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single PXXP motif and binding appears to involve the c-Src SH2 domain.
73
It is unclear whether c-Src exhibits a binding preference for the receptor-
bound conformation of arrestins, but immunostaining for the active (Y
530
dephosphorylated) form of c-Src suggests that c-Src in the receptor-arrestin
complex is active.
6
It is also unclear whether the association of arrestin and
c-Src is regulated, although phosphorylation of Ser
412
in the C-terminus of
arrestin2, which destabilizes the receptor-arrestin complex, has been
reported to disrupt the arrestin-Src interaction.
47
Arrestin-dependent recruitment of Src family kinases appears to regulate
clathrin-dependent GPCR endocytosis. Arrestin-scaffolded c-Src phos-
phorylates GRK2, providing negative feedback on receptor desensitization
by destabilizing GRK2 and promoting its entry into the proteosome path-
way where it is rapidly degraded.
60
Arrestin-Src binding is required for
phosphorylation of Tyr
497
of dynamin 1, which regulates dynamin self-
assembly.
59,74,75
Expression of a Y497F mutant of dynamin 1 impairs the
internalization of both the
b
2-adrenergic
74
and the M2 muscarinic acetyl-
choline receptor.
76
The
b
2-adaptin subunit of AP-2 is another endocytic
protein whose regulation by Src is arrestin dependent.
48,77,78
c-Src stabilizes
the constitutive association between arrestin3 and
b
2-adaptin independent
of its kinase activity. Src-mediated phosphorylation of
b
2-adaptin Tyr
737
occurs in clathrin-coated pits in response to AT
1A
,
b
2 adrenergic, V2 vaso-
pressin, or B2 bradykinin receptor activation, leading to dissociation of AP-2
from the complex.
If
b
2-adaptin phosphorylation is blocked,
rec-
eptor-arrestin complexes are retained at the membrane.
The involvement of arrestin-Src complexes in vesicle trafficking extends
to exocytosis. Arrestin-dependent activation of the Src family kinases,
c-Hck and c-Fgr, by the interleukin 8 receptor (CXCR1) appears to be
important for granule release, since expression of P91G/P121G arrestin2
with mutations in the PXXP motifs antagonizes CXCR1-induced exocy-
tosis in granulocyte cells.
12
Similarly, the endothelin type A receptor assem-
bles an arrestin2-dependent complex with c-Yes that positively regulates
endothelin-1-stimulated translocation of the glucose transporter Glut4 to
the plasma membrane.
79
Arrestin-dependent Src signaling has been implicated in several other
GPCR-regulated processes, notably activation of ERK1/2. Src recruitment
to
b
2-adrenergic receptors contributes to ERK1/2 MAP activation.
6
The
neurokinin NK1 receptor forms a receptor-arrestin-c-Src signalsome in
response to substance P stimulation.
11
Assembly of this signalsome has been
implicated in NK1 receptor-mediated ERK1/2 activation, cell survival, and
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