CCR5 signaling in macrophages and T
Chemokine (C-C motif) receptor 5 (CCR5) is a functional
receptor for various inflammatory CC-chemokines, including Chemokine (C-C motif) ligands
3, 4 and 5 (MIP-1-alpha,
MIP-1-beta and CCL5).
CCR5 is expressed on memory T cells, macrophages, dendritic
cells, and migroglia and has been shown to modulate chemotaxis, proliferation, and immune
functions , , , .
CCR5 belongs to family of G-protein coupled receptors and
mediates its action via activation of G-protein alpha-i
family and G-protein alpha-q . CCR5 stimulation of G-protein
alpha-i family leads to inhibition of Adenylate cyclase 1
(Adenylate cyclase type I) activity and decreasing cellular
levels of Cyclic AMP cytosol production .
Additionally, CCR5 stimulates -G-protein
alpha-i family -coupled G-protein beta/gamma
activity leading to Phosphoinositide-3-kinase, regulatory subunit 5 (PI3K
reg class IB (p101)) and subsequently to
Phosphoinositide-3-kinase, catalytic, gamma polypeptide (PI3K cat class IB
(p110-gamma)) activation . PI3K cat
class IB (p110-gamma) enhances
PtdIns(3,4,5)P3 production leading to activation of
Ras-related C3 botulinum toxin substrate 1 (Rac1) (most
likely via T-cell lymphoma invasion and metastasis 1 (Tiam1)
stimulation). Rac1 activates p21 protein
(Cdc42/Rac)-activated kinase 2 (PAK2) and promotes
lamellipodia formation that stimulates macrophage migration during chemotaxis , , . PI3K cat
class IB (p110-gamma) also activates v-akt murine thymoma
viral oncogene homolog (AKT(PKB)) leading to macrophage
survival . CCR5 via G-protein
alpha-i family induces Mitogen-activated protein kinase kinases 1, 2
Mitogen activated protein kinases 1/3 (ERK1/2) pathway
activation leading to enhanced survival and cell proliferation , , .
CCR5 stimulation of G-protein
alpha-q and G-protein beta/gamma leads to
Phospholipase C, beta 1 (PLC-beta1) activation and enhanced
production of 1,2-Diacyglycerol and IP3
cytosol. IP3 cytosol promotes
Ca('2+) release from endoplasmic reticulum.
Ca('2+) depletion in endoplasmic reticulum leads to rapid
translocation of calcium adapter Stromal interaction molecule 1
(STIM1) to plasma membrane and activation of ORAI calcium
release-activated calcium modulator 1 (CRACM1) , , . CRACM1
induces Ca('2+) influx into the cell .
Elevated Ca('2+) cytosol and
1,2-Diacyglycerol levels activate Protein kinase C, alpha
(PKC-alpha), which phosphorylates PTK2B protein tyrosine
kinase 2 beta (Pyk2(FAK2)) .
Pyk2(FAK2) activates Paxillin
stimulating chemotaxis , .
Pyk2(FAK2) also activates Mitogen-activated protein kinase 8
-10 (JNK(MAPK8-10)) and Mitogen-activated protein kinase 14
(p38 MAPK) most likely via Mitogen-activated protein kinase
kinase kinase 4 (MEKK4(MAP3K4))/ Mitogen-activated protein
kinase kinases 3, 4 (MEK3(MAP2K3),
MEK4(MAP2K4)) , , . JNK(MAPK8-10) and p38
MAPK phosphorylates Jun oncogene (c-Jun) and
Activating transcription factor 2 (ATF-2) respectively,
stimulating cytokine production and T cell proliferation , , , . p38 MAPK also
phosphorylates Mitogen-activated protein kinase-activated protein kinase 2
CCR5 via increase in Ca('2+)
cytosol activates Calmodulin 2 (Calmodulin)
and protein Phosphatase 3 (formerly 2B), catalytic subunits (Calcineurin A
(catalytic)) leading to Nuclear factor of activated T-cells, cytoplasmic,
calcineurin-dependent 1 (NF-AT2(NFATC1)) nuclear
translocation and activation of Interleukin 2 (IL-2)
transcription. CCR5 -induced
IL-2 signaling stimulates T cell proliferation .
Activated CCR5 could act also via G-protein-independent
manner. Ligand binding to CCR5 stimulates its association
with Janus kinases 1, 2 and 3 (JAK1,
JAK2, JAK3) leading to Signal
transducers and activators of transcription 1 and 3 (STAT1
and STAT3) activation , , . STAT1 and
STAT3 enhance transcription of v-fos FBJ murine osteosarcoma
viral oncogene homolog (c-Fos) promoting cytokine production
and T cell proliferation during immune response . In addition,
JAK3 in response to CCR5
activation phosphorylates Lymphocyte-specific protein tyrosine kinase
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