title: CXCR7 participates in CXCL12-induced CD34+ cell cycling through β-arrestin-dependent Akt activation.
abstract: In addition to its well-known effect on migration and homing of hematopoietic stem/progenitor cells (HSPCs), CXCL12 chemokine also exhibits a cell cycle and survival-promoting factor for human CD34(+) HSPCs. CXCR4 was suggested to be responsible for CXCL12-induced biological effects until the recent discovery of its second receptor, CXCR7. Until now, the participation of CXCR7 in CXCL12-induced HSPC cycling and survival is unknown. We show here that CXCL12 was capable of binding CXCR7 despite its scarce expression at CD34(+) cell surface. Blocking CXCR7 inhibited CXCL12-induced Akt activation as well as the percentage of CD34(+) cells in cycle, colony formation, and survival, demonstrating its participation in CXCL12-induced functional effects in HSPCs. At steady state, CXCR7 and β-arrestin2 co-localized near the plasma membrane of CD34(+) cells. After CXCL12 treatment, β-arrestin2 translocated to the nucleus, and this required both CXCR7 and CXCR4. Silencing β-arrestin expression decreased CXCL12-induced Akt activation in CD34(+) cells. Our results demonstrate for the first time the role of CXCR7, complementary to that played by CXCR4, in the control of HSPC cycling, survival, and colony formation induced by CXCL12. We also provide evidence for the involvement of β-arrestins as signaling hubs downstream of both CXCL12 receptors in primary human HSPCs.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U972, Villejuif, France;
authors.forename: Frédéric
authors.initials: F
authors.lastname: Torossian
authors.forename: Adrienne
authors.initials: A
authors.lastname: Anginot
authors.forename: Aurélie
authors.initials: A
authors.lastname: Chabanon
authors.forename: Denis
authors.initials: D
authors.lastname: Clay
authors.forename: Bernadette
authors.initials: B
authors.lastname: Guerton
authors.forename: Christophe
authors.initials: C
authors.lastname: Desterke
authors.forename: Laetitia
authors.initials: L
authors.lastname: Boutin
authors.forename: Stefano
authors.initials: S
authors.lastname: Marullo
authors.forename: Mark G H
authors.initials: MG
authors.lastname: Scott
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lataillade
authors.forename: Marie-Caroline
authors.initials: MC
authors.lastname: Le Bousse-Kerdilès
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D019390:Arrestins / Q000378:metabolism*; D002453:Cell Cycle; D002470:Cell Survival; D054377:Chemokine CXCL12 / Q000378:metabolism*; D003114:Colony-Forming Units Assay; D004789:Enzyme Activation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D054387:Receptors, CXCR / Q000378:metabolism*; D000071557:beta-Arrestins
chemical_list: C501896:ACKR3 protein, human; D018952:Antigens, CD34; D019390:Arrestins; D054377:Chemokine CXCL12; D054387:Receptors, CXCR; D000071557:beta-Arrestins; D051057:Proto-Oncogene Proteins c-akt