talks with ScienceWatch.com and answers a few
questions about this month's Fast Moving Front in the field
of Biology & Biochemistry.
Article: The chemokine SDF-1/CXCL12 binds to and
signals through the orphan receptor RDC1 in T
Authors: Balabanian, K;Lagane, B;Infantino, S;Chow,
KYC;Harriague, J;Moepps, B;Arenzana-Seisdedos, F;Thelen,
Journal: J BIOL CHEM, 280 (42): 35760-35766 OCT 21
Addresses: Inst Pasteur, Unite Immunol Virale, 28 Rue Dr
Roux, F-75015 Paris, France.
Inst Pasteur, Unite Immunol Virale, F-75015 Paris,
Inst Biomed Res, CH-6500 Bellinzona, Switzerland.
Univ Ulm, Dept Pharmacol & Toxicol, D-89081 Ulm,
Why do you think your paper is highly
Chemokines are cytokines that display chemotactic functions and coordinate
the homeostatic circulation of leukocytes by binding to G protein-coupled
receptors (GPCRs). Dysfunction of the 50 chemokines and 20 receptors
identified so far is also implicated in the pathogenesis of many diseases
and these proteins consequently constitute very attractive targets for
Whereas in many cases, chemokines and their receptors exhibit promiscuous
binding properties, the CXC chemokine stromal cell-derived factor 1
(SDF-1/CXCL12) was long thought to exclusively bind to and signal through
the CXC chemokine receptor 4 (CXCR4).
This article defines the orphan receptor RDC1 that was originally cloned
from a dog cDNA library (Receptor Dog cDNA)—Libert, F et
al., "Complete nucleotide sequence of a putative G protein coupled
receptor: RDC1" (Nucleic Acids Res. 18: 1917, 1990) as CXCR7, a
second receptor for CXCL12.
"Future research will help define
the molecular mechanisms underlying CXCR7
biological activities and particularly the
signaling pathways set in motion downstream
of the receptor and how they are spatially
Thereafter, others identified that CXCR7 also bind to the CXC chemokine
ITAC—Burns, JM et al., "A novel chemokine receptor for SDF-1
and I-TAC involved in cell survival, cell adhesion, and tumor development,"
(JEM 23: 2201-13, 2006). Owning to the pleiotropic activities
of CXCL12, this discovery is of marked interest to investigators in many
different research areas such as developmental biology, immunology,
virology, and cancer.
Would you summarize the significance of your paper
in layman's terms?
The orphan receptor RDC1 was primarily believed to act as a receptor for
vasointestinal peptide, a possibility later dismissed. On the bases of
sequence similarity, chromosomal location, and phylogenetic studies, RDC1
was connected to the CXC chemokine receptors 1, 2, and 4, pointing to CXC
chemokines as potential ligands.
Supporting this hypothesis, RDC1 can serve in experimental systems as
co-receptor for certain genetically divergent human immunodeficiency virus
(HIV) and simian immunodeficiency virus (SIV) strains, in particular for
the HIV-2 ROD, an X4-tropic viral isolate.
In our paper, we provide evidence that RDC1 also shares with CXCR4 the
chemokine CXCL12 as a natural ligand. The interaction of CXCL12 with
CXCR7/RDC1 promotes internalization of the receptor and chemotactic signals
of CXCR4-negative cells expressing CXCR7. This binding is specific,
saturable, and with nanomolar affinity.
Because CXCR7/RDC1 displays a wide expression pattern in mammalian tissues
and is also expressed in some tumor cells, primary tumors, and
tumor-associated endothelial cells, these data support the view that
engagement of CXCL12 to CXCR7 might contribute to physiological but also
pathological functions of the chemokine.
How did you become involved in this research and
were any particular problems encountered along the way? Where do you
see your research leading in the future?
Recent studies indicated that, similarly to the CXCL12 or CXCR4 knockout
mice, CXCR7-deficient animals died perinataly and pointed to a dedicated
physiological role for CXCR7 in fetal endothelial biology, cardiac
development, and B-cell localization.
We and others provide evidence that CXCR7 and CXCR4 can differentially
contribute to CXCL12-mediated responses and that CXCR7 also displays the
propensity to modulate CXCR4 functions notably by means of CXCL12
scavenging or formation of CXCR7/CXCR4 heterodimers. However, at a
mechanistic level, it is not well understood how this GPCR functions.
Future research will help define the molecular mechanisms underlying CXCR7
biological activities and particularly the signaling pathways set in motion
downstream of the receptor and how they are spatially and temporarily
CXCL12 dysfunctions are involved in pathological processes which include
the profusion of papillomavirus-induced warts associated with the rare
immunodeficiency syndrome myelokathexis (WHIM), and the development of
primary epithelial tumors, where the chemokine regulates proliferation and
survival of tumor cells, tumor angiogenesis, and metastasis. We anticipate
that a more detailed comprehension of the contribution of CXCR7 and CXCR4
in these processes will facilitate their therapeutic manipulation.
Françoise Bachelerie, Ph.D.
Unité de Pathogénie Virale