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the endocytic machinery and other families of cell-surface receptors, thus
underscoring their importance in cellular trafficking.
14,21,22
A significant turning point in our understanding about
b
-arrestin's func-
tions was the discovery that they not only initiate receptor endocytosis but also
“switch on” signal transduction as they “switch off” G protein coupling
(Ref.
23
;
Fig. 7.1
). Thus, through the second decade after their cloning,
b
-arrestins were shown to function as signaling adaptors for the nonreceptor
tyrosine kinase c-Src, extracellular signal-regulated kinases 1 and 2 (ERK1/2),
c-Jun-N-terminal kinase 3 (JNK3), p38 MAP kinase, and AKT.
23-27
By far
the most critical landmark is the proposal and subsequent proving of the
paradigm-changing hypotheses that
b
-arrestins are stand-alone signal trans-
ducers and that 7TMRs (and perhaps other receptors) could assume a unique
set(s) of activated conformations to specifically signal through
b
-arrestins,
independent of G protein activation.
28-32
The ubiquitous protein posttranslationalmodificationcalled ubiquitination,
in which the protein ubiquitin becomes covalently appended to substrate
proteins,
33
plays a critical role in 7TMR-
b
-arrestin endocytic and signaling
pathways.
34
As will be described through this chapter, not only do
b
-arrestins
become ubiquitinated, which remarkably impacts their adaptor and scaffolding
roles, but they also serve as integral components of theubiquitinationmachinery
by functioning as indispensible adaptors that link substrate proteins including
7TMRs with the cognate E3 ubiquitin ligases that mediate ubiquitination.
1.2. Ubiquitination: A pleiotropic posttranslational
modification
Ubiquitin is a small, ubiquitously expressed, 76-amino acid highly con-
served protein found in all eukaryotic cells from yeast to mammals. It is
the best characterized member of a class of small protein modifiers con-
taining a characteristic ubiquitin fold in the tertiary structure.
35
The post-
translational covalent attachment of one or several ubiquitin molecules to
a targeted protein is known as ubiquitination (also known as ubiquitylation
or ubiquitinylation). It is a highly regulated process in which the carboxyl
group of the C-terminal glycine within a di-glycine motif of the activated
ubiquitin forms an amide bond with the
e
-amino group of a lysine residue in
the modified protein.
33
This process is carried out by the action of three
distinct enzymes: an ubiquitin-activating enzyme (E1), an ubiquitin-
conjugating enzyme (E2), and an ubiquitin-ligating enzyme (E3). E1 carries
out the ATP-dependent activation of the carboxyl-terminal glycine residue
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