Biology Reference
In-Depth Information
However, cofilin in particular is capable of generating new barbed ends
quickly and independently of Ca
2+
leading to actin polymerization proximal
to the receptor. Actin polymerization is required for proper signalling by the
EGF receptor presumably because only the F-actin-associated receptor
assembles a signalling complex that amplifies and moderates the signalling
(Rijken et al., 1998). Localized receptor activation would lead to the
recruitment and activation of Class I (p85/p110) PI3Ks, through the SH2-
domain-mediated binding of p85/p110 to ErbB1/ErbB3 heterodimers or to
receptor substrates such as Gab1/2 (Kim et al., 1994; Kong et al., 2000;
Rodrigues et al., 2000; Soltoff et al., 1994). Alternatively, p85 binds to adapter
proteins such as Grb2 (Wang et al., 1995), which are recruited to autopho-
sphorylated EGF receptors (Lowenstein et al., 1997). EGF-stimulated
activation of Ras could also increase PI3K activity at the site of the
receptor-associated signalling complex (Rodriguez-Viciana et al., 1994). The
initial activation of PI3K by tyrosine-phosphorylated receptors/substrates
could lead to the activation of the Rhofamily GTPases Rac and Cdc42, via
PIP
3
-regulated guanine nucleotide exchange factors (Han et al., 1998; Olson et
al., 1996). Activation of Rac or Ccd42 could in turn feed back onto Class IA
PI3Ks via binding to the BCR-homology domain of p85, which activates p85/
p110 PI3Ks (Zheng et al., 1994; Beeton et al., 1999). Therefore, cofilin-induced
actin polymerization could cause an initial asymmetry compartment near the
high-a
nity receptor that would mark the membrane as a site for subsequent
recruitment and activation of PI3K and Rhofamily GTPases. Consistent with
this proposal is the identification of an F-actin-dependent positive feedback
loop for PIP
3
production involving PI3K and Rhofamily GTPases in
neutrophils (Orion et al., 2002).
Do the early and late actin polymerization transients result
from different mechanisms?
All actin polymerization in vivo is dependent on free barbed ends (Wear et al.,
2000). Therefore, to understand the regulation of actin polymerization during
cell motility and chemotaxis, one must understand the molecular mechanisms
responsible for the appearance of free barbed ends after the stimulation. It is
generally agreed that free barbed ends can arise in vivo by de novo nucleation
of filaments from the Arp2/3 complex (see Chapters by Pollard and
Machesky), uncapping of the barbed end by the loss of a capping protein
from the barbed end, and severing of non-covalent bonds between monomers
in F-actin to produce short filaments with free barbed ends. Which
combination of these mechanisms is at work during chemotaxis in the
