title: Transactivation of RON receptor tyrosine kinase by interaction with PDGF receptor beta during steady-state growth of human mesangial cells.
abstract: Although it is well known that platelet-derived growth factor (PDGF) causes mesangial cell proliferation (presumably contributing to progression of glomerular disease), targeted inhibition of the PDGF receptor system has shown only limited efficacy against glomerular diseases. To examine whether this discrepancy is due to the involvement of other pathways, we used phosphorylated receptor tyrosine kinase arrays and found that RON (recepteur d'origine nantais) was phosphorylated while the PDGF receptor was dephosphorylated (thus inactive) in human mesangial cells (HMCs) at the time of cell cycle entry. Further, RON remained active during steady-state growth. Activation of RON was independent of its canonical ligand, macrophage-stimulating protein, but was mediated by transactivation from the PDGF-engaged PDGF receptor. Following stimulation with PDGF we found that the two receptors physically interacted. Knockdown of RON by siRNA increased the number of apoptotic cells without affecting the rate of DNA synthesis, suggesting that RON has anti-apoptotic functions. Immunohistochemical analysis found phosphorylated RON in glomerular lesions of patients with IgA nephropathy but not those with minimal change nephrotic syndrome, a disease not associated with mesangial proliferation. These results suggest that RON is involved in mesangial cell proliferation under both physiological and pathological conditions, and may be a relevant target for therapeutic intervention.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan; Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan. Electronic address: furuyu@jichi.ac.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Furukawa
authors.affiliation: Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Kikuchi
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Ito
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Miyata
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Muto
authors.affiliation: Department of Pathology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kusano
mesh_terms: D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D005922:Glomerulonephritis, IGA / Q000473:pathology; D006801:Humans; D050527:Mesangial Cells / Q000166:cytology*; D009402:Nephrosis, Lipoid / Q000473:pathology; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D010982:Platelet-Derived Growth Factor; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta