Blood Journal
Leading the way in experimental and clinical research in hematology

Semaphorin3A signaling controls Fas (CD95)-mediated apoptosis by promoting Fas translocation into lipid rafts

  1. Simona Moretti1,2,
  2. Antonio Procopio1,2,
  3. Raffaella Lazzarini1,2,
  4. Maria Rita Rippo1,2,
  5. Roberto Testa3,
  6. Maurizio Marra3,
  7. Luca Tamagnone4, and
  8. Alfonso Catalano1,2
  1. 1Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona;
  2. 2Center of Cytology and
  3. 3Diabetology Unit, Research Department, Italian National Research Centers on Aging, Ancona; and
  4. 4Institute for Cancer Research and Treatment, University of Turin, Candiolo, Italy

Abstract

Semaphorins and their receptors (plexins) have pleiotropic biologic functions, including regulation of immune responses. However, the role of these molecules inside the immune system and the signal transduction mechanism(s) they use are largely unknown. Here, we show that Semaphorin3A (Sema3A) triggers a proapoptotic program that sensitizes leukemic T cells to Fas (CD95)-mediated apoptosis. We found that Sema3A stimulation provoked Fas translocation into lipid raft microdomains before binding with agonistic antibody or FasL (CD95L). Disruption of lipid rafts reduced sensitivity to Fas-mediated apoptosis in the presence of Sema3A. Furthermore, we show that plexin-A1, together with Sema3A-binding neuropilin-1, was rapidly incorporated into membrane rafts after ligand stimulation, resulting in the transport of actin-linking proteins into Fas-enriched rafts. Cells expressing a dominant-negative mutant of plexin-A1 did not show Fas clustering and apoptosis on Sema3A/Fas costimulation. This work identifies a novel biologic function of semaphorins and presents an unexpected signaling mechanism linking semaphorin to the tumor necrosis factor family receptors.

  • Submitted June 19, 2007.
  • Accepted November 20, 2007.
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