A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development.
The chemokine stromal cell-derived factor (SDF-1; also known as chemokine ligand 12 [CXCL12]) regulates many essential biological processes, including cardiac and neuronal development, stem cell motility, neovascularization, angiogenesis, apoptosis, and tumorigenesis. It is generally believed that SDF-1 mediates these many disparate processes via a single cell surface receptor known as chemokine receptor 4 (CXCR4). This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell alpha chemoattractant (I-TAC; also known as CXCL11). Membrane-associated CXCR7 is expressed on many tumor cell lines, on activated endothelial cells, and on fetal liver cells, but on few other cell types. Unlike many other chemokine receptors, ligand activation of CXCR7 does not cause Ca2+ mobilization or cell migration. However, expression of CXCR7 provides cells with a growth and survival advantage and increased adhesion properties. Consistent with a role for CXCR7 in cell survival and adhesion, a specific, high affinity small molecule antagonist to CXCR7 impedes in vivo tumor growth in animal models, validating this new receptor as a target for development of novel cancer therapeutics.
Burns
Jennifer M
JM
ChemoCentryx, Inc., Mountain View, CA 94043, USA.
Summers
Bretton C
BC
Wang
Yu
Y
Melikian
Anita
A
Berahovich
Rob
R
Miao
Zhenhua
Z
Penfold
Mark E T
ME
Sunshine
Mary Jean
MJ
Littman
Dan R
DR
Kuo
Calvin J
CJ
Wei
Kevin
K
McMaster
Brian E
BE
Wright
Kim
K
Howard
Maureen C
MC
Schall
Thomas J
TJ
D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D002470:Cell Survival; D054371:Chemokine CXCL11; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D011247:Pregnancy; D011485:Protein Binding; D054387:Receptors, CXCR; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D050819:Transcription Factor Brn-3A / Q000235:genetics / Q000378:metabolism*
C501896:ACKR3 protein, human; C515202:CXCL11 protein, human; C515255:CXCL12 protein, human; D054371:Chemokine CXCL11; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515203:Cxcl11 protein, mouse; C515256:Cxcl12 protein, mouse; C494188:POU4F1 protein, human; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D043562:Receptors, G-Protein-Coupled; D050819:Transcription Factor Brn-3A