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

• DOI: 10.1083/jcb.201602002
• Publication Date: 2017-01-20T19:56:41Z
• Authors: Tianliang Sun; Lida Yang; Harmandeep Kaur; Jenny Pestel; Mario Looso; Hendrik Nolte; Cornelius Krasel; Daniel Heil; Ramesh K. Krishnan; Marie-Josée Santoni; Jean-Paul Borg; Moritz Bünemann; Stefan Offermanns; Jakub M. Swiercz; Thomas Worzfeld
• Keywords: 0301 basic medicine; Genotype; [SDV]Life Sciences [q-bio]; Nerve Tissue Proteins; Receptors, Cell Surface; Semaphorins; Mass Spectrometry; 03 medical and health sciences; Cell Movement; Neoplasms; Animals; Humans; Neoplasm Invasiveness; Research Articles; Mice, Knockout; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Dendritic Cells; [SDV] Life Sciences [q-bio]; Mice, Inbred C57BL; HEK293 Cells; Phenotype; RNA Interference; Rho Guanine Nucleotide Exchange Factors; HeLa Cells

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.