Biology Reference
In-Depth Information
which are bound to unstimulated Scar, forming an inactive complex (Eden et
al., 2002). These proteins have been identified as NCKAP1, PIR121, Abi2 and
HSPC300, which encodes a 9 kDa protein of unknown function.
Nck Associated protein 1 (NCKAP1) was first identified as Nap125 in a
screen for Nck binding proteins (Kitamura et al., 1996) and has an
association with Alzheimer's disease, where its expression was found to be
down-regulated (Suzuki et al., 2000; Yamamoto et al., 2001). NCKAP1 was
found to bind Rac indirectly through a 140 kDa protein (Kitamura et al.,
1997), which is now presumed to be PIR121. Abl interactor 2 (Abi2) is an
SH3 domain containing protein which interacts with the c-Abl tyrosine kinase
and is implicated in cytoskeletal function, cell migration and transformation
(Dai et al., 2001; Dai and Pendergast, 1995). This protein has also been shown
to localize to sites of actin polymerization (Stradal et al., 2001). Abi2 may be
an important link between Scar and Abl, which were found to co-precipitate
together (Westphal et al., 2000). It is also homologous to hNap1bp, a protein
previously identified as a binding partner of NCKAP1 (Yamamoto et al.,
2001).
PIR121 (p53-inducible messenger RNA) (Saller et al., 1999) is thought to
bind directly to both Scar and Rac. It may therefore be the missing link in the
signalling process involved in membrane ru
ing and lamellipodia formation.
Eden et al. (2002) and Kitamura et al. (1996, 1997) suggest that Rac1 and Nck
can cause dissociation of the Scar complex by binding to PIR121, and by
doing so causing the release of active Scar and HSPC300. These proteins,
which remain bound to one another, could in turn nucleate via the Arp2/3
complex. Although there is as yet no biological evidence for this model, it does
fit well with the various confusing strands of data, so it remains our preferred
working hypothesis. Various pieces of evidence are in agreement with the idea
of an inhibitory Scar complex. For example, NCKAP1 and PIR121 have been
identified as proteins that bind to Nck and activated Rac (Kitamura et al.,
1996, 1997; Kobayashi et al., 1998), whereas Scar and HSPC300 do not bind
these proteins.
The proteins thought to be present in a complex with Scar in mammalian
cells are also found in Dictyostelium discoideum. Recent work by our group
has demonstrated that disruption of the PIR121 gene leads to severe defects in
shape, motility and chemotaxis of this amoeba.
Recently, an unrelated study in C. elegans has also suggested the association
of PIR121 and NCKAP1 (in this case named GEX-2 and GEX-3 respectively)
and their role in development (Soto et al., 2002). This study finds that GEX-2
and GEX-3 are essential for proper tissue morphogenesis, as these two
proteins together regulate cell migration and shape change. This provides
more evidence from an entirely different perspective that NCKAP1 and
PIR121 act together to regulate actin polymerization, and consequently cell
movement, in vivo.
