title: Synaptopodin Is a Coincidence Detector of Tyrosine versus Serine/Threonine Phosphorylation for the Modulation of Rho Protein Crosstalk in Podocytes.
abstract: Tyrosine and serine/threonine signal-transduction pathways influence many aspects of cell behavior, including the spatial and temporal regulation of the actin cytoskeleton. However, little is known about how input from diverse tyrosine and serine/threonine kinases is integrated to control Rho protein crosstalk and actin remodeling, which are critically important in podocyte health and disease. Here we unveil the proteolytically-regulated, actin organizing protein synaptopodin as a coincidence detector of tyrosine versus serine/threonine phosphorylation. We show that serine/threonine and tyrosine kinases duel for synaptopodin stability versus degradation. EGFR/Src-mediated tyrosine phosphorylation of synaptopodin in podocytes promotes binding to the serine/threonine phosphatase calcineurin. This leads to the loss of 14-3-3 binding, resulting in synaptopodin degradation, Vav2 activation, enhanced Rac1 signaling, and ultimate loss of stress fibers. Our studies reveal how synaptopodin, a single proteolytically-controlled protein, integrates antagonistic tyrosine versus serine/threonine phosphorylation events for the dynamic control of the actin cytoskeleton in podocytes.
authors.affiliation: Departments of Physiology, Institute of Neuroscience and Physiology, and.
authors.forename: Lisa
authors.initials: L
authors.lastname: Buvall
authors.affiliation: Clinical and Molecular Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Wallentin
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.|Kidney Disease Initiative, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Jonas
authors.initials: J
authors.lastname: Sieber
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Andreeva
authors.affiliation: Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hoon Young
authors.initials: HY
authors.lastname: Choi
authors.affiliation: and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Peter
authors.initials: P
authors.lastname: Mundel
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts; agreka@bwh.harvard.edu agreka@broadinstitute.org.|Kidney Disease Initiative, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Anna
authors.initials: A
authors.lastname: Greka
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002478:Cells, Cultured; D051379:Mice; D008840:Microfilament Proteins / Q000502:physiology*; D010766:Phosphorylation; D050199:Podocytes / Q000502:physiology*; D020239:Receptor Cross-Talk; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
chemical_list: D008840:Microfilament Proteins; C503968:Synpo protein, mouse; D013912:Threonine; D014443:Tyrosine; D012694:Serine; D019703:Calcineurin; D020742:rhoA GTP-Binding Protein
keywords: EGFR; FSGS; Rac1; TRPC5; cytoskeleton; glomerular disease