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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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NEOPLASIA
Semaphorin3A signaling controls Fas (CD95)-mediated apoptosis by promoting Fas translocation into lipid rafts
Simona Moretti1,2,
Antonio Procopio1,2,
Raffaella Lazzarini1,2,
Maria Rita Rippo1,2,
Roberto Testa3,
Maurizio Marra3,
Luca Tamagnone4, and
Alfonso Catalano1,2
1 Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona;
2 Center of Cytology and
3 Diabetology Unit, Research Department, Italian National Research Centers on Aging, Ancona; and
4 Institute for Cancer Research and Treatment, University of Turin, Candiolo, Italy
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.
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