Biology Reference
In-Depth Information
found that
b
-arrestins interact with other components of the clathrin-coated
pit machinery including AP2
37
and ARF6.
38
More recently, this endocytic
adaptor function has been extended to non-GPCRs such as the tyrosine
kinase IGF1 receptor.
39
The involvement of
b
-arrestins in receptor trafficking is now known to
be complex and multifaceted.
b
-Arrestins appear to be involved in receptor
recycling as well as trafficking to other cellular compartments.
40
The ability
of
b
-arrestins to serve as adaptors linking the receptor to several cellular
motors is also undoubtedly involved in these processes.
41
7. ARRESTINS AND SIGNALING
Having been discovered and named in the context of their roles in
desensitization, the idea that the arrestins might actually serve as signal trans-
ducers in their own right was not initially considered. However, it was
observed that in some systems GPCR activation of ERK appeared to require
receptor endocytosis.
42
Since the idea that
b
-arrestins were involved in
clathrin-mediated 7TMR endocytosis was gaining credence at this time (late
1990s), it was hypothesized that perhaps
b
-arrestins were involved at some
stage of the assembly of multiprotein signaling complexes such as the MAP
kinase cascade.
43
In fact, the first signaling pathway to be demonstrated to be
activated in a
b
-arrestin-dependent fashion was c-Src downstream of the
b
2AR.
44
b
-Arrestin1 was shown to function as an adaptor protein recruiting
c-Src to the activated receptor and facilitating activation of downstream
ERK 1 and 2. Subsequently, over the next few years,
b
-arrestin was shown
to scaffold MAP kinase complexes of the ERK cassette,
45,46
p38,
47
and Jnk 2
and 3.
48
These signaling pathways appear to function in parallel with those
mediated by G proteins but lead to activation of distinct pools of the
enzymes. For example, activation of ERK1/2 downstream of G proteins
generally leads to its translocation into the nucleus and phosphorylation
and activation of various transcription factors. In contrast, activation of
ERK1 and 2 by scaffolding by
b
-arrestin2 leads to retention of the activated
ERK in the cytosol due to the fact that
b
-arrestin2 contains a nuclear exclu-
sion signal, and hence, a completely different set of substrates, in this case
cytosolic, are phosphorylated, with quite different cellular consequences.
49
Moreover, the kinetics of G protein versus
b
-arrestin-mediated ERK acti-
vation are often distinct with G protein signaling being rapid in onset and
quite transient (due to
b
-arrestin-mediated desensitization).
49
In contrast,
b
-arrestin-mediated ERK activation is slower in onset and more persistent.
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