title: A reverse signaling pathway downstream of Sema4A controls cell migration via Scrib.
abstract: Semaphorins comprise a large family of ligands that regulate key cellular functions through their receptors, plexins. In this study, we show that the transmembrane semaphorin 4A (Sema4A) can also function as a receptor, rather than a ligand, and transduce signals triggered by the binding of Plexin-B1 through reverse signaling. Functionally, reverse Sema4A signaling regulates the migration of various cancer cells as well as dendritic cells. By combining mass spectrometry analysis with small interfering RNA screening, we identify the polarity protein Scrib as a downstream effector of Sema4A. We further show that binding of Plexin-B1 to Sema4A promotes the interaction of Sema4A with Scrib, thereby removing Scrib from its complex with the Rac/Cdc42 exchange factor βPIX and decreasing the activity of the small guanosine triphosphatase Rac1 and Cdc42. Our data unravel a role for Plexin-B1 as a ligand and Sema4A as a receptor and characterize a reverse signaling pathway downstream of Sema4A, which controls cell migration.
authors.affiliation: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany tianliang.sun@mpi-bn.mpg.de thomas.worzfeld@staff.uni-marburg.de.
authors.forename: Tianliang
authors.identifier: http://orcid.org/0000-0003-2407-5747
authors.initials: T
authors.lastname: Sun
authors.affiliation: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Lida
authors.initials: L
authors.lastname: Yang
authors.affiliation: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Harmandeep
authors.initials: H
authors.lastname: Kaur
authors.affiliation: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Pestel
authors.affiliation: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Looso
authors.affiliation: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Nolte
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, Biochemical-Pharmacological Center, University of Marburg, 35043 Marburg, Germany.
authors.forename: Cornelius
authors.identifier: http://orcid.org/0000-0001-8309-8696
authors.initials: C
authors.lastname: Krasel
authors.affiliation: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0002-2709-1868
authors.initials: D
authors.lastname: Heil
authors.affiliation: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Krishnan
authors.affiliation: Cell Polarity, Cell Signaling and Cancer, Equipe labellisée Ligue Contre le Cancer, Institut National de la Santé et de la Recherche Médicale, U1068, 13009 Marseille, France.|Institut Paoli-Calmettes, 13009 Marseille, France.|Aix-Marseille Université, 13284 Marseille, France.|Centre National de la Recherche Scientifique, UMR7258, 13273 Marseille, France.
authors.forename: Marie-Josée
authors.identifier: http://orcid.org/0000-0002-2619-7257
authors.initials: MJ
authors.lastname: Santoni
authors.affiliation: Cell Polarity, Cell Signaling and Cancer, Equipe labellisée Ligue Contre le Cancer, Institut National de la Santé et de la Recherche Médicale, U1068, 13009 Marseille, France.|Institut Paoli-Calmettes, 13009 Marseille, France.|Aix-Marseille Université, 13284 Marseille, France.|Centre National de la Recherche Scientifique, UMR7258, 13273 Marseille, France.
authors.forename: Jean-Paul
authors.identifier: http://orcid.org/0000-0001-8418-3382
authors.initials: JP
authors.lastname: Borg
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, Biochemical-Pharmacological Center, University of Marburg, 35043 Marburg, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Bünemann
authors.affiliation: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.|Medical Faculty, University of Frankfurt, 60590 Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Jakub M
authors.initials: JM
authors.lastname: Swiercz
authors.affiliation: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany tianliang.sun@mpi-bn.mpg.de thomas.worzfeld@staff.uni-marburg.de.|Institute of Pharmacology, Biochemical-Pharmacological Center, University of Marburg, 35043 Marburg, Germany.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0003-3908-403X
authors.initials: T
authors.lastname: Worzfeld
mesh_terms: D000818:Animals; D002465:Cell Movement; D003713:Dendritic Cells / Q000378:metabolism*; D005838:Genotype; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D039961:Semaphorins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D064067:Rho Guanine Nucleotide Exchange Factors; D039961:Semaphorins; D025521:Tumor Suppressor Proteins; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; C492119:PLXNB1 protein, human; C492118:Plxnb1 protein, mouse; C480591:SCRIB protein, human; C574096:SEMA4A protein, human; C534721:Sema4A protein, mouse; C508433:scrib protein, mouse