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The finding that plasma membrane recruitment of arrestin3 independent
of receptor binding is sufficient to activate ERK1/2, albeit inefficiently, is
consistent with this model. 41 ERK1/2 bound to the signalsome complex
is also relatively protected from dephosphorylation by MAP kinase phospha-
tases, suggesting that a slower rate of inactivation also promotes sustained
activity. 39 The converse situation, where receptor binding releases an
arrestin-bound effector allowing it to become active, occurs during
arrestin-dependent regulation of the small G protein, Ral, by Ral-GDP
dissociation simulator (Ral-GDS). Ral-GDS constitutively interacts with
cytoplasmic arrestin2 and 3. Upon activation of the formyl-Met-Leu-Phe
receptor and arrestin recruitment, Ral-GDS is released from the arrestin
complex, whereupon it regulates cytoskeleton rearrangement and exocytic
granule release in polymorphonuclear neutrophilic leukocytes. 20
In contrast to ERK1/2, both the receptor-bound and free conformations
of arrestin3 are able to bind and activate the ASK1-MKK4-JNK3 cascade
equivalently, indicating that the scaffold complex is preformed in cells
and an activated GPCR is not required for signaling. 37 In fact all four mam-
malian arrestins bind JNK3 comparably and can remove it from the nucleus,
where it otherwise spontaneously resides. 42 Yet only arrestin3 is able to sup-
port JNK3 activation in cells. 30,43,44 Targeted mutagenesis studies identified
several residues in arrestin3, most notably Val343, that enable it alone to acti-
vate JNK3. 43 The finding that the ability of arrestins to bind pathway com-
ponents is not synonymous with the ability to activate them has significant
implications for the ability of arrestin scaffolds to positively or negatively
regulate kinase activity in cells.
2.3. Spatial and temporal control of kinase activity
Because arrestin-dependent ERK1/2 activation occurs within relatively
stable receptor-arrestin signalsomes, the arrestin-bound pool of activated
ERK1/2 remains with the receptor, first appearing at the plasma membrane
and later within the endosomal compartment, but not transiting to the
nucleus. 14,15,45 The kinetics of pathway activation differ markedly as well.
Whereas G protein activation leads to a rapid and transient rise in ERK1/2
activity, arrestin-dependent ERK1/2 activation is slow and sustained, likely
because ERK1/2 activated via the arrestin pathway is protected from rapid
dephosphorylation by nuclear MAPK phosphatases 34,37 ( Fig. 5.2 B).
These differences have profound effects on ERK1/2 function. Whereas
ERK1/2 activated by classical receptor tyrosine kinase growth factor
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