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in response to the specific ligand CXCL12/SDF-1.
76
CXCR4 can also
form a heteromeric complex with the CXCR7 chemokine receptor
upon in response to CXCL12.
65
Defects in chemokine receptor-
b
-arrestin
interactions may promote human disease states. WHIM (warts, hyp-
ogammaglobulinemia, infections, and myelokatexis) syndrome is an immu-
nodeficiency syndrome linked to heterozygous mutations of the chemokine
receptor CXCR4 resulting in truncations of its cytoplasmic tail. WHIM-
associated mutant CXCR4 was unable to recruit
b
-arrestin 2, leading to
the impaired CXCR4 internalization and enhanced chemotaxis in response
to CXCL12.
77
CC chemokines are a second group of chemokines. Reports show that
b
-arrestins regulate CC chemokine-induced CC chemokine receptor acti-
vation by desensitization and internalization. CCL2 (MCP-1) binds to
CCR2 inducing the activation of CCR2 and, shortly after stimulation,
recruits a protein complex including GRK2 and
b
-arrestin.
30
In addition,
the actin binding protein filamin A binds CCR2B
78
and together with
b
-arrestin regulates the internalization of the receptor complex. The che-
mokine CCL5 (RANTES) binding to the CCR5 induces the phos-
phorylation of CCR5.
b
-Arrestin 1 is able to desensitize and internalize
homo- and hetero-oligomers of CCR5.
79,80
b
-Arrestins thus regulate
immune and inflammatory responses, in part, by desensitization and inter-
nalization of activated chemokine receptors.
b
-Arrestins also regulate chemokine signaling via noncanonical Gprotein
pathways.
b
-Arrestin 2 and GRK6 play positive regulatory roles, mediating
the chemotactic responses of T and B lymphocytes toCXCL12.
45
b
-Arrestin
2 strengthened CXCR4 activation through the ASK1-p38MAPK path-
way.
54
In addition to the formation of a CXCR4 homodimer, CXCL12
also binds to CXCR7
81,82
and induces CXCR4-CXCR7 heterodimers.
65
Upon CXCL12 binding, the CXCR4-CXCR7 heterodimer complex
recruits
b
-arrestin, resulting in the preferential activation of
b
-arrestin-
linked signaling pathways over canonical G protein pathways.
65
This activa-
tion was dependent on
b
-arrestin-mediated cell signaling pathways, such
as ERK1/2, p38 MAPK, and SAPK, leading to enhanced cell migration
in response to CXCL12 stimulation.
65
The CC chemokine CCL4 (MIP-
1
b
) binds to CCR5-regulating macrophage migration. Chemotaxis
upon CCR5 stimulation by CCL4 requires activation of Pyk2, PI3K
p85, Lyn, and ERK.
b
-Arrestins regulate the receptor complex formation
and enhance macrophage chemotaxis toward the ligand.
29
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