title: CXCR4-mediated bone marrow progenitor cell maintenance and mobilization are modulated by c-kit activity.
abstract: BACKGROUND
  The mobilization of bone marrow (BM) progenitor cells (PCs) is largely governed by interactions between stromal cell-derived factor (SDF)-1 and CXC chemokine receptor (CXCR)4. Ischemic injury disrupts the SDF-1-CXCR4 interaction and releases BM PCs into the peripheral circulation, where the mobilized cells are recruited to the injured tissue and contribute to vessel growth. BM PCs can also be mobilized by the pharmacological CXCR4 antagonist AMD3100, but the other components of the SDF-1-CXCR4 signaling pathway are largely unknown. c-kit, a membrane-bound tyrosine kinase and the receptor for stem cell factor, has also been shown to play a critical role in BM PC mobilization and ischemic tissue repair.
  
  
  OBJECTIVE
  To investigate the functional interaction between SDF-1-CXCR4 signaling and c-kit activity in BM PC mobilization.
  
  
  RESULTS
  AMD3100 administration failed to mobilize BM PCs in mice defective in c-kit kinase activity or in mice transplanted with BM cells that expressed a constitutively active c-kit mutant. Furthermore, BM levels of phosphorylated (phospho)-c-kit declined after AMD3100 administration and after CXCR4 deletion. In cells adhering to culture plates coated with vascular cell adhesion molecule 1, SDF-1 and stem cell factor increased phospho-c-kit levels, and AMD3100 treatment suppressed SDF-1-induced, but not SCF-induced, c-kit phosphorylation. SDF-1-induced c-kit phosphorylation also required the activation of Src nonreceptor tyrosine kinase: pretreatment of cells with a selective Src inhibitor blocked both c-kit phosphorylation and the interaction between c-kit and phospho-Src.
  
  
  CONCLUSIONS
  These findings indicate that the regulation of BM PC trafficking by SDF-1 and CXCR4 is dependent on Src-mediated c-kit phosphorylation.
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Chicago, IL 60611, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Cheng
authors.forename: Junlan
authors.initials: J
authors.lastname: Zhou
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Chan
authors.initials: C
authors.lastname: Boriboun
authors.forename: Tina
authors.initials: T
authors.lastname: Thorne
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Xiang
authors.forename: Qiutang
authors.initials: Q
authors.lastname: Zeng
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Tanaka
authors.forename: Yao Liang
authors.initials: YL
authors.lastname: Tang
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.forename: Michael H
authors.initials: MH
authors.lastname: Tomasson
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Miller
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
mesh_terms: D000818:Animals; D001596:Benzylamines; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000502:physiology; D000080027:Cyclams; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019009:Proto-Oncogene Proteins c-kit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D001596:Benzylamines; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D019009:Proto-Oncogene Proteins c-kit; D019061:src-Family Kinases; C088327:plerixafor