title: SDF-1α induces differential trafficking of CXCR4-CXCR7 involving cyclophilin A, CXCR7 ubiquitination and promotes platelet survival.
abstract: Platelet-derived SDF-1α (CXCL12) mediates inflammatory and regenerative mechanisms. The present study characterizes the effect of SDF-1α ligation in platelets. SDF-1α (0-100 μM) dose and time dependently caused internalization of its receptor CXCR4 (28.9 ± 1.6 vs. 16.1 ± 1.9 in SDF-1α-treated platelets), coupled to the surface externalization of CXCR7 (65.5 ± 8 vs. 162.8 ± 27.6 following SDF-1α treatment), both in vitro and in vivo. This was inhibited in the presence of AMD3100 (100 μM), CXCR4 blocking and vesicular transport inhibitors (brefeldin A, 10 μM; rapamycin, 100 nM). SDF-1α/CXCR-4-mediated CXCR7 translocation was significantly reduced by inhibitors of ERK1/2-(U0126-10 μM) and cyclophilinA (CyPA)-(NIM811-10 μM) by 28 and 46%, respectively. Further, SDF-1α-induced downstream phosphorylation of Erk1/2 led to CyPA-dependent ubiquitination of CXCR7, which is essential for its surface translocation. CyPA-PPIase-activity inhibitor NIM-811, Erk1/2, and E1-ligase inhibitor-(PYR-41-25 μM) significantly abolished SDF-1α-driven CXCR7 ubiquitination and subsequent surface translocation. SDF-1α induced CXCR7 ubiquitination, and its surface exposure was observed in wild-type murine platelets, but not in CyPA-deficient platelets. SDF-1α/CXCR4-CyPA-dependent CXCR7 translocation and its subsequent ligation attenuated activation-induced apoptosis both in vitro and when administered in vivo. This antiapoptotic effect of SDF-1α was abrogated by blocking CXCR7, also significantly affected in Cypa(-/-) platelets. Thus, we decipher a novel mechanism, whereby SDF-1α regulates relative receptor availability in circulating platelets and exerts its prosurvival benefits.-Chatterjee, M., Seizer, P., Borst, O., Schönberger, T., Mack, A., Geisler, T., Langer, H. F., May, A. E., Vogel, S., Lang, F., Gawaz, M. SDF-1α induces differential trafficking of CXCR4-CXCR7 involving cyclophilin A, CXCR7 ubiquitination and promotes platelet survival.
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen.
authors.forename: Madhumita
authors.initials: M
authors.lastname: Chatterjee
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen.
authors.forename: Peter
authors.initials: P
authors.lastname: Seizer
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen.
authors.forename: Oliver
authors.initials: O
authors.lastname: Borst
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schönberger
authors.affiliation: Institute of Anatomy, Universität Tübingen, Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mack
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen.
authors.forename: Tobias
authors.initials: T
authors.lastname: Geisler
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen.
authors.forename: Harald F
authors.initials: HF
authors.lastname: Langer
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: May
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Vogel
authors.affiliation: Institute of Physiology, and.
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, meinrad.gawaz@med.uni-tuebingen.de.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001792:Blood Platelets / Q000378:metabolism* / Q000502:physiology; D054377:Chemokine CXCL12 / Q000378:metabolism*; D021984:Cyclophilin A / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D010766:Phosphorylation / Q000502:physiology; D021381:Protein Transport / Q000502:physiology*; D054387:Receptors, CXCR / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D054377:Chemokine CXCL12; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D021984:Cyclophilin A
keywords: apoptosis; chemokine; platelets; receptor