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of SII-mediated protein phosphorylation identified two peptide inhibitors of
PP2A (I1PP2A and I2PP2A) as targets for increased phosphorylation. 58
Agonist-stimulated phosphorylation of I2PP2A was associated with rapid
and transient inhibition of the arrestin3-associated pool of PP2A, leading
to activation of Akt and increased phosphorylation of GSK3 b in an arrestin
signalsome complex. Thus, while arrestins maintain tonic inhibition of
GSK3 b under homeostatic conditions in vivo , 57 mechanisms may exist to
release that inhibition in response to GPCR stimulation.
4. ARRESTIN-REGULATED KINASE AND PHOSPHATASE
PATHWAYS
Table 5.1 summarizes many of the experimentally validated arrestin-
dependent GPCR-signaling pathways reported to date. 10,72 The evidence
supporting their existence ranges from coprecipitation studies using over-
expressed pathway components to isolation of endogenous arrestin-effector
complexes from native tissues and from loss of function studies using arrestin
dominant-negative mutants and isoform-selective RNA interference to res-
cue studies performed using arrestin2/3 null murine embryo fibroblasts
(MEFs). Viewed as a whole, arrestin-regulated kinase and phosphatase sig-
naling appear to encompass a fairly discrete set of functions, linking GPCRs
to receptor and nonreceptor tyrosine kinases, MAPKs, regulators of NF- k B
and b -catenin signaling, and a few protein phosphatases and lipid kinases.
Many of these putative effectors are not known to be regulated by hetero-
trimeric G protein subunits, suggesting that these GPCR-arrestin-effector
pathways function in parallel with GPCR-G protein-effector pathways to
add additional dimensions to GPCR signaling.
4.1. Tyrosine protein kinases
4.1.1 Src family nonreceptor tyrosine kinases
Arrestins bind to several members of the Src family of nonreceptor tyrosine
kinases and recruit them to activated GPCRs. Arrestin-dependent recruit-
ment of c-Src to b 2-adrenergic receptors on the plasma membrane can be
visualized after isoproterenol stimulation. 6 As with several other non-
receptor arrestin-binding partners, Src kinases appear to make contact with
arrestins at several points. The N-terminus of arrestin2 is proline rich and
contains three PXXP motifs that interact with the Src homology (SH)3
domain of c-Src. 6 Additional contacts involving the c-Src SH1 (catalytic)
domain confer added binding affinity. 59
In contrast, arrestin1 has only a
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