CXCR4 signaling via second messengers
Chemokine (C-X-C motif) receptor-4 (CXCR4) is a G
protein-coupled receptor (GPCR). CXCR4 is the only known
receptor for Stromal-derived factor-1 (SDF-1), and
SDF-1 is the only known ligand for
CXCR4 is expressed in cells of immune and central nervous
systems, haematopoietic stem cells. CXCR4 was also found on
the surface of primordial germ cells, skeletal muscle satellite progenitor cells, neural
stem cells, liver oval/stem cells and retinal pigment epithelium progenitors murine
embryonic stem cells. SDF-1 is expressed/secreted by several
tissues/organs in the body (bone marrow-, lymph node-, muscle- and lung-derived
fibroblasts liver and kidney cells and in several regions of the central nervous system).
SDF-1-CXCR4 signaling plays an
important and unique role in the regulation of stem/progenitor cell trafficking,
inflammation, embryo/organogenesis and tissue/organ regeneration. Association of
SDF-1 with CXCR4 activates
multiple signaling pathways .
SDF-1 stimuli activate receptor and promote interaction
between the receptor and the trimeric G-protein
alpha (i), beta/gamma. This causes the
exchange of GDP for GTP bound to G protein
alpha subunits and the dissociation of the
The G-protein beta/gamma
heterodimers activate PI3K gamma, recruiting noncatalytic
p101 subunit and directly stimulating catalytic p110 gamma
subunits. PI3K converts phosphatidylinositol 4,5-biphosphate
[PI(4,5)P2] to phosphatidylinositol 3,4,5-triphosphate
PI(3,4,5)P3 is a second messenger that directly binds to
PtdIns (3,4,5)P3-dependent protein kinase-1 (PDK1) and
protein kinase B (AKT). PDK
phosphorylates AKT, AKT in
turn, activates Inhibitor of nuclear factor kappa-B kinase
(IKK), and IKK phosphorylates
the I-kappa-B (I-kB) proteins, making them available for
destruction via the ubiquitination pathway, thereby allowing activation of the NF-kappa-B
SDF-1 induces tyrosine phosphorylation of Leukocyte
common antigen precursor phosphatase
CD45 and its association with
dephosphorylation of Src family tyrosine-protein kinases FYN
and LCK activates these kinases. Activated
LCK promotes the recruitment and subsequent activation of
another tyrosine kinase ZAP70 , which in
turn regulates phosphorylation of adaptor proteins, Lymphocyte cytosolic protein
(SLP-76) and Linker for activation of T cells
(LAT). The binding of both LAT
and SLP-76 via the ITK SH3 and
SH2 domains mediates the optimal activation of PLC gamma1.
G-alpha q11 activates phospholipase C beta
(PLC-beta). PLC beta
hydrolyses PI(4,5)P2 to generate two second
messengers inositol 1,4,5-trisphosphate (IP3) and
1,2-diacyl-glycerol (DAG). IP3
generation leads to an increase of the intracellular concentrations of free
Ca2+. DAG activates protein
kinase C (PKC-theta).
PKC-theta in turn,
activates IKK and of the NF-kB
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