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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2290-2299.
Prepublished online as a Blood First Edition Paper on December 3, 2007; DOI 10.1182/blood-2007-06-096529.
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Submitted June 19, 2007
Accepted November 20, 2007
Semaphorin3A signaling controls Fas (CD95)-mediated apoptosis by promoting Fas translocation into lipid rafts
Simona Moretti, Antonio Procopio, Raffaella Lazzarini, Maria Rita Rippo, Roberto Testa, Maurizio Marra, Luca Tamagnone, and Alfonso Catalano*
Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona, Italy
Center of Cytology, Research Department, Italian National Research Centers on Aging (INRCA-IRCCS), Ancona, Italy
Diabetology Unit, Research Department, Italian National Research Centers on Aging (INRCA-IRCCS), Ancona, Italy
Institute for Cancer Research and Treatment, University of Turin, Turin, Italy
* Corresponding author; email: catgfp{at}yahoo.it.
Semaphorins and their receptors (plexins) have pleiotropic biological functions, including regulation of immune responses. However, the role of these molecules inside the immune system and the signal transduction mechanism(s) they utilize are largely unknown. Here, we show that Semaphorin3A (Sema3A) triggers a proapoptotic programme 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 upon Sema3A/Fas co-stimulation. This work identifies a novel biological function of semaphorins and presents an unexpected signaling mechanism linking semaphorin to the tumor necrosis factor family receptors.
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