title: The role of the cysteine-rich domain and netrin-like domain of secreted frizzled-related protein 4 in angiogenesis inhibition in vitro.
abstract: Secreted frizzled-related protein 4 (sFRP4) is a Wnt signaling antagonist. Classically, sFRP4 antagonizes the canonical Wnt signaling pathway, resulting in decreased cellular proliferation and increased apoptosis. Recent research from our laboratory has established that sFRP4 inhibits angiogenesis by decreasing proliferation, migration, and tube formation of endothelial cells. The objective of this study was to examine the role of sFRP4's cysteine-rich domain (CRD) and netrin-like domain (NLD) in angiogenesis inhibition. Experiments were carried out to examine cell death and tube formation of endothelial cells after treatment with the CRD and the NLD. The CRD was seen to inhibit tube formation of endothelial cells, which suggests that this domain is important to sFRP4's antiangiogenesis property. In addition, the NLD promoted endothelial cell death and may also inhibit angiogenesis. Furthermore, treatment with the CRD and the NLD increased endothelial intracellular calcium levels. Our findings implicate a role for both the CRD and NLD in angiogenesis inhibition by sFRP4. It is suggestive of alternative antiangiogenic downstream targets of canonical Wnt signaling and a possible importance of the noncanonical Ca2+ Wnt signaling pathway in sFRP4-mediated angiogenesis inhibition.
authors.affiliation: School of Anatomy and Human Biology, Faculty of Life and Physical Sciences, The University of Western Australia, Crawley, Western Australia.
authors.forename: David
authors.initials: D
authors.lastname: Longman
authors.forename: Frank
authors.initials: F
authors.lastname: Arfuso
authors.forename: Helena M
authors.initials: HM
authors.lastname: Viola
authors.forename: Livia C
authors.initials: LC
authors.lastname: Hool
authors.forename: Arunasalam M
authors.initials: AM
authors.lastname: Dharmarajan
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003545:Cysteine / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D017434:Protein Structure, Tertiary / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D020533:Angiogenesis Inhibitors; D003545:Cysteine; D011518:Proto-Oncogene Proteins; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins