title: A critical role of CXCR2 PDZ-mediated interactions in endothelial progenitor cell homing and angiogenesis.
abstract: Bone marrow-derived endothelial progenitor cells (EPCs) contribute to neovessel formation in response to growth factors, cytokines, and chemokines. Chemokine receptor CXCR2 and its cognate ligands are reported to mediate EPC recruitment and angiogenesis. CXCR2 possesses a consensus PSD-95/DlgA/ZO-1 (PDZ) motif which has been reported to modulate cellular signaling and functions. Here we examined the potential role of the PDZ motif in CXCR2-mediated EPC motility and angiogenesis. We observed that exogenous CXCR2 C-tail significantly inhibited in vitro EPC migratory responses and angiogenic activities, as well as in vivo EPC angiogenesis. However, the CXCR2 C-tail that lacks the PDZ motif (ΔTTL) did not cause any significant changes of these functions in EPCs. In addition, using biochemical assays, we demonstrated that the PDZ scaffold protein NHERF1 specifically interacted with CXCR2 and its downstream effector, PLC-β3, in EPCs. This suggests that NHERF1 might cluster CXCR2 and its relevant signaling molecules into a macromolecular signaling complex modulating EPC cellular functions. Taken together, our data revealed a critical role of a PDZ-based CXCR2 macromolecular complex in EPC homing and angiogenesis, suggesting that targeting this complex might be a novel and effective strategy to treat angiogenesis-dependent diseases.
authors.affiliation: Department of Biochemistry and Molecular Biology, Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Yuning
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Biochemistry and Molecular Biology, Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Yanning
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Shukkur M
authors.initials: SM
authors.lastname: Farooq
authors.affiliation: Department of Biochemistry and Molecular Biology, Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Guan
authors.affiliation: Department of Biochemistry and Molecular Biology, Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Oblak
authors.affiliation: Department of Biochemistry and Molecular Biology, Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Holcomb
authors.affiliation: Department of Biochemistry and Molecular Biology, Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strieter
authors.affiliation: Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Lasley
authors.affiliation: Cellular and Molecular Imaging Laboratory, Department of Radiology, Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: Ali S
authors.initials: AS
authors.lastname: Arbab
authors.affiliation: Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology, Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA. Electronic address: cl@med.wayne.edu.
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA. Electronic address: zyang@med.wayne.edu.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D066026:Endothelial Progenitor Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000502:physiology; D054731:PDZ Domains; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D023063:Receptors, Interleukin-8B