Biomedical Engineering Reference
In-Depth Information
10.10 Summary
Throughout this review we have attempted to highlight both the currently under-
stood key functions of different members of the ARF family as well as the fact that
most, likely all, function at more than one location in cells and in different signaling
pathways. This paradox, that location is so important and at the same time one ARL
acts at multiple locations, is a central aspect of regulatory GTPases that we believe
provides the cells with vital cross talk between signaling pathways but also offers
challenges in our dissection of specificity in signal output. We summarize the
locations of ARF family members in Fig.
10.1
. But note that some of these location
assignments are based on functional consequences of (over)expression of mutant
and/or epitope-tagged proteins. The dangers of tagging ARFs have been well
documented (Jian et al.
2010
) and certainly extend to at least some (and we should
assume all) ARLs. The need for better, specific antibodies that allow localization of
endogenous proteins in several different cell and tissue types, and in response to
different conditions or stressors, is obvious and should be a goal of the community
of researchers working with ARLs. As highlighted in Fig.
10.1
there are multiple
members of the ARF family in just about every organelle shown and we have very
incomplete information regarding their regulators or extent of functional overlap.
This remains one of the key challenges in developing better, more complete,
models of ARF family mechanisms.
Not shown in Fig.
10.1
is the fact that each of the members of the ARF family is
also found in the cytosol. In fact, in most cases it is likely the majority of the
GTPase that resides there and only transiently binds to membranes or proteins
there. We mentioned in our introduction the key role of translocation onto a
membrane that is thought to be coincident with activation of ARFs and ARL1.
This is less of a hallmark of most ARLs, some of which contain nuclear localization
signals (ARL4s) or are inside organelles (e.g., ARL2 in mitochondria and the
nucleus; ARL13B in cilia). ARL2 is currently the most promiscuous member of
the family as far as localization, with most in the cytosol bound to cofactor D, but
also pools specifically localizing to mitochondria, the nucleus, centrosomes, and
cilia. The extent to which these different pools of a single GTPase interact or, stated
differently, the effect of increasing one of those pools at the expense of another
creates opportunities for higher order signaling but we suspect also is contributing
to some misinterpretation of data (our own and that of others) resulting from protein
overexpression. We believe this idea of higher order signaling in the ARF family is
an important one and is based in part on the following logic, using ARL2 as the
example. (1) Expansion in each of the families of GTPases in the RAS superfamily
has been commonplace. (2) Yet there is only one ARL2 found in eukaryotes that
has been preserved during the same evolutionary distance that ARFs have expanded
from one to six in mammals. (3) ARL2 is present in and performs important/
essential functions in multiple cellular locations. (4) We conclude that by
maintaining these functions linked to a single GTPase there is consequent cross
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