A reverse signaling pathway downstream of Sema4A controls cell migration via Scrib

J Cell Biol. 2017 Jan 2;216(1):199-215. doi: 10.1083/jcb.201602002. Epub 2016 Dec 22.


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.

Publication types

  • Video-Audio Media

MeSH terms

  • Animals
  • Cell Movement*
  • Dendritic Cells / metabolism*
  • Genotype
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mass Spectrometry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Invasiveness
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Nerve Tissue Proteins / metabolism
  • Phenotype
  • RNA Interference
  • Receptors, Cell Surface / metabolism
  • Rho Guanine Nucleotide Exchange Factors / metabolism
  • Semaphorins / deficiency
  • Semaphorins / genetics
  • Semaphorins / metabolism*
  • Signal Transduction*
  • Time Factors
  • Transfection
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • cdc42 GTP-Binding Protein / metabolism
  • rac GTP-Binding Proteins / metabolism


  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • PLXNB1 protein, human
  • Plxnb1 protein, mouse
  • Receptors, Cell Surface
  • Rho Guanine Nucleotide Exchange Factors
  • SCRIB protein, human
  • SEMA4A protein, human
  • Sema4A protein, mouse
  • Semaphorins
  • Tumor Suppressor Proteins
  • scribble protein, mouse
  • cdc42 GTP-Binding Protein
  • rac GTP-Binding Proteins