Biology Reference
In-Depth Information
recent Drosophila studies demonstrate that static structures (such as bristles),
as well as the actin protrusions of motile cells, are constructed using the
WASp family and Arp2/3 complex (Hudson and Cooley, 2002; Miller, 2002;
Zallen et al., 2002).
However, the WASp family proteins are not the only regulators of Arp2/3
complex activity. Members of a related group, the Ena/VASP family, have
also been shown to promote actin assembly in mammalian cells (Laurent et
al., 1999). Similarly, cortactin (in mammalian cells) and Abp1p (in
Saccharomyces) have been shown to be capable of activating the Arp2/3
complex and stabilize newly synthesized actin filaments (Olazabal and
Machesky, 2001). Studies on yeast have also shown that the cortactin-like
filament binding protein Abp1p, which contains acidic domains similar to
those of the WASp family, may function by recruiting Arp2/3 to the sides of
actin filaments (Goode et al., 2001).
Regulation of WASp and Scar
WASp contains a GBD (GTPase Binding Domain), also known as a CRIB
(Cdc42 and Rac Interactive Binding) domain, through which it binds Cdc42.
This interaction is thought to couple extracellular signals to activation of the
Arp2/3 complex and stimulation of actin polymerization (Ma et al., 1998).
WASp appears to be regulated in part by auto-inhibition; isolated, native
WASp is inactive until stimulated (Higgs and Pollard, 2000). It has been found
that the N-terminal domain (including the GBD domain) binds the C-terminal
domain (the WA domain which binds Arp2/3 and actin) thereby inhibiting its
function. Cdc42 binding to the GBD domain relieves this inhibition,
presumably by causing a conformational change, thereby activating WASp
and, subsequently, the Arp2/3 complex (Higgs and Pollard, 2000; Rohatgi et
al., 2000). PIP
2
appears to fulfil a similar activating role, leading to suggestions
that WASp plays a part in integrating lipid and GTPases signals, though it is
not clear how far changes in PIP
2
levels can explain alterations in the actin
cytoskeleton.
The control of Scar has been harder to dissect, in particular because of the
lack of obvious signal-related domains. Scar1 has been found to be recruited
to the tips of protruding lamellipodia, but not of filopodia, in living
mammalian cells (Hahne et al., 2001), suggesting that Scar is somehow
coupled to Rac. However, direct binding to Rac has not been found (Miki et
al., 1998). It therefore seems likely that the activity of Scar proteins is
controlled through binding to other proteins.
Unlike N-WASp, Scar is not autoinhibited, and pure protein is thought to
be constitutively active. It therefore appears that other binding proteins act to
inhibit Scar activity in vivo. Recent work has identified a complex of proteins
