CXCR4 signaling via small GTPases
Chemokine (C-X-C motif) receptor-4 (CXCR4) is a G
protein-coupled receptor (GPCR). It is the only known receptor for stromal-derived
factor-1 (SDF-1), and SDF-1 is
the only known ligand for CXCR4 .
The CXCR4 is expressed in cells of immune and central
nervous systems, and 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 progenitor
murine embryonic stem cells. SDF-1 is expressed/secreted by
several tissues/organs in the body such as 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
stimulates kinase activity of the downregulated Src family kinase tyrosine-protein kinase
c-Src, binds to the catalytic domain and changes the
conformation of c-Src. In turn,
pathway through phosphorylation of adaptor protein Shc and
recruitment of adaptor protein GRB2 and positive regulator
of RAS guanine nucleotide exchange protein SOS, leading to
the increased transactivation ability of transcription factor Elk1
and the repressed transactivation ability of transcription factor
STAT3 which both are
phosphorylated by ERK2 , .
SDF-1alpha activates the JAK/STAT pathway.
JAK2 is activated and associated with the
CXCR4. This association enables the recruitment, tyrosine
phosphorylation and activation of the transcription factor
SDF-1 induces tyrosine phosphorylation of
CD45 and its association with the
dephosphorylation of Src family kinases Fyn and
Lck activates these kinases. Activated
Lck promotes the recruitment and subsequent activation of
the guanine nucleotide exchange factor VAV1.
VAV1 belongs to the family of GTPase exchange factors (GEF).
GEFs facilitate the GDP to GTP exchange thereby activating members of the Rho GTPase
family such as RhoA, Rac1 and
CDC42 that are involved in actin cytoskeleton
reorganization. Fyn phosphorylates
Pyk2, and Pyk2 associates with
SDF-1 stimulates the tyrosine phosphorylation of docking
protein 1 (DOK1) by Lck that
induces significant association of DOK1 with RAS p21 protein
activator (GTPase activating protein) 1 (p120GAP) and v-crk
sarcoma virus CT10 oncogene homolog (avian)-like (CrkL).
p120GAP reduces H-Ras activity
and decreases phosphorylation of ERK1 in response to
Protein-tyrosine phosphatase SHP-2 constitutively
associates with CXCR4, and this association is enhanced upon
SDF-1 stimulation. SHP-2, which
can act as an adaptor molecule, associates with the adaptor molecule
c-Cbl. c-Cbl associates with
the adaptor proteins CrkL and
CRK. Integrin clustering promotes
FAK1 autophosphorylation and binding with
c-Src. The active
FAK1-c-Src complex facilitates
SH3-mediated binding of p130CAS and
paxillin to FAK1 and its
subsequent phosphorylation. CRK is recruited to the nascent
focal complex by p130Cas .
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