title: Crk1/2-dependent signaling is necessary for podocyte foot process spreading in mouse models of glomerular disease.
abstract: The morphology of healthy podocyte foot processes is necessary for maintaining the characteristics of the kidney filtration barrier. In most forms of glomerular disease, abnormal filter barrier function results when podocytes undergo foot process spreading and retraction by remodeling their cytoskeletal architecture and intercellular junctions during a process known as effacement. The cell adhesion protein nephrin is necessary for establishing the morphology of the kidney podocyte in development by transducing from the specialized podocyte intercellular junction phosphorylation-mediated signals that regulate cytoskeletal dynamics. The present studies extend our understanding of nephrin function by showing that nephrin activation in cultured podocytes induced actin dynamics necessary for lamellipodial protrusion. This process required a PI3K-, Cas-, and Crk1/2-dependent signaling mechanism distinct from the previously described nephrin-Nck1/2 pathway necessary for assembly and polymerization of actin filaments. Our present findings also support the hypothesis that mechanisms governing lamellipodial protrusion in culture are similar to those used in vivo during foot process effacement in a subset of glomerular diseases. In mice, podocyte-specific deletion of Crk1/2 prevented foot process effacement in one model of podocyte injury and attenuated foot process effacement and associated proteinuria in a delayed fashion in a second model. In humans, focal adhesion kinase and Cas phosphorylation - markers of focal adhesion complex-mediated Crk-dependent signaling - was induced in minimal change disease and membranous nephropathy, but not focal segmental glomerulosclerosis. Together, these observations suggest that activation of a Cas-Crk1/2-dependent complex is necessary for foot process effacement observed in distinct subsets of human glomerular diseases.
authors.affiliation: Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Britta
authors.initials: B
authors.lastname: George
authors.forename: Rakesh
authors.initials: R
authors.lastname: Verma
authors.forename: Abdulsalam A
authors.initials: AA
authors.lastname: Soofi
authors.forename: Puneet
authors.initials: P
authors.lastname: Garg
authors.forename: Jidong
authors.initials: J
authors.lastname: Zhang
authors.forename: Tae-Ju
authors.initials: TJ
authors.lastname: Park
authors.forename: Laura
authors.initials: L
authors.lastname: Giardino
authors.forename: Larisa
authors.initials: L
authors.lastname: Ryzhova
authors.forename: Duncan B
authors.initials: DB
authors.lastname: Johnstone
authors.forename: Hetty
authors.initials: H
authors.lastname: Wong
authors.forename: Deepak
authors.initials: D
authors.lastname: Nihalani
authors.forename: David J
authors.initials: DJ
authors.lastname: Salant
authors.forename: Steven K
authors.initials: SK
authors.lastname: Hanks
authors.forename: Tom
authors.initials: T
authors.lastname: Curran
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rastaldi
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Holzman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002460:Cell Line; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism* / Q000648:ultrastructure; D050737:Proto-Oncogene Proteins c-crk / Q000235:genetics / Q000378:metabolism*; D011554:Pseudopodia / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D055815:Young Adult
chemical_list: D050719:Crk-Associated Substrate Protein; D008565:Membrane Proteins; D050737:Proto-Oncogene Proteins c-crk; D011993:Recombinant Fusion Proteins; C113267:nephrin; D019869:Phosphatidylinositol 3-Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases