The Role of Arrestins in Visual and Disease Processes of the Eye - Progress in Molecular Biology and Translational Science - page 246

no animal model in which the binding of arrestin1 to microtubules is spe-
cifically disrupted currently exists that permits direct testing of these func-
tions. It is worth noting, however, that there is no reason to consider
these potential functions as mutually exclusive.

6.2. Kinases
Scaffolding interactions for arrestin1 and arrestin4 with kinases in the
mitogen-activated protein kinase (MAPK) pathway have been demonstrated
similar to those previously demonstrated for arrestin2 and arrestin3. 84-87
Using a fluorescence relocalization assay and coimmunoprecipitation, Song
et al. have convincingly demonstrated that both arrestin1 and arrestin4 bind
all three kinases in the c-Jun N-terminal kinase stress response arm of the
MAPK cascade—apoptosis signal-regulating kinase 1, MAPK4, and c-Jun
N-terminal kinase 3(JNK3). 82,88 Interestingly, although the kinases are bound
in a complex, they do not lead to the activation of JNK3, in contrast to
arrestin3 which both binds and activates JNK3. 82
Arrestin1 also binds extracellular signal-related kinases 1 and 2 (ERK1/2)
of the classical arm of the MAPK pathway. In this case, interaction with
arrestin1 leads to the sequestration of ERK1/2 to microtubules and, unlike
the association with JNK3, appears to functionally reduce the catalytic activ-
ity of the kinases. 67 This association with ERK1/2 appears to be specific for
arrestin1, as ERK1/2 does not bind to arrestin4. Although these associations
between the visual arrestins and the MAP kinases have been clearly demon-
strated in cell culture in COS-7 and HEK-293 cells, there is currently no
indication if scaffolding of these kinases by arrestin1 and 4 has a role in
rod and cone photoreceptors.

6.3. Ubiquitin ligases
In addition to the interaction with above-described kinases, arrestin1 and 4
also have the potential to associate with the ubiquitin ligases parkin and
murine double minute 2 (Mdm2). 67,83,88,89 In the case of parkin, an E3
ubiquitin ligase classically implicated in familial recessive Parkinson's disease,
both arrestin1 and arrestin4 can be coimmunoprecipitated with parkin. 83
Importantly, using purified arrestin1 and parkin proteins, a direct interaction
between these proteins was demonstrated, indicating that no additional
elements are required to facilitate the association between the visual arrestins
and this ubiquitin ligase. 83

Although arrestin2 and arrestin3 are