title: Glomerular overexpression and increased tyrosine phosphorylation of focal adhesion kinase p125FAK in lupus-prone MRL/MP-lpr/lpr mice.
abstract: Much progress has been made in understanding how mammalian cells receive a diverse array of external stimuli and convert them into intracellular biochemical signals. Such efforts have identified a large number of signalling molecules. However, our knowledge is limited as to their pathophysiological role in particular diseases. We demonstrate herein that an integrin-linked signalling molecule, focal adhesion kinase p125FAK (FAK), is overexpressed in glomeruli of lupus-prone MRL/MP-lpr/lpr (MRL-lpr) mouse as compared to its congeneic MRL-+/+ strain. Increased expression was specifically demonstrated in glomeruli but not in other tissues examined. The overexpression was observed in 16-week-old MRL-lpr mice with active nephritis, as well as in younger animals at 4 weeks of age. Thus, the upregulation of FAK clearly preceded the clinical onset of nephritis. FAK in MRL-lpr glomeruli is highly tyrosine phosphorylated and is associated with adapter protein Grb2. Previous in vitro studies have shown that the association of FAK/Grb2 links cell adhesion to the Ras pathway, which ultimately stimulates mitogen-activated protein (MAP) kinase, an important regulator of cell proliferation. In accordance, we observed constitutive MAP kinase activation in MRL-lpr glomeruli. Our findings suggest that signalling pathways involving FAK are activated in MRL-lpr glomeruli, and are likely to play a role in the development and progression of autoimmune-mediated murine nephritis.
authors.affiliation: Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Morino
authors.forename: T
authors.initials: T
authors.lastname: Matsumoto
authors.forename: K
authors.initials: K
authors.lastname: Ueki
authors.forename: T
authors.initials: T
authors.lastname: Mimura
authors.forename: K
authors.initials: K
authors.lastname: Hamasaki
authors.forename: H
authors.initials: H
authors.lastname: Kanda
authors.forename: T
authors.initials: T
authors.lastname: Naruse
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
authors.forename: Y
authors.initials: Y
authors.lastname: Nojima
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051380:GRB2 Adaptor Protein; D007672:Kidney Cortex / Q000276:immunology; D007678:Kidney Glomerulus / Q000201:enzymology*; D008181:Lupus Nephritis / Q000201:enzymology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D011506:Proteins; D014443:Tyrosine; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse