Actin Isoforms in Neuronal Development and Function - International Review of Cell and Molecular Biology - page 164

(UTR) of β-actin mRNA called the zipcode sequence ( Kislauskis et al., 1994 ).
No other actin isoform has an analogous sequence in the 3′ UTR nor has
any other actin isoform mRNA been found to be actively localized to the
leading edge of a cell. At least two proteins have been shown to directly
bind the zipcode sequence within the β-actin 3′ UTR, one of which, zip-
code binding protein 1 (ZBP1), has been extensively characterized ( Gu
et al., 2002 ; Ross et al., 1997 ). ZBP1 is one member of a family of RNA-
binding proteins expressed in a broad range of species ( Nielsen et al., 2001 ;
Yisraeli, 2005 ). ZBP1 was first cloned from chick fibroblasts and is most
closely related to IMP1 in humans and mIMP or CRD-BP in mice. Less
is known regarding the function of ZBP2/IMP2, while the third family
member ZBP3/IMP3 is most closely related to the Xenopus homolog Vg1
RBP. Because the majority of work in neurons has used the ZBP nomen-
clature, we will use this throughout the chapter but note that ZBP family
members are homologous to the mammalian IMP family.
Additional work in fibroblasts established a model whereby β-actin
mRNA is bound cotranscriptionally by ZBP1, which facilitates the trans-
port of β-actin mRNA from the nucleus to the leading edge of the cell
while also inhibiting its translation to prevent ectopic synthesis ( Huttel-
maier et al., 2005 ; Oleynikov and Singer, 2003 ). Src kinase can phosphory-
late Y396 on ZBP1, which reduces the affinity of ZBP1 for the β-actin
mRNA zipcode sequence, thus freeing the mRNA for local translation
( Huttelmaier et al., 2005 ). Treatment of fibroblasts with antisense
oligonucleotides to the zipcode sequence disrupts the localization of β-actin
mRNA and protein, and leads to delocalized sites of actin polymerization
and reduced directional motility ( Kislauskis et al., 1997 ; Shestakova et al.,
2001 ). Thus, the localization and local translation of β-actin mRNA may
provide one mechanism by which cells can regulate localized actin dynam-
ics and promote directional cell migration. It is critical to note, however,
that β-actin is not the only mRNA target of ZBPs. In fact, in HeLa cells,
roughly 3% of the transcriptome was found within ZBP1/IMP1 ribonu-
cleoprotein granules, including a number of RNAs with specific relevance
to actin regulation in neurons including cofilin1, profilin 1, paxilin, rhoA
and zyxin ( Jonson et al., 2007 ). Thus, functions of ZBPs cannot exclusively
be attributed to localization of β-actin without additional direct evidence.
Given the large excess of actin in most cells ( Pollard et al., 2000 ), it
is worth asking why cells would need to locally synthesize more actin in
the first place. The simplest explanation is that locally synthesizing actin
may be a mechanism to increase the G-actin concentration specifically in