7.15 Extracellular Signaling and Regulation of Actin
Polymerization
As mentioned previously, actin polymerization is regulated by small GTPases: there
are three types of Rho family proteins (RhoA, Rac 1 and cdc42). RhoA is involved in
the formation of stress fibers, Rac1 is involved in the formation of actin network in
lamellipodium, and cdc42 is involved in the formation of bundle in filopodium
[140]. The function of small GTPase is regulated by the extracellular signals such as
thrombin or various growth factors. These molecules bind to transmembrane receptors, and those receptors activate a heterotrimeric G protein (a complex of alpha-,
beta- and gamma-subunits). As a result of the activation, the alpha-subunit dissociate
from the beta-gamma subunits. The former and the latter subunits are respectively
involved in the activation of small GTPases [140–143]. In the absence of the
extracellular signals, the small GTPase binds GDP and remains inert (OFF state);
the OFF state is stabilized by a protein called GDI that inhibits the dissociation of
the bound GDP. In the activation, the bound GDP is exchanged with GTP by a
protein called guanine nucleotide exchange factor (GEF). GEF is activated by the
alpha- or beta-gamma-subunit of the heterotrimeric G protein and facilitates the
dissociation of GDP from the small GTPase. The small GTPase thus is brought to the
GTP-bound (ON) state (Fig. 7.23). The small GTPase binds to adaptor proteins that
transmit the signal so that the process of nucleation of actin polymerization is
activated. The activation of a small GTPase is thus under a multiple regulation.
This is natural because as mentioned above, in the cell, without regulation actin
would polymerize at any location.
The transduction of the signal from small GTPases to the localized actin polymerization depends on another group of proteins that promote the nucleation of actin
polymerization and are localized to the cell membrane. To take a lamellipodium as
an example, the factor that promotes the nucleation of actin is Arp2/3 protein
complex that allows the branched growth of the actin filament from the barbed end
[144]. A nucleator, arp2/3 is bound to and activated by WASP (Wiskott-Aldrich
syndrome protein) family proteins (WASP, N-WASP and WAVE; [145]). These
proteins are localized to the cell membrane and targets of the activated small
GTPases; in the case of lamellipodium, the small GTPase is Rac, which has a
hydrocarbon chain attached by the posttranslational modification, and hence, is
localized to the cell membrane. Rac interacts with WAVE and activates the nucleating activity of arp2/3. Likewise, Cdc42 and arp2/3 interact with N-WASP in the
formation of filopodium. Hence, the extracellular signal is translated into actin
dynamics through the activation of the actin-nucleating proteins.
7.15 Extracellular Signaling and Regulation of Actin Polymerization
131
Polymerization
As mentioned previously, actin polymerization is regulated by small GTPases: there
are three types of Rho family proteins (RhoA, Rac 1 and cdc42). RhoA is involved in
the formation of stress fibers, Rac1 is involved in the formation of actin network in
lamellipodium, and cdc42 is involved in the formation of bundle in filopodium
[140]. The function of small GTPase is regulated by the extracellular signals such as
thrombin or various growth factors. These molecules bind to transmembrane receptors, and those receptors activate a heterotrimeric G protein (a complex of alpha-,
beta- and gamma-subunits). As a result of the activation, the alpha-subunit dissociate
from the beta-gamma subunits. The former and the latter subunits are respectively
involved in the activation of small GTPases [140–143]. In the absence of the
extracellular signals, the small GTPase binds GDP and remains inert (OFF state);
the OFF state is stabilized by a protein called GDI that inhibits the dissociation of
the bound GDP. In the activation, the bound GDP is exchanged with GTP by a
protein called guanine nucleotide exchange factor (GEF). GEF is activated by the
alpha- or beta-gamma-subunit of the heterotrimeric G protein and facilitates the
dissociation of GDP from the small GTPase. The small GTPase thus is brought to the
GTP-bound (ON) state (Fig. 7.23). The small GTPase binds to adaptor proteins that
transmit the signal so that the process of nucleation of actin polymerization is
activated. The activation of a small GTPase is thus under a multiple regulation.
This is natural because as mentioned above, in the cell, without regulation actin
would polymerize at any location.
The transduction of the signal from small GTPases to the localized actin polymerization depends on another group of proteins that promote the nucleation of actin
polymerization and are localized to the cell membrane. To take a lamellipodium as
an example, the factor that promotes the nucleation of actin is Arp2/3 protein
complex that allows the branched growth of the actin filament from the barbed end
[144]. A nucleator, arp2/3 is bound to and activated by WASP (Wiskott-Aldrich
syndrome protein) family proteins (WASP, N-WASP and WAVE; [145]). These
proteins are localized to the cell membrane and targets of the activated small
GTPases; in the case of lamellipodium, the small GTPase is Rac, which has a
hydrocarbon chain attached by the posttranslational modification, and hence, is
localized to the cell membrane. Rac interacts with WAVE and activates the nucleating activity of arp2/3. Likewise, Cdc42 and arp2/3 interact with N-WASP in the
formation of filopodium. Hence, the extracellular signal is translated into actin
dynamics through the activation of the actin-nucleating proteins.
7.15 Extracellular Signaling and Regulation of Actin Polymerization
131