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through a Gq/11-Ca 2 รพ -dependent pathway involving the nonreceptor
tyrosine kinase Pyk2 and c-Src. 70 Arrestin2 can directly associate with the
catalytic p110 a subunit of PI3K and inhibit its activity. PI3K is recruited into
a PAR2-arrestin1 complex, and arrestin2 colocalizes with the regulatory
p85 PI3K subunit within the pseudopodia of cells during PAR2-mediated
chemotaxis, suggesting that the arrestin2-PI3K association may spatially
restrict PI3K activity and that this localized inhibition PI3Kmay be involved
in PAR2-stimulated chemotaxis.
4.5.3 Phosphatidylinositol 4-phosphate 5-kinase
Another lipid kinase, phosphatidylinositol 4-phosphate 5-kinase (PIP5K)
1 a , regulates clathrin and AP2 function during clathrin-dependent GPCR
endocytosis. 71 PIP5K1 a produces phosphatidylinositol 4,5-bisphosphate
(PIP2) on the inner leaflet of the clathrin-coated pit, promoting polymeri-
zation of clathrin and AP-2 and assembly of the clathrin coat. Arrestin3
recruits PIP5K1 a to activated b 2-adrenergic receptors, increasing PIP2 for-
mation and enhancing receptor endocytosis.
5. CONCLUSIONS
Arrestins regulate a robust network of protein and lipid kinases and
phosphatases that allow GPCRs to modulate several downstream signaling
cascades not available to heterotrimeric G protein-regulated effectors.
In functioning as ligand-regulated scaffolds, they control the timing and loca-
tion of signaling, directing multifunctional enzymes, like ERK1/2 and
PP2A, toward some substrates and away from others. In a curious parallel
to their role in terminating G protein signaling, arrestins appear to provide
tonic inhibition of some kinase pathways, like JNK3 andNF- k B, while at the
same time enabling GPCR-catalyzed activation of others. Arrestin kinase/
phosphatase scaffolds regulate cytoskeletal rearrangement, vesicle endocyto-
sis and exocytosis, cell migration and chemotaxis, and transmit signals to
the cell nucleus to control cell proliferation, apoptosis, and survival.
As subsequent chapters in this volume will attest, arrestin-dependent
kinase/phosphatase signaling is integrated into GPCR-regulated physiologic
processes at multiple levels, and improving our understanding of these
multifunctional scaffolds may provide keys to novel treatments for diseases
as seemingly diverse as cancer, inflammation, osteoporosis, and mental
illness.
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