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lysosomal trafficking, which could be attributed to the functional comple-
mentation by other two ARRDCs. Because of the redundant nature of
ARRDC binding with the internalized b 2 AR, deciphering their exact role
in b 2 AR trafficking poses the technical challenge of simultaneous and effi-
cient silencing of all three genes in mammalian cells. Although yeast ARTs
function as primary adaptors for cell-surface transporters, mammalian
ARRDCs most likely function as secondary adaptors for 7TMRs and their
functional interaction with the 7TMRs could require b -arrestin-mediated
receptor internalization, as demonstrated for the b 2 AR. 118 Although the
ARRDCs share common features with the b -arrestins, each appears to have
unique
roles
in mediating
cellular
homeostasis
and
embryonic
development. 9,117
7. CONCLUSIONS
Ubiquitination is a highly versatile, precisely timed, dynamic, and
ubiquitous posttranslational modification, which plays a crucial regulatory
role in not only determining levels but also activity and subcellular localiza-
tion of modified proteins. The mammalian multifunctional adaptor protein,
b -arrestin, which regulates various facets of 7TMR signal transduction and
intracellular trafficking, is both a substrate and adaptor for ubiquitination.
Ubiquitination of b -arrestin promotes its tight binding to activated 7TMRs
as well as to nonreceptor binding partners such as clathrin, c-Raf, and
pERK. The time course of b -arrestin ubiquitination is dictated by confor-
mational changes induced by 7TMR activation and is regulated by binding
or dissociation of DUBs. The E3 ubiquitin ligases that append the modifi-
cation on b -arrestin and the site(s) of modification appear to be specific for
receptor- b -arrestin pair. Differential ubiquitination on b -arrestin, con-
sisting of distinct types of chain architecture occurring in a dynamic fashion,
can be one mechanism that allows interactions with various protein partners.
Because of their binding to DUBs, b -arrestins may be able to change their
interaction surfaces to accommodate necessary protein recognition domains
as demanded by the cellular context by ubiquitin editing (complete or partial
removal of ubiquitin linkages). Thus, ubiquitination could be a critical
molecular modification of b -arrestin needed for its multifaceted adaptor
functions and perhaps for its activity in scaffolding and stabilizing various
signaling kinases.
Remarkably, besides their own modification, b -arrestins also serve as E3
ubiquitin ligase adaptors to mediate ubiquitin-dependent regulation of a
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