invasive growth in pancreatic cancer cells, yet the mechanisms that underlie RON-mediated phenotypes remain poorly characterized. To better understand RON function in pancreatic cancer cells, we sought to identify novel RON interactants using multidimensional protein identification analysis. These studies revealed plectin, a large protein of the spectrin superfamily, to be a novel RON interactant. Plectin is a multifunctional protein that complexes with integrin-β4 (ITGB4) to form hemidesmosomes, serves as a scaffolding platform crucial to the function of numerous protein signaling pathways and was recently described as an overexpressed protein in pancreatic cancer (Bausch D et al., Clin Cancer Res 2010; Kelly et al., PLoS Med 2008;5:e85). In this study, we demonstrate that on exposure to its ligand, macrophage-stimulating protein, RON binds to plectin and ITGB4, which results in disruption of the plectin-ITGB4 interaction and enhanced cell migration, a phenotype that can be recapitulated by small hairpin ribosomal nucleic acid (shRNA)-mediated suppression of plectin expression. We demonstrate that disruption of plectin-ITGB4 is dependent on RON and phosphoinositide-3 (PI3) kinase, but not mitogen-activated protein kinase (MEK), activity. Thus, in pancreatic cancer cells, plectin and ITGB4 form hemidesmosomes which serve to anchor cells to the extracellular matrix (ECM) and restrain migration. The current study defines a novel interaction between RON and plectin, provides new insight into RON-mediated migration and further supports efforts to target RON kinase activity in pancreatic cancer.
authors.affiliation: Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Yu
authors.forename: Michele
authors.initials: M
authors.lastname: Babicky
authors.forename: Dawn
authors.initials: D
authors.lastname: Jaquish
authors.forename: Randy
authors.initials: R
authors.lastname: French
authors.forename: Karly
authors.initials: K
authors.lastname: Marayuma
authors.forename: Evangeline
authors.initials: E
authors.lastname: Mose
authors.forename: Sherry
authors.initials: S
authors.lastname: Niessen
authors.forename: Heather
authors.initials: H
authors.lastname: Hoover
authors.forename: David
authors.initials: D
authors.lastname: Shields
authors.forename: David
authors.initials: D
authors.lastname: Cheresh
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lowy
mesh_terms: D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D005455:Fluorescent Antibody Technique; D022002:Hemidesmosomes / Q000378:metabolism*; D006801:Humans; D039663:Integrin beta4 / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D051190:Plectin / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014945:Wound Healing
chemical_list: C059834:ITGB4 protein, human; D039663:Integrin beta4; C495332:PLEC protein, human; D051190:Plectin; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases