Biology Reference
In-Depth Information
The mammalian WASp/Scar family currently consists of five members.
WASp is apparently only expressed in haematopoietic cell lines, while N-
WASp is a more widely expressed relative of WASp, and three Scar isoforms
(which have also been named WAVEs). All family members contain a proline-
rich domain, a WH2 (WASp homology 2) actin monomer binding domain
and a conserved acidic domain, which lies carboxy-terminal to the WH2
domain. It is this acidic domain which binds to the Arp2/3 complex
(Machesky and Insall, 1998). The C-terminal WH2 and acidic domains are
referred to together as the WA domain. At the amino terminus, WASp
contains a WH1 (WASp homology 1) domain, while Scar contains a Scar
homology 1 domain, which is not homologous to WASp, but is conserved
within the Scar family (Bear et al., 1998). The binding interaction of this Scar
homology domain remains unknown.
WASp was first identified as the product of the gene mutated in Wiskott-
Aldrich syndrome (WAS), an X-linked disease which affects platelets and
lymphocytes (Derry et al., 1994). It was subsequently found that WASp
interacts with Cdc42, providing a link between this GTPase and the
cytoskeleton (Kirchhausen and Rosen, 1996; Symons et al., 1996). Phospha-
tidylinositol 4,5-bisphosphate (PIP
2
) has also been found to be important in
normal WASp function; PIP
2
and Cdc42 are capable of synergistically
activating N-WASp (Rohatgi et al., 2000). It is thought that PIP
2
can reduce
the a
nity between the N- and C-termini of N-WASp, thereby relieving an
autoinhibitory interaction, and that it can also indirectly activate Cdc42
(Rohatgi et al., 2000). Additionally, a recent study has demonstrated a Cdc42-
independent pathway of N-WASp activation, which involves the synergistic
action of PIP2 and the adaptor protein Nck (binding through its SH3 domains
to the N-WASp polyproline domain), leading to Arp2/3 dependent actin
polymerization (Rohatgi et al., 2001). In agreement with this work, it had been
previously shown that Nck coordinates the assembly of an actin nucleation
complex at the surface of vaccinia virus by binding to a tyrosine-
phosphorylated viral protein through its SH2 domain, and recruiting N-
WASp through its SH3 domain (Frischknecht et al., 1999).
Scar, also known as WAVE (WASp/verprolin homologous protein) in
mammalian cells (Miki et al., 1998), has three isoforms in humans (Suetsugu
et al., 1999). Recombinant Scar1 has been found to interact with cAMP-
dependent protein kinase (PKA) and Abl kinases when expressed in HEK-293
cells, and endogenous Scar has been found to co-purify with these proteins in
brain extracts (Westphal et al., 2000). This study therefore proposes that Scar1
can be classified as an A-kinase anchoring protein (AKAP), that can tether
PKA to defined subcellular sites, and puts forward the idea of Scar1 as an
actin-associated scaffolding protein that recruits PKA and Abl.
The WASp family and Arp2/3 complex members are conserved in all
eukaryotes, and are clearly essential to normal cell function. Furthermore,
