title: Common interactions between S100A4 and S100A9 defined by a novel chemical probe.
abstract: S100A4 and S100A9 proteins have been described as playing roles in the control of tumor growth and metastasis. We show here that a chemical probe, oxyclozanide (OX), selected for inhibiting the interaction between S100A9 and the receptor for advanced glycation end-products (RAGE) interacts with both S100A9 and S100A4. Furthermore, we show that S100A9 and S100A4 interact with RAGE and TLR4; interactions that can be inhibited by OX. Hence, S100A4 and S100A9 display similar functional elements despite their primary sequence diversity. This was further confirmed by showing that S100A4 and S100A9 dimerize both in vitro and in vivo. All of these interactions required levels of Zn++ that are found in the extracellular space but not intracellularly. Interestingly, S100A4 and S100A9 are expressed by distinct CD11b+ subpopulations both in healthy animals and in animals with either inflammatory disease or tumor burden. The functions of S100A9 and S100A4 described in this paper, including heterodimerization, may therefore reflect S100A9 and S100A4 that are released into the extra-cellular milieu.
authors.affiliation: Active Biotech AB, Lund, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Björk
authors.forename: Eva
authors.initials: E
authors.lastname: Källberg
authors.forename: Ulf
authors.initials: U
authors.lastname: Wellmar
authors.forename: Matteo
authors.initials: M
authors.lastname: Riva
authors.forename: Anders
authors.initials: A
authors.lastname: Olsson
authors.forename: Zhifei
authors.initials: Z
authors.lastname: He
authors.forename: Marie
authors.initials: M
authors.lastname: Törngren
authors.forename: David
authors.initials: D
authors.lastname: Liberg
authors.forename: Fredrik
authors.initials: F
authors.lastname: Ivars
authors.forename: Tomas
authors.initials: T
authors.lastname: Leanderson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D039481:CD11b Antigen / Q000378:metabolism; D040502:Calgranulin B / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019281:Dimerization; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008223:Lymphoma / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015335:Molecular Probes / Q000378:metabolism*; D015394:Molecular Structure; D010097:Oxyclozanide / Q000378:metabolism* / Q000494:pharmacology; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000737:chemistry / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D040502:Calgranulin B; D015335:Molecular Probes; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C077591:S100A4 protein, human; D010097:Oxyclozanide; D015032:Zinc